pathmegaset

What stimulates the secretion of TNF and IL-1?

-endotoxin & other microbial products -immune complexes -physical injury

What is the sufix associated with inflamed tissue?

-itis ex: myocarditis is inflamation of the heart muscle

List the 3 hemodynamic changes seen in acute inflammation

1. transient vasoconstriction 2. progressive vasodilation 3. increased vascular permeability

What are the four aspects of disease process?

1.etiology: cause 2. pathogenesis: mechanisms of its development 3. molecular and morphologic changes: biochemical and structural altercations 4. clinical manifestations: functional consequences of these changes

How are transudate and exudate formed?

A transudate is formed when fluid leaks out because of increased hydrostatic pressure or decreased osmotic pressure. An exudate is formed in inflammation because vascular permeability increases as a result of the increase in interendothelial spaces.

Be able to identify morphologic changes in reversible cell injury and necrosis histologically

A, Normal kidney tubules with viable epithelial cells. B, Early (reversible) ischemic injury showing surface blebs, increased eosinophilia of cytoplasm, and swelling of occasional cells. C, Necrosis (irreversible injury) of epithelial cells, with loss of nuclei, fragmentation of cells, and leakage of contents.

Be familiar with the morphologic features of apoptosis

A: reduced size, highly eosinophilic, condensed nucleus B:nuclei with condensed chromatin C: blebbing and apoptotic bodies, staining for activation of caspase 3

What is the most common cause of suppurative inflammation?

Bacteria (staph) that are pyogenic Example: acute appendicitis

What are the pro-apoptotic proteins and what is their function?

Bax and Bak form channels in the mitochondrial membrane leading to leakage of cytochrome C

What type of inflammation will display cells from the blood and which will display cells from bone marrow origin?

Blood: acute Bone marrow: chronic (monocytes/macrophages)

A 3-year-old child has been diagnosed with ornithine transcarbamylase deficiency and has developed hepatic failure. The left lobe of an adult donor liver is used as an orthotopic transplant. A year later, the size of each liver in donor and recipient is greater than at the time of transplantation. Which of the following cellular alterations is most likely to explain this phenomenon? OA. Metaplasia OB. Dysplasia OC. Hyperplasia OD. Anaplasia OE. Neoplasia

C

A 5-year-old boy is brought to the hospital in respiratory distress. X-rays showed bilateral infiltrates. Despite antibiotic therapy he dies. The photomicrograph of lung is from his autopsy mimic the accompanying image. Which of the following is the most likely cause of pulmonary lesion? a.Acute bacterial pneumonia b.TB c.Viral pneumonia d.Aspiration pneumonia

C

Draw the marophage-lymphocyte interactions in chronic inflammation

Activated T cells produce cytokines that recruit macrophages (TNF, IL-17, chemokines) & others that activate macrophages (IFN-gamma). Activated macrophages in turn stimulate T cells by presenting antigens and via cytokines (such as IL-12). post-bacc

How does hageman factor affect kinins?

Active form of factor XII (factor XIIa) Converts plasma prekallikrein into an active proteolytic form (kallikrein) Cleaves a plasma glycoprotein precursor high-molecular-weight kininogen, to produce bradykinin

Which type of inflammation is more likely to be reversible?

Acute chronic not as likely due to fibrosis and other irreversible changes that can occur

In which type of inflammation will edema be seen, and what causes this?

Acute inflammation When neutrophils leave blodo they bring along fluid (exudate) that will accumulate leading to edema

Describe what will occur during leukocyte migration through endothelium body

After traversing the endothelium leukocytes pierce the basement membrane Enter the extravascular tissue Cells then migrate toward the chemotactic gradient Cells accumulate in the extravascular site

What is hyaline change?

Alteration within the cells or in the extracellular space in which proteins accumulate leads to a glassy pink homogeneous appearance

When might immunologic reactions lead to cellular injury?

Autoimmune: reactions to endogenous self-antigens Can also occur in response to external agents such as microbes and environmental substances

A 43-year-old male has complained of mild burning substernal pain following meals for the past 3 years. Upper GI endoscopy is performed and biopsies are taken of an erythematous area of the lower esophageal mucosa 3 cm above the gastroesophageal junction. There is no mass lesion, no ulceration, and no hemorrhage noted. The biopsies show the presence of columnar epithelium with goblet cells. Which of the following mucosal alterations is most likely represented by these findings? OA. Dysplasia OB. Metaplasia OC. Hypertrophy OD. Hyperplasia OE. Ischemia

B

What are the four classifications of chemokines?

C-X-C chemokines (α chemokines) C-C chemokines (β chemokines) C chemokines (γ chemokines) CX3C chemokines

What are the three best know acute-phase proteins associated with systemic inflammation?

C-reactive protein (CRP) Fibrinogen Serum amyloid A (SAA) protein

Chart the parts of complement discussed

C3 made by all of the different pathways C3a: involved in chemotaxis and phagocytosis (inflammation) C3b: involved in phagocytosis and formation of MAC

What complement protein will act as an opsonin?

C3b

Give examples of conversion to toxic metabolites

CCl4 converted by P-450 to CCl3 free radical that causes lipid peroxidation and damages cellular structures, acetaminophen converted to a toxic product during detoxification in the liver that can lead to cell damage

What are the two enzymes that produce prostaglandins?

COX 1: always expressed COX2: inuced when there is injury

What are the pharmacologic targets involving arachidonic acid?

Can target PLA2 using glucocorticoids or COX through NSAIDS this prevents the formation of leukotrienes and prostaglandins which are involved in inflammation

What is major basic protein?

Cationic protein of eosinophils Limited bactericidal activity Cytotoxic to many parasites

Chart the sequential development of biochemical and morphologic changes in cell injury

Cells may become rapidly nonfunctional after the onset of injury, although they are still viable, with potentially reversible damage; a longer duration of injury may eventually lead to irreversible injury and cell death. Note that irreversible biochemical alterations may cause cell death, and typically this precedes ultrastructural, light microscopic, and grossly visible morphologic changes.

What are the two characteristic features of reversible cell injury?

Cellular swelling and fatty change

List the plasma derived mediators

Complement cascade (C3a, C5a) Coagulation cascade (Fibrinopeptides) Fibrinolytic cascade (Fibrinolytic products) Kinin system *(Bradykinin)* Opsonins *(Ig, Fibronectin, C3b)* (think COCK F)

What is the chemokine for eosinophil recruitment?

Eotaxin

What type of inflammation is shown in the following picture?

Fibrinous inflammation: diptheria

What are the steps of the inflammatory response?

Five R's (1) Recognition of the injurious agent (2) Recruitment of leukocytes (3) Removal of the agent (4) Regulation (control) of the response (5) Resolution (repair)

What is an example of CX3C chemokine?

Fractalkine (can be soluble or cell surface bound)

What type of cells are suceptible to mercuric chloride poisoning?

GI and Kidney cells

Where will cyclooxygenase and lipoxygenases bind?

GPCR

What will PAF bind on target cell?

GPCR PAF receptors (PAFR)

What are the two divisions of pathology?

General and system

What are the generalized features of reversible cell injury?

Generalized swelling of the cell and its organelles Blebbing of the plasma membrane Detachment of ribosomes from the ER Clumping of nuclear chromatin

Label the main functions of inflammatory mediators

HIGH YIELDDD!!

What is the intrinsic clotting pathway activated by?

Hageman factor (factor 12)

What are the plasma derived factors that will affect vascular permeability, and what will be their effects?

Hageman factor activation and complement sysytem activation lead to edema from increased vascular permeability

What type of inflammation is shown in the following?

Hemorrhagic inflammation notice the loss of epithelium and heavy red cell infiltrate often seen in hemorrhagic cystitis in chemo/radiation

Identify eosinophils in the following image

Highly eosinophilic (pink) granules

What are the main cytokines involved in inflammation?

IL-1 and TNF

What are the pathologic changes associated with systemic inflammation?

Increased pulse and BP Decreased sweating Rigors (shivering) Chills Anorexia Somnolence: sleepiness

What are the physiologic effects of bradykinin?

Increases vascular permeability Causes contraction of smooth muscle Dilation of blood vessels

What effect will IL-1 and TNF have on the endothelium?

Induce the expression of endothelial adhesion molecules Synthesis of chemical mediators, i.e., other cytokines, chemokines, growth factors, eicosanoids & NO Production of enzymes associated with *matrix remodeling* Increases in the surface thrombogenicity of the endothelium

What is exudate?

Inflammatory extravascular fluid containing high protein concentration

What are the principal actions of lipoxins?

Inhibit leukocyte recruitment & the cellular components of inflammation Inhibit neutrophil chemotaxis & adhesion to endothelium

Draw the vascular response involved in acute inflammation

Initial response of the vessels will be to constrict for a few seconds, then will dilate Increased hydrostatic pressure causes fluid to leave blood and enter the interstitial space Endothelial cells retract in order to make a gap in the vessels to help fluid and inflammatory cells leave the blood vessel and enter the tissue 2 main changes: vasodilation, and structure changes of the endothelial cells to increase the gaps in the vessel

How is plasmin generated?

Kallikrein cleaves plasminogen Plasma protein that binds to the evolving fibrin clot to generate plasmin

What are the two types of granules seen on neutrophils and monocytes?

Larger azurophil (primary) granules and smaller specific (secondary) granules

How will loss of fluid and increased vessel diameter affect blood flow?

Leads to slower blood flow, increased concentration of red cells in small vessels, & increased viscosity of the blood (changes result in dilation of small vessels) packed with slowly moving red cells stasis

Be able to identify edema histologically

Left: alveoli of the lungs, normal Right: Pulmonary edema, fluid within the alveoli

Chart the timeline of edema and leukocyte infiltrate in inflamation

Left: neutrophil infiltrations in the heart Right: heart, neutrophils replaced by monocytes/macrophages

How do leukotrienes and lipoxins differ?

Leukotrienes are inflammatory molecules while lipoxins are anti-inflammatory (minimize damage and stop inflammation when needed)

What are the three main pathologic effects of free radicals?

Lipid peroxidation of membranes Oxidative modification of proteins Lesions in DNA

List the different types of tissue macrophages

Liver (Kupffer cells) Spleen Lymph nodes (sinus histiocytes) Lungs (alveolar macrophages) Central nervous system (microglia)

What are abscesses?

Localized collections of pus, suppuration buried in a tissue, organ, or a confined space produced by deep seeding of pyogenic bacteria into a tissue

What are the steps of extravasation?

Lumen margination rolling adhesion to endothelium Migration across endothelium & vessel wall Move in the tissues toward a chemotactic stimulus

What type of cell is shown and what type of inflammation are these cells seen in?

Lymphocytes: notice the single rounded nucleus with scant cytoplasm chronic inflammation

What is the function of MAC?

MAC lyses microbes by creating a hole in the cell membrane (becomes permeable to water and ions)

When will ROS be released?

May be released extracellularly from leukocytes, after exposure to microbes, chemokines & immune complexes

What are possible physical agents that can lead to cell injury?

Mechanical trauma Extremes in Temp Sudden changes in Atmospheric pressure Radiation Electric Shock

How will a fatty liver appear under gross examination?

Mild fatty change may not affect the gross appearance Progressive accumulation: Organ enlarges and becomes increasingly yellow Extreme instances--liver may weigh 2-4 times normal Bright yellow, soft, greasy

What is the major prostaglandin made by mast cells?

PGD2

What are the most important prostaglandins in inflammation?

PGD2, PGE2, PGF2α, PGI2 (prostacyclin) & TxA2 (thromboxane)

Which prostaglandin is involved in cytokine-induced fever during infections?

PGE2

Which prostaglandin will act as a hyperalgesic?

PGE2 (skin abnormally heightened sensitivity to pain)

What are the possible stimuli for release of histamine from mast cells?

Physical injury such as trauma, cold or heat Binding of antibodies to mast cells (allergic reactions) Fragments of complement called anaphylatoxins -C3a & C5a Histamine-releasing proteins derived from leukocytes Neuropeptides (substance P) Cytokines (IL-1, IL-8)

What type of cell is seen and what type of inflammation will these cells be found in?

Plasma cells: notice the dark staining nuclei WITH cytoplasm (also darker staining) produce antibodies!! found in chronic inflammation

What type of cells can elaborate PAF?

Platelets, basophils, mast cells, neutrophils, macrophages & endothelial cells

List cells that can produce mediators

Platelets, neutrophils, monocytes/macrophages & mast cells Mesenchymal cells (endothelium, smooth muscle, fibroblasts) Most epithelia

What are the physiologic effects of Leukotriene B4?

Potent chemotactic agent & activator of neutrophils Causes aggregation & adhesion of the cells to venular endothelium (aid in diapedesis) Generation of ROS (aids in phagoctosis) Releases lysosomal enzymes

What occurs during autophagy?

Process in which cell eats it's own contents Cellular stresses, such as nutrient deprivation, activate autophagy genes that create vacuoles in which cellular organelles are taken up and then degraded following fusion of the vesicles with lysosomes. The digested materials are recycled to provide nutrients for the cell.

Draw the outcomes of acute inflammation, note the highlighted events

Pus formation=suppurative inflammation want to limit the extent of the injury

What are the ways in which mediators are eliminated after activation?

Quickly decay: Arachidonic acid metabolites Inactivated by enzymes:*Kininase inactivates bradykinin* Scavenged or inhibited: Antioxidants scavenge toxic oxygen metabolites Inhibited: Complement regulatory proteins break up & degrade activated complement components

What are the three sequential steps of phagocytosis?

Recognition & attachment of the particle to be ingested by the leukocyte Engulfment with subsequent formation of a phagocytic vacuole Killing or degradation of the ingested material (reactive oxygen species)

WHat is the role of leukocytes in inflammation?

Recruitment from the blood into extravascular tissues Recognition of microbes & necrotic tissues Removal of the offending agent

How will NO affect cells involved in inflammation?

Reduces platelet aggregation & adhesion (opposite of prostacylcin) Inhibits several features of mast cell-induced inflammation Inhibits leukocyte recruitment

What type of reaction will lead to free radicals?

Reduction-oxidation reactions that occur normally in metabolic processes

What is the dual action of NO in inflammation?

Relaxes vascular smooth muscle Promotes vasodilation Inhibitor of the cellular component of inflammatory responses

What are the cardinal signs of inflammation?

Rubor (redness) Tumor (swelling) Calor (heat) Dolor (pain) Functio laesa (loss of function), 5th clinical sign was added by Rudolf Virchow in the 19th century (think really tall carl doesnt eff when he's inflamed)

Who is considered the father of modern pathology?

Rudolf virchow

What are two antioxidant mechanisms in the mitochondria?

SOD and glutathione peroxidase

What are Neuropeptides secreted by and what role do they play?

Secreted by sensory nerves & various leukocytes Play a role in the initiation & propagation of inflammation

Identify the type of inflammation shown in the following image

Serous inflammation notice the separation of the epidermis from the dermis filled with serous fluid also not the inflammatory cell infiltrate (neutrophils)

What is the specific gravity of transudate?

Specific gravity <1.012

How are free radicals degraded?

Through enzymes, spontaneous decay, and antioxidants. (cellular defense systems)

In what ways can free radicals be made that are not normal to physologic processes?

UV light, xrays, and ionizing radiation (hydrolyzes water into OH and hydrogen free radicals), rapid birsts of ROS from activated leukocytes, and enzymatic metabolism of exogenous chemicals or drugs

What is shown in the following image?

Ulcer with surrounding hyperemia (congestion of blood vessels) caused by sloughing off the mucosal tissue

What is transcytosis induced by?

VEGF

What is transudate?

a fluid with LOW protein content (albumin)

What are possible causes of nongranulomatous chronic inflammation (just be familiar)?

a. chronic viral infections B. chronic autoimmune diseases C. chronic chemical intoxications D. chronic nonviral infections E. allergic inflammation

What is steatosis?

abnormal accumulations of triglycerides within parenchymal cells, seen in liver (major organ of fat metabolism), heart, muscle, and kidney

Describe what happens in an accumulation abnormality caused by a defect in protein folding

abnormal endogenous substance accumulates because of defects in protein folding and transport and an inability to degrade the abnormal protein efficiently Ex: accumulation of mutates a-1-antitrypsin in liver cells Mutated proteins in degenerative disorders of the CNS

What will occur during an accumulation abnormality due to ingestion of indigestible materials?

abnormal exogenous substance is deposited and accumulates because the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites ex: accumulations of carbon particles and nonmetabolizable chemicals (silica)

What causes endometrial hyperplasia and what can this lead to?

abnormal hormone-induced hyperplasia that is the most common cause of abnormal menstrual bleeding

What are the four types of abnormalities that can lead to intracellular accumulations?

abnormal metabolism, defect in protein folding transport, lack of enzyme, and ingestion of indigestible materials

What are the characteristic features of nongranulomatous inflammation?

accumulation of sensitized lymphocytes, plasma cells, & macrophages in the injured area these cells are scattered *diffusely throughout the tissue* scattered tissue necrosis & fibrosis are common

What is cholesterolosis?

accumulations of cholesterol-laden macrophages in the lamina propria of the gallbladder

What do plasma cells develop from?

activated B lymphocytes

What cells will produce TNF and IL-1?

activated macrophages

What type of cells will produce alpha chemokines?

activated macrophages and endothelial cells (IL-8)

What is an epithelioid granuloma?

activated macrophages that appear as large cells with abundant pale, foamy cytoplasm

What affect would increased cytosolic Ca2+ levels have?

activates a number of enzymes, has deletrious cellular effects, and phospholipases (membrane damage)

What is the production of ROS dependent on?

activation of NADPH oxidase system

What cells are involved in granulomatous inflammation?

activation of T lymphocytes leading to activation of macrophages (cause injury to normal tissues)

What does intrinsic pathway of apoptosis lead to?

activation of the initiator caspase-9

What type of inflammation are the cardinal signs most prominent in?

acute inflammation

List clinical examples of necroptosis

acute panncreatitis, reperfusion injury, neurodegenerative diseases (parkinsons), cell death in steatohepatitis, and during formation of the mammalian bone growth plate

What type of inflammation is shown?

acute, notice the neutrophils and congested blood vessels

What are the main cells involved in acute and chronic inflammation?

acute: neutrophils chronic: monocytes/macrophages and lymphocytes

What will occur in metaplasia?

adaptive substitution of cells in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type that is better able to withstand adverse environments think Barrets esophagus

How will leukocytes behave during acute inflammation?

adhere to endothelium and transverse into tissue then migrate to the site of injury where they will release toxic metabolies and proteases (leads to pain)

What type of metabolism is compromised in ischemic tissue?

aerobic metabolism compromised

What is reduced during hypoxia?

aerobic oxidative respiration

What does hemosiderin represent?

aggregates of ferritin micelles

In what type of patients will lipofuscin be seen in the liver and heart?

aging patients and patients with severe malnutrition and or cancer/cachexia

What are the common causes of fatty change in the liver?

alcohol abuse, nonalcoholic fatty liver disease associated with diabetes and obesity

List two examples of accumulation of cytoskeletal proteins

alcoholic hyaline: eosinophilic cytoplasmic inclusion in liver cells, composed predominantly of keratin intermediate filament neurofibrillary tangle-Alzheimer disease: neurofilaments and other proteins

What will happen to an ischemic cell when oxygen is restored?

all disturbances are reversible once O2 is returned

What classes of lipids can accumulate within cells?

all major classes, triglycerides, cholesterol/cholesterol esters, and phospholipids (components of myelin figures in necrotic cells)

What might excessive inflammation lead to?

allergies

What type of chemokine is IL-8?

alpha chemokine (C-X-C)

What is a specific inhibitor of elastase?

alpha-1 antitrypsin

What are the three major components/events of acute inflammation?

alteration in vascular caliber (vasodilation) Structural changes in microvasculature ( endothelial cells) Emigration of leukocytes

How does hepatotoxin from alcohol affect the liver?

alters mitochondrial and microsomal functions which leads to increased synthesis and reduced breakdown of lipids

What is an autophagolysosome?

an autophagic vacuole fused with a lysosome

What fragments of complement are involved in the release of histamine?

anaphylatoxins C3a and C5a

What are possible causes of decreased oxygen-carrying capacity of the blood?

anemia, CO poisoning, and severe blood loss

What is Bcl-2 and what is it's function?

anti-apoptotic protein maintains the integrity of mitochondrial membranes to prevent leakage of mitochondrial proteins

What is mutated in chronic granulomatous disease?

any one of the five components of the NADPH oxidase system

Which type of cell death does not initiate an inflammatory response in the host?

apoptosis

What type of cell death eliminates cells WITHOUT eliciting a host reaction?

apoptosis: no collateral tissue damage

What type of cell death will display cytoplasmic blebs on the surface?

apoptotic cells, will fragment into membrane-bound apoptotic bodies

How will glycogen accumulations appear histologically?

appear as clear vacuoles within the cytoplasm (think clumped tissue paper)

How will fatty chage appear histologically?

appears as clear vacuoles within parenchymal cells

What are eicosanoids?

arachidonic acid metabolites (prostaglandins, leukotrienes, lipoxins)

What is coagulative necrosis?

architecture of dead tissues that displays a firm texture

What do macrophages arise from?

arise from blood monocytes from the bone marrow

What type of infection is leukocytosis seen in?

bacterial infection: can lead to a left shift if more immature neutrophils are released from the bone marrow

What is cellular lifespan determined by?

balance between damage resulting from metabolic events within the cell and counteracting molecular responses that repair the damage

How will a heart that has undergone fatty change appear under histological examination?

bands of yellow myocardium alternating with bands of dark uninvolved myocardium (tigered effect)

What is the appearance of calcium salts?

basophilic, amorphous granular, clumped appearance Form *psammoma bodies* in benign and malignant conditions

Besides mast cells, where else is histamine found?

basophils and platelets

What types of cells are involved in allergies?

basophils/mast cells and eosinophils

What is anthracosis?

blackening of the lungs and lymph nodes due to accumulation of carbon

What plasma membrane alterations will be seen in a reversible injury?

blebbing, blunting, and loss of microvilli

What are the main cells of chronic inflammation and where do they generate?

blood monocytes and tissue macrophages originate from the bone marrow (reticuloendothelial system)

What is myositis ossificans and what causes this?

bone formation in muscle (connective tissue metaplasia) can occur followin and intramuscular hemorrhage (aka a person injures a muscle and bone shows up in XRAY)

What is the treatment for chediak higashi?

bone marrow transplant

What to both the intrinsic and extrinsic methods of apoptosis have in common?

both activate executioner caspases (3, 6, and 7)

What type of inflammatory reaction will mast cells participate in?

both acute and chronic reactions

What type of injury is ATP depletion associated with?

both hypoxic and chemical injury

How are macrophages activated?

by IFN-gamma, produced by Th1 cells also activated by endotoxin and other cytokines

How is the conversion to toxic metabolites accomplished?

by cytochrome P-450 mixed-function oxidases

How are the contents of autophagic vacuoles digested?

by lysosomal enzymes

How is benign prostatic hyperplasia induced?

by responses to androgens

How will fatty change due to reversible injury be manifested?

by the appearance of lipid vacuoles in the cytoplasm

How is the apoptotic pathway activated in irreversible cell injury?

by the release of pro-apoptotic molecules from leaky mitochondria

What are two properties of the caspase family of enzymes?

c refers to cystein protease, aspase refers to the unique ability of these enzymes to cleave after aspartic acid residues

Give two examples of exogenous pigments

carbon (coal dust) and tattooing

Identify the following image

carbon laden macrophages in the lung

What is shown in the following image?

caseating granuloma of mycobacterium tuberculosis: also referred to as tubercle subtype of epithelioid granuloma

What type of granuloma is shown in the following image?

caseating granuloma of tuberculosis notice the central caseous necrosis, giant cells, and blood vessel proliferation (in periphery)

What type of granuloma is shown in the following image?

caseating granuloma: tuberculosis, notice the langhans-type giant cells, necrosis foci and lymphocytes

What caspases are activated by the extrinsic pathway of apoptosis?

caspase 8 and 10

What antioxidant is found in peroxisomes?

catalase

What is the function of phospholipase A2 (PLA2)?

catalyzes the hyrolysis of the sn-2 position on membrane glycerophospholipids to liberate arachidonic acid

What is the downstream result of C3a and C5a?

cause the release of histamine from mast cells leading to increased vascular permeability and vasodilation

How does toxic chemicals form free radicals?

causes membrane damage and cell injury that will form free radicals and subsequent lipid peroxidation

WHat will be the effect of PGD2 with PGE2?

causes vasodilation and increases the permeability of post-capillary venules potentiating edema formation

Where will oxidative DNA damage be seen?

cell aging and malignant transformation

What is one of the most crucial events in the evolution of disease?

cell death (end result of progressive cell injury)

What are the two ways that mediators of inflammation can be derived?

cell derived or plasma derived

What will be the result of continuous damage to a cell?

cell injury will become irreversible, cell cannot recover and it dies

What is arachidonic acid derived from?

cell membrane phospholipids

How would a cell respond to irreversible damage to the mitochondrial and lysosomal membranes?

cell necrosis

Where are the two places that mediators can be derived from?

cell-derived or plasma-derived

What type of cells will display lipofuscin?

cells undergoing slow, regressive changes

What is common in infectious granulomas (gross and microscopic)

central caseous necrosis gross: yellowish-white and resembles crumbly cheese microscopic: finely granular, pink and amorphous

What is metaplasia?

change in the phenotype of cells

How are molecular and morphologic changes used in diagnosis?

characteristics of a disease that can be used it identify etiologic process

Describe the appearance of caseous necrosis

cheeselike, friable white appearance of the area of necrosis

What is the major limitation to drug therapy?

chemical (toxic) injury

What are free radicals?

chemical species that have a single unpaired electron in an outer orbit, energy is created by this unstable configuration

What is the function of PGD2?

chemoattractant for neutrophils (made by mast cells)

What is the main function of chemokines in inflammation?

chemoattractants: stimulate leukocyte recruitment in inflammation

What is the fucntion of fractalkine?

chemotactic for T cells and monocytes (CX3C chemokine)

What is the function of C5a?

chemotactic for neutrophils activates lipoxygenase pathway of AA metabolism

How are neutrophils drawn to site of infection in acute inflammation?

chemotaxis

How does the body recruit neutrophils?

chemotaxis

What is the main function of alpha chemokines?

chemotaxis of neutrophils (IL-8)

What type of lipid is used in most cells for synthesis of cell membranes?

cholesterol

What is the most characteristic feature of apoptosis?

chromatin condensation, aggregates peripherally into dense masses, nucleus may break up

What type of inflammation is tissue damage characteristic of?

chronic

What type of inflammation will display angiogenesis?

chronic inflammation

What type of inflammation will have mononuclear cells, tissue destruction, and fibrosis?

chronic inflammation

What type of inflammation is shown here?

chronic inflammation note the presence of chronic inflammatory cells ( star) and the deposition of ECM (fibrosis) Also, the normal alveoli are replaced by spaces lined by cuboidal epithelium

What type of inflammation will display proliferation of blood vessels and fibrosis?

chronic inflammation fibrosis: collagen formation and matrix remodeling leading to scar tissue formation

What is a granuloma?

chronic inflammation consisting of an aggregation of macrophages (transformed to epithelium-like cells) that are usually surrounded by a collar of chronic inflammatory cells (lymphocytes, plasma cells, fibroblasts, and collagen)

What is atherosclerosis and what is it induced by?

chronic inflammatory process of the arterial wall induced by endogenous toxic plasma lipid components

How might the lung epithelium of a chronic smoker compensate and what will this cause?

chronic irritation causes normal PSCE to be replaced by stratified squamous epithelial cells, causes a lack of mucociliary elevator

What does collagenase target?

collagen found in ECM, also involved in phagocytosis

Describe what will be seen upon microscopic examination of caseous necrosis

collection of fragmented or lysed cells, amorphous granular debris enclosed within distinctive inflammatory border (*granuloma*)

What are pigments within cells?

colored substances: some normal (melanin) and others abnormal

What is the most common epithelial metaplasia, and where does this occur?

columnar to squamous, occurs in the respiratory tract of smokers

What are the three interconnected systems involving plasma protein-derived mediators?

complement, kinin, and clotting systems

What is seen in arteries in fibrinoid necrosis?

complexes of antigens and antibodies deposited in the walls of arteries

Give an example of a severe defect associated with genetic derangements

congenital malformations associated with down syndrome (due to trisomy 21, chromosomal anomaly)

Identify the histological changes in acute inflammation of the lung

congestion of the vasculature and neutrophil infiltrate, spaces that normally contain air are now filled with leukocyte infiltrate

what is the danger of prostatic hyperplasia?

constitutes a fertile soil in which cancerous proliferation may eventually arise

What is the most common mechanism of vascular leakage?

contraction of endothelial cells

How is vascular permeability increased in inflammation?

contraction of endothelial cells leads to increased interendothelial spaces

What broad spectrum inhibitor of eicosanoid synthesis was discussed and how does it work?

corticosteroids: reduces the transcription of genes encoding COX-2, phospholipase A2, pro-inflammatory cytokines (such as *IL-1 & TNF*)

What is the gross appearance of liquefactive necrosis?

creamy yellow due to dead leukocytes and purulent matter

How might cells try to contain an offending agent?

creating a granuloma (chronic inflammation)

How do mitochondria activate apoptotic pathways?

cytochrome c and caspases indirectly activate apoptosis-inducing enzymes increased permeability of the outer mitochondrial membrane, leakage of proteins into the cytosol, death by apoptosis

List examples of synthesized mediators of inflammation

cytokines and prostaglandins

What are the locations of abnormal substances within a cell?

cytoplasm (frequently in phagolysosomes), and nucleus

What is the death domain?

cytoplasmic domain involved in protein-protein interactions that delivers apoptotic signals Part of extrinsic pathway of apoptosis

What are the mechanism by which cells may die during reperfusion?

damage may be initiated during reoxygenation due to increased generation of reactive oxygen and nitrogen species cellular antioxidant defense mechanism can be compromised by ischemia leading to accumulation of free radicals calcium can enter reperfused cells leading to damage of various organelles (increased free radicals)

What effect would calcium entering a reperfused cell have?

damages various organelles increasing production of free radicals

What is ischemia?

decrease in blood flow that can decrease supply of oxygen and nutrients consequence of a mechanical obstruction in the arterial system/reduced venous drainage

What is atrophy?

decrease in the size and metabolic activity of cells (reduced size and number of cells)

What are known changes that contribute to cellular aging?

decreased cellular replication and accumulation of metabolic and genetic damage

Give an example of a subtle defect caused by genetic derangements

decreased life span of red blood cells due to single amino acid substitution inhemoglobin sickle cell anemia

What are the mechanisms by which atrophy can occur?

decreased protein synthesis (reduced metabolic activity) or increased protein degradation (ubiquitin-proteasome pathway)

List common causes of atrophy

decreased workload (atrophy of disuse) loss of innervation (denervation atrophy) diminished blood supply inadequate nutrition loss of endocrine stimulation (breast and reproductive organs) pressure (tissue compression)

What is the function of the enzymes activated during apoptosis?

degrade cells nuclear dna and nuclear and cytoplasmic proteins

What is metastatic calcification?

deposition of calcium slats in otherwise normal tissues, hypercalemia secondary to some disturbance in the calcium metabolism

What will be seen upon microscopic examination of fibrinoid necrosis?

deposits of immune complexes and fibrin, bright pink amorphous appearance ("fibrinoid")

What type of patient would display the following?

diabetics and chronic smokers

What are the physiologic effects of histamine on the blood vessels?

dialtion of arterioles and increased permeability of venules (due to increased endothelial gaps in venules)

What mechanisms do cell injury result from?

different biochemical mechanisms, cannot blame one single or even dominant biochemical derangement act on several essential cellular components includign mitochondria, cell membranes, and DNA in nuclei

What causes the moth-eaten appearance of necrotic cells?

digestion of cytoplasmic organelles leaving a vacuolated cytoplasm

What are the morphologic hallmarks of inflammation?

dilation of small blood vessels increased blood flow accumulation of leukocytes and fluid (extravascular tissue)

What changes will be seen in the ER in a reversible injury?

dilation of the ER, detachment of polysomes, and intracytoplasmic myelin figures

What nuclear alterations will be seen in a reversible injury?

disaggregation of granular and fibrillar elements

How should a tissue be prepared to view glycogen?

dissolves in aqueous fixatives, are best fixed in absolute alcohol, staining with best carmine or the PAS reaction (rose to violet color to the glycogen)

What is shown in the following image and what can cause this?

duodenal ulcer: notice the loss of mucosa and inflammatory exudate at the base of the ulcer can be caused by increased acidity which can lead to necrosis

When will rapid bursts of reactive oxygen species be seen?

during inflammation: made by activated leukocytes

When will lymphatic vessels proliferate?

during inflammatory reactions

What enzymes are involved in NO synthesis?

eNOS: endothelial NO synthase iNOS: inducidble NO synthase (macrophages)

Where are chemical mediators found within the body?

either in the plasma or in cells

What would result from a lack of a1 antitrypsin?

elastase would destroy tissue surrounding alveoli of the lung leading to trapped air and emphysema

What are the actions of activated macrophages?

eliminate injurious agents (microbes) and initiate repair

What is the normal physiologic purpose of apoptosis?

eliminates cells that are no longer needed to maintain a steady number of various cell populations in tissue

How can apoptosis be used to prevent autoimmune disease?

elimination of potentially harmful self-reactive lymphocytes to prevent reactions against one's own tissues

What is the goal of inflammation?

elimination, dilution, or walling off of injurious agents

What processes require cell death?

embryogenesis and maintenance of homeostasis

Give examples of physiologic atrophy

embryonic structures (notochord and thyroglossal duct), and uterus after pregnancy

What would be caused by an alpha1-antitrypsin deficiency?

emphysema

What are functional abnormalities and what do these lead to?

end results of genetic, bicohemical, and structural changes in cells and tissues Lead to clinical manifestations and progression of disease *clinicopathologic correlations*

What is melanin?

endogenous pigment that is a non-hemoglobin-derived brown-black pigment

Where is NO release from?

endothelial cells

What cells produce NO?

endothelial cells, macrophages, and some neurons

Where is nitric oxide generated within the body?

endothelial cells, macrophages, neurons, and others

What leads to caspase activation in the extrinsic pathway of apoptosis?

engagement of the death receptors leads to activation directly

How is melanin formed?

enzyme tyrosinase catalyzes the oxidation of tyrosine to dihydroxyphenylalanine in melanocytes

How will coagulative necrosis appear histologically?

eosinohilic anucleate cells (cells on the left in this pic)

How will fibrinous exudate appear microscopically?

eosinophilic meshwork of threads amorphous coagulum

How do leukocytic infiltrates differ in hypersensistivity reactions?

eosinophils may be the main cell type

What are the two types of granulomas?

epithelioid and foreign body

What type of granuloma will display langhans-type giant cells?

epithelioid granuloms: fusion of macrophages with nuclei in the periphery

What is shown in the following image?

esophageal ulcer secondary to viral infection notice that the stratified squamous epithelium is sloughed off on the left side, also the presence of inflammatory cells int he ulcerative area

What is edema?

excess interstitial fluid: can be exudate or transudate

What causes pathologic hyperplasia?

excess or inappropriate actions of hormones or growth factors acting on target cells (think endometrial hyperplasia and protstatic hyperplasia )

Where is phosphatidylserine expressed on healthy cells?

expressed on the inner leaflet of plasma membrane of healthy cells

What type of fluid will move into interstital space as a result of increased vascular permeability?

exudate, high protein content

What is Karyolysis?

fading of the basophilia of the chromatin change that reflects loss of DNA because of enzymatic degradation by endonucleases

What causes cellular swelling in reversible cell injury?

failure of energy-dependent ion pumps in the plasma membrane

What is the systemic sign of inflammation?

fever

What is the main systemic effect of inflammation?

fever!!

What type of inflammation is displayed in the following image?

fibrinous inflammation notice eosinophilic meshwork of threads leading to a bread and butter appearance

What type of inflammation is shown in the following?

fibrinous inflammation; fibrin appears as an eosinophilic meshwork of threads (butter & bread appearances)

What is the function of lymphatics and lymph nodes?

filters and polices extravascular fluids, puts fluid back into the vascular system through the subclavian veins normally drain extravascular fluid that leaked from capillaries

How do phospholipids in apoptotic cells differ from healthy?

flips out and is expressed on outer layer of membrane (recognized by macrophage receptors) (phsphatidylserine)

What causes edema in acute inflammation?

fluid leaking out of blood vessel into interstitial space protein rich!!

Describe the appearance of atherosclerotic plaques

foamy appearance (foam cells)

What will be seen upon examination of fat necrosis?

focal areas of fat destruction, release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity

Where will liquefactive necrosis be seen?

focal bacterial infections and occasionally in fungal infections

What will be seen upon microscopic examination of fat necrosis?

foci of shadowy outlines of necrotic fat cells, basophilic calcium deposits, and inflammatory reaction

When will a cell produce arachidonic acid?

following mechanical, chemical, or physical stimuli

What type of granuloma is shown?

foreign body granuloma notice the macrophage nuclei are not lined up in the periphery

What type of granuloma is shown in the following image?

foreign body: notice the presence of multinucleated giant cells containing foreign material (nuclei not in the periphery as they would be in epithelioid granuloma)

What is necroptosis?

form of cell death that is a hybrid of both necrosis and apoptosis

What is connective tissue metaplasia?

formation of cartilage, bone, or adipose tissure (mesenchymal tissues) in tissues that do not contain these elements

What is suppurative inflammation characterized by?

formation of pus (neutrophils and dead cells)

How can O2 radicals affect membranes?

free radicals may cause peroxidation of lipids within plasma and organellar membranes

How does the glycolytic pathway work?

generates ATP in the absence of oxygen, uses glucose derived from body fluids or hydrolysis of glycogen

What is the function of cyclooxygenase?

generates prostaglandins from arachidonic acid

What are the two major classes of etiology?

genetic: inherited mutations and disease-associated gene variants acquired: infectious, nutritional, chemical, and physical

What cellular process is interrupted as a result of ischemia?

glycolysis, delivery of substrates is compromised

What are the two types of chronic inflammation?

granulomatous and non-granulomatous

What are the two types of chronic inflammation?

granulomatous and nongranulomatous

Be familiar wit beta and gamma chemokines

he skipped these so just have a general understanding

Give an example of ischemic cell injury that is reversible

heart muscle ceases to contract within 60 seconds of coronary occlusion

What are the two phases of microvasculature alteration seen in acute inflammation?

hemodynamic changes: increased blood flow and vasodilation changes in vascular permeability

What is hemosiderin?

hemoglobin-derived golden yellow-brown, granular or crystalline pigment

Which pigment serves as the major storage form of iron?

hemosiderin prussian blue stain

In what types of cells will fatty change be seen?

hepatocytes and myocardial cells

What may be formed over time in the focus of calcification?

heterotopic bone

List examples of preformed mediators of inflammation

histamine (early inflammation from mast cell)

What mediators will induce vasodilation?

histamine and NO

What mediators are released from degranulation of mast cells?

histamine and prostaglandins: can lead to anaphylactic shock

What are the first mediators to be released during inflammation?

histamine and serotonin

What are the two major vasoactive amines?

histamine and serotonin

What are the two main cell-derived mediators of inflammation?

histamine and serotonin stored as preformed molecules in cells

Give an example of a cell-derived mediator of inflammation that is rapidly sereted

histamine in mast cell granules rapidly secreted through granule exocytosis

What mediators will increase vascular permeability?

histamine, bradykinin, leukotrienes, and substance P *know this for the test* (think his balls look silly)

What are the two types of physiologic hyperplasia?

hormonal: will increase functional capacity of a tissue when needed compensatory:will be used to increase tissue mass after damage or partial resection

What events lead to lymphadenitis?

hyperplasia of the lymphoid follicles increased numbers of lymphocytes and macrophages

What pathologic effect may papillomavirus cause?

hyperplasia, skin warts and mucosal lesions caused by masses of hyperplastic epithelium

What usually accompanies hormonal hyperplasia?

hypertrophy

What cellular change will be seen in the uterus during pregnancy?

hypertrophy B normal, C hypertrophy

What type of injury will cause fatty change?

hypoxic injury and many forms of toxic or metabolic injury

What is the function of nitric oxide?

important chemical mediator, acts as a free radical

Where might atrial natriuretic factor be found in adults?

in cardiac hypertrophy normally downregulated after birth as it is expressed in atrium and ventricle of embryo

Where is necroptosis a backup mechanism?

in host defense against certain viruses that encode caspase inhibitors (cytomegalovirus)

Where can genes from early development be re-expressed later on?

in hypertrophic cells

When will eosinophils be seen?

in immune reactions and parasitic infections (mediated by IgE)

Where are cell-derived mediators of inflammation normally stored?

in intracellular granules

Where is intracellular calcium sequestered?

in mitochondria and the ER

Where will foam cells be found in xanthomas?

in subepithelial connective tissue of the skin and tendons

Where is caseous necrosis most often encountered?

in the foci of the tuberculous cavity (lungs) seen in tuberculosis infections

What is hyperplasia?

increase in the number of cells

What is hypertrophy?

increase in the size of cells

What is atrophy accompanied by?

increased autophagy

What is the vascular phenomena that occurs in acute inflammation?

increased blood flow, vasodilation (histamine), and increased vascular permeability

What causes hypertrophy?

increased functional demand and stimulation by hormones and growth factors

What are the two main causes of hypertrophy?

increased functional demand or stimulation by hormones and growth factors

What drives fluid into the interstitium in acute inflammation?

increased hydrostatic pressure

What will be increased in response to activation of macrophages?

increased levels of lysosomal enzymes, ROS, nitrogen species, cytokines, and growth factors

How will lymphatics respond to inflammation?

increased lymph flow to help drain edema fluid

what is the intrinsic (mitochondrial) pathway of apoptosis the result of?

increased mitochondrial permeability and release of pro-apoptotic molecules in the cytoplasm

What will occur as a result of mitochondrial membrane damage?

increased mitochondrial permeability will lead to decreased ATP, release of proteins that will trigger apoptotic death

What is the function of leukotrienes?

increased permeability and vasodilation, chemotaxis for leukocytes

What might defective inflammation lead to?

increased susceptibility to infections and delayed wound healing

What is transcytosis?

increased transport of fluids and proteins through the endothelial cells (doesn't result in endothelial injury!!)

What is the main cause of exudate?

increased vascular permeability

What is the function of cleavage products of complement?

increased vascular permeability chemotaxis opsonization

How does hypertrophy affect an organ?

increases its size (no new cells, just larger sized cells) due to synthesis and assembly of additional intracellular structural components

List examples of things that can cause damage to mitochondria

increases of cytosolic Ca2+, reactive oxygen species, and oxygen deprivation can also see mutations in mitochondrial genes

Give an example of selective hypertrophy

individual treated with barbituates can exhibit hypertrophy of smooth ER in hepatocytes, this will increase the amount of enzymes available to detoxify drugs, and eventually patients respond less to the drug

What will be the effect of increased intracellular Ca2+ levels?

induction of apoptosis: direct activation of caspases increasing mitochondrial permeability

What is the most common cause of acute inflammation?

infection

What are the characteristic signs of chediak higashi?

infection, albinism (abnormalities in melanocytes) , and bleeding (platelets) also associated with nerve defects

Be familiar with the stimuli for acute inflammation

infections are the most common and medically important causes

What happens to the surrounding tissue when necrosis occurs?

inflammation due to contents leaking from necrotic cell, cell cannot maintain membrane integrity

What is lymphadenitis?

inflammation of the lymph nodes

What are the three functional categories of complement?

inflammation, phagocytosis, and cell lysis

What pathologic process is ischemia often associated with?

inflammation: result of cytokine production, causes addition tissue damage

What effect may variations in genetic makeup have on cells?

influence the susceptibility of cells by chemicals and other environmental insults

How can ATP depletion affect the Ca2+ pump and how will this change with prolonged depletion?

influx of Ca2+ damages intracellular organelles prolonged worsening depletion of ATP: detachment of ribosomes from the rough ER, reduced protein synthesis (dissociation of polysomes)

Why might pharaceuticals target eicosanoid synthesis and how?

inhibit the synthesis of eicosanoids to prevent inflammation both COX1 and COX2 can be inhibited to inhibit prostaglandin synthesis ( NSAIDS)

What timeline does pathogenesis cover?

initial stimulus to the ultimate expression of the disease follows the exposure of cells or tissues to an injurious agent

What initiates the extrinsic (death receptor) pathway of apoptosis?

initiated by engagement of plasma membrane death receptors on a variety of cells

What are the two phases of apoptosis?

initiation in which caspases become catalytically active, and execution in which caspases trigger the degradation of critical cellular components

What are the two functional groups within the caspase family?

initiator (8 and 9) and executioner (3 and 6)

What are the events leading to cardiac hypertrophy?

integrated actions: mechanical sensors, GFs, casoactive agents activation of signal transduction pathways activation of a set of transcription factors

What is the physiologic action of cysteinyl-containing leukotrienes (C4, D4, E4)

intense vasoconstriction, bronchospasm, and increased vascular permeability

What is a xanthoma?

intracellular accumulation of cholesterol within macrophages (acquired and hereditary hyperlipidemic states)

What pathology may be seen in a cell undergoing metabolic derangements and chronic injury?

intracellular accumulations (proteins, lipids, carbs) or pathologic calcification

Where will calcium salts be found?

intracellular, extracellular, or both

What are the two pathways of apoptosis?

intrinsic (mitochondrial) and extrinsic (death-receptor initiated)

What is the major mechanism of apoptosis in mammalian cells?

intrinsic (mitochondrial) pathway

Describe the relationship between lipoxins and leukotrienes

inverse relationship lipoxins may be endogenous negative regulators of leukotrienes thus playing a role in resolution of inflammation

What is the cause of apoptosis on hormone-dependent tissues?

involution of tissue upon hormone withdrawl (ex: endometrial breakdown during the menstrual cycle, ovarian follicular atresia in menopause, regression of lactatin breast after weaning, prostatic atrophy after castration)

Why is ATP depletion detrimental?

involved in virtually all synthetic and degradative processes within the cell depletion of just 5-10% can have widespread effects

What role do transition metals play in generation of free radicals?

iron and copper donate and accept free electrons during intracellular reactions Ex: Fenton reaction (H2O2 + Fe2+ → Fe3+ + OH + OH

What will happen if a noxious stimuli persists on a cell?

irreversible injury and cell death

What will happen to an ischemic cell if oxygen is not restored?

irreversible injury and necrosis occur

Give an example of coagulative necrosis

ischemia caused by obstruction in a vessel may lead to coagulative necrosis of the supplied tissue Infarct

Which is more serious ischemia or hypoxia?

ischemia tend to cause more rapid and severe cell and tissue injury than does hypoxia in the absence of ischemia

What is the most common type of cell injury in clinical medicine?

ischemic and hypoxic injury

List nuclear changes of necrotic cells

karyolysis, pyknosis, and karyorrhexis

How is bradykinin inactivated?

kininase inactivates it

Be familiar with the diverse functions of activated marophages in inflammation

know this!!

What is shown in the following image?

langhans-type giant cell: notice peripheral nuclei found in epithelioid type granuloma

How is fibrinous inflammation formed?

large amounts of fibrinogen pass the vessel wall (due to large vasclar leaks) and fibrins are formed in the ECM

What will replace cells that have died from necrosis?

large whorled phospholipid masses (myelin figures) derived from damaged cell membranes

How can free radicals affect membranes of cells?

leads lipid peroxidation within plasma and organellar membranes in presence of O2 leads to oxidative damage: double bonds of FA in membranes are attacked by O2 derived free radicals

How might atherosclerotic cerebrovascular disease (reduced blood supply) affect the brain

leads to atrophy

What activates caspases in the intrinsic pathway of apoptosis?

leakage of cytochrome C and other proteins from the mitochondria

What will happen as a result of injury to lysosomal membranes?

leakage of enzymes into the cytoplasm, activation of acid hydrolases in the acidic intracellular pH of the injured cell, activation of these enzymes leads to enzymatic digestion, cells die by necrosis

What will be the downstream effect of leaking out of the vessels during inflammation?

leaking of the fluid leads to increased concentration of blood cells increasing hemoconcentration (blood more viscous) this will lead to *stasis* slowing blood flow in the vessels

What does binding of PAF to PAFR promote?

leukocyte adhesion, chemotaxis, degranulation and ROS generation

What must be activated for leukocytes to perform their functions?

leukocyte recruitment Recognition of the offending agents & deliver signal Activate the leukocytes to ingest & destroy the offending agents Amplify the inflammatory reaction

Which type of cell will secrete leukotrienes?

leukocytes

What is delivered to sites of infection by acute inflammation?

leukocytes and plasma proteins

On what level should cellular swelling in response to injury most apparent?

level of the whole organ

What area of the body will gangrenous necrosis most likely be seen?

limb (usually lower limb)

Where will fibrinous exudate be seen characteristically?

lining of body cavities: meninges, pericardium, pleura

What is the function of platelet-activating factor (PAF)?

lipid mediator that has the ability to cause platelet aggregation, inflammation and induce allergic response (at very low picomolar concentratioons)

Which pigment is known as the wear and tear pigment or lipochrome?

lipofuscin

What enzymes are responsible for the production of leukotrienes?

lipoxygenase enzyme

What type of necrosis is hypoxic death of cells in the CNS?

liquefactive necrosis

Where are plasma derived mediators produced?

liver

Give an example of compensatory hyperplasia

liver transplant donor, remaining cells will proliferate to return the cells to original size (myth of prometheus)

What are surface features that can be used for diagnosis of acute inflammation?

local cardinal signs

What occurs in dystrophic calcification?

local deposition in dying tissues, normal serum calcium levels, absence of derangements in calcium metabolism encountered in areas of necrosis (coagulative, caseous, or liquefactive)

What is the cause of iron pigments?

localized breakdown of red blood cells

What is the typical cause of gangrene?

loss of blood supply to the area leading to necrosis

What causes the glassy homogeneous appearance of necrotic cells?

loss of glycogen particles

What will occur as a result of plasma membrane damage?

loss of osmotic balance with an influx of fluids and ions, loss of cellular contents, and cells may leak metabolites further depleting energy stores

Where will bradykinin cause contraction of smooth muscle?

lungs

Where are granulomas associated wiht CGD found?

lungs, skin, and GI system

How is edema removed?

lymph system will draw up the fluid from the interstitial space removing edema

What cell type will be increased in viral infections?

lymphocytes (lymphocytosis)

What type of cells are present in chronic inflammation?

lymphocytes and macrophages

What other cells may be found in chronic inflammation besides monocytes?

lymphocytes and plasma cells

How will leukocytic infiltrate differ in viral infections?

lymphocytes will be the first cells to arive

What type of cells will prduce cytokines?

lymphocytes, macrophages, and endothelial cells also epithelial and connective tissue cells

What normally surrounds granulomas?

lymphocytes, plasma cells, fibroblasts, and collagen

What is Niemann-Pick disease type C?

lysosomal storage disease caused by mutations affecting an enzyme involved in cholesterol trafficking, will have cholesterol accumulation in multiple organs

What do autophagic vacuoles fuse with?

lysosomes

What is found in specific/secondary granules?

lysozyme, *collagenase*, gelatinase, lactoferrin

What is responsible for tissue damage in chronic inflammation?

macrophages

What type of cells phagocytose apoptotic cells?

macrophages

What induves alpha chemokine synthesis?

main inducers are microbial products & cytokines, like IL-1 & TNF

What vessels are involved in progressive vasodilation?

mainly arterioles

What is the purpose of apoptosis in proliferating cell populations?

maintains constant number (ex: B lymphocytes in germinal centers, epithelial cells in intestinal crypts, immature lymphocytes in bone marrow, thymus that fails to express useful antigen receptors)

What is contained within the granules of eosinophils and what is it's effect?

major basic protein: causes lysis of mamallian epithelial cells to control parasitic infections (hihgly cationic protein that is toxic to parasites) also involved in allergies

What is the major and secondary pathway in which ATP will be made?

major: oxiadtive phosphorylation of adenosine diphosphate secondary: glycolytic pathway, works in absence of oxygen and uses glucose

What may be initiated in a smoker that is PERSISTENTLY undergoing metaplasia?

malignant transformation in metaplastic epithelium

Give an example of atrophy caused by malnutrition

marasmus, body will break down muscle leading to cachexia

What is hemorrhagic inflammation characterized by?

marked hemorrhage seen commmonly in bladder cystitis in patients receiving chemo

What is seen in a myocardial ischemic injury?

massive influx of calcium, cell death (mainly necrosis), widespread leakage of cellular enzymes into extracellular space, and dead cells replaced by large masses (myelin figures)

What is the main source of histamine?

mast cells (normally present in connective tissue adjacent to blood vessels) present in granules of the mast cell

What cells produce prostaglandins?

mast cells, macrophages, and edothelial cells

Depending on the severity, how may a cell respond to hypoxia?

may adapt, undergo injury, or die

What type of proteins will cause intracellular accumulations?

may be normal secreted proteins that are produced in excessive amounts (plasma cells synthesizing immunoglobulins)

What is the function of the complement system in cell injury?

may contribute to ischemia-reperfusion injury: involved in host defense and an important mechanism of immune injury

What is the only endogenous brown/black pigment?

melanin

What is an autophagic vacuole?

membrane-bound vacuole that contains fragments of cell components

What occurs during a mercuric chloride poisioning injury? (chemical injury)

mercury binds to sulfhydryl groups of cell membrane: direct injury, increases membrane permeability and inhibits ion transport damages cells that absorb, excrete, or concentrate the chemicals (cells of GI and kidney)

What is barrett esophagus an example of and what may cause this?

metaplasia, GERD causes esophageal squamous epithelium to be replaced by intestinal-like columnar cells

What are inactive mediators activated by?

microbes and damaged tissues (substances released from necrotic cells)

What are the cytoskeletal proteins that may accumulate?

microtubules, thin actin filaments, thick myosin filaments, and intermediate filaments

What are exogenous abnormal substances?

mineral or products of infectious agents

What is the main goal of anitoxidants?

minimize the effects of ROS

What are the 3 most important sites of membrane damage during cell injury?

mitochondrial membrane, plasma membrane, and lysosomal membranes

What starts disease?

molecular or structural altercations in cells causing injury to cells and ECM

How do neutrophils and monocytes/macrophages differ in inflammation?

monocytes survive longer and are able to proliferate in the tissue

Describe the life span of monocytes/macrophages

monocytes: about 1 day in the blood macrophages: several months or years in tissue

What cells are involved in systemic hemosiderosis?

mononuclear phagocytes

Where is hemosiderin normally seen?

mononuclear phagocytes of the bone marrow, spleen, and liver (actively engaged in red cell breakdown)

What type of necrosis would be seen in a gangrenous situation in which bacteria are involved?

more liquefactive necrosis because of actions of degradative enzymes in the bacteria and the attracted leukocytes (wet gangrene)

What is the specific gravity of exudate?

more than 1.020

Where are ulcers commonly encountered?

mucosa, skin, and subcutaneous tissues of the lower extremities (think older individuals with circulatory disturbances

What comprises cell injury?

mutations that affect essential cellular constituents

What is contained within azurophil/primary granules?

myeloperoxidase and bactericidal factors (lysosozyme, defensins)

Give an example of an irreversible injury due to ischemia

myocardium, seen as early as 30-40 minutes after ischemia

What factors influence the outcomes of acute inflammation?

nature and intensity of the injury site of tissue infected responsiveness of the host

What does cellular response to injurious stimuli depend upon?

nature of the injury, it's duration and it's severity small doses of toxin or brief ischemia: may induce reversible injury large doses or prolonged ischemia: instantaneous death, slow irreversible injury leading to cell death

What does necroptosis resemble morphologically and biochemically?

necrosis

Which type of cell death is always a pathologic process?

necrosis

What are the two principal pathways of cell death?

necrosis and apoptosis

What are the two principle types of cell death?

necrosis and apoptosis

What is an infarct, and what type of necrosis is associated?

necrosis of a localized area (caused by ischemia), can lead to coagulative necrosis in this pic note the pink anucleate cells characteristic of coagulative necrosis

How will necrotic cells appear different in H&E and what causes this?

necrotic cells have loss of cytoplasmic RNA (binds to blue dye), and denatured cytoplasmic proteins (bind to red dye) increased eosinophilia

What are the leukocyte abnormalities seen in chediak higashi?

neutropenia (decreased neutrophils), defective degranulation, and delayed microbial killing

What cell will be increased in bacterial infection?

neutrophils (neutrophilia)

What type of cells will use phagocytosis in inflammation?

neutrophils and macrophages

Give examples of when apoptosis would occur in host cells that have served their purpose

neutrophils in an acute inflammatory response, and lymphocytes at the end of an immune response

Describe the leukocytic infiltrate in inflammation

neutrophils predominate in the first 6-24 hours replaced by monocytes in 24-48 hours: become the dominant population in chronic inflammation

How might the leukocytic infilitrate differ in pseudomonas bacteria infections?

neutrophils will dominate for several days rather than a few hours

What are the first cells to the site of injury and what is their function?

neutrophils: provide important defense against infection by attacking bacteria

What type of granuloma is shown in the following?

non-caseating granuloma, no necrosis, notice lymphocytes at the top

What causes the nuclear changes seen in necrotic cells?

nonspecific breakdown of DNA

What two categories do stockpiled substances within a cell fall into?

normal cellular constituents and abnormal structures

What will occur during an accumulation abnormality caused by lack of enzyme?

normal endogenous substance accumulates because of defects, usually inherited, in enzymes that are required for the metabolism of the substance Ex: storage diseases, genetic enzymes involved in metabolism of lipid and carbohydrates defective

Describe what happens in an accumulation mutation in which there is abnormal metabolism

normal endogenous substance is produced at a normal or increased rate, but the rate of metabolism is inadequate to remove it Ex: fatty change in the liver and reabsorption protein droplets in the tubules of the kidneys

What is bilirubin?

normal major pigment found in bile, derived from hemoglobin, contains no iron

What normally happens to free fatty acids that are transported to liver?

normally transported into hepatocytes where they will be esterified to triglycerides, converted into cholesterol or phospholipids, or oxidized to ketone bodies

Draw the production of prostaglandins

note: both vascular and systemic effects

Be able to identify the parts of epithelioid cell granuloma

notice lymphocytes and collagen deposition in the left hand side, Langhans-type cell with peripheral nuclei

How does the cell kill itself via apoptosis?

nuclear dissolution, fragmentation of the cell without complete loss of membrane integrity, and rapid removal of the cellular debris

What occurs during pyknosis?

nuclear shrinkage, increased basophilia chromatin condenses into solid shrunken basophilic mass

What does the number associated with a prostaglandin respresent?

number of double bonds

What role does the ubiquitin-proteasome pathway play in atrophy?

nutrient deficiency and disuse activate ubiquitin ligases that will decrease proteins leading to atrophy

What triggers autophagy?

nutrient deprivation

How might fibrinous exudate affect the heart?

obliteration of the pericardial space, loss of pericardial fluid can result in the adhesion of the pericardium to the heart

What is the advantage to the activation system of inactive mediators?

only activated when needed, this ensures that they won't cause unnecessary inflammation

how will formation of a high-conductance channel affect the mitochondria?

opening of the channel leads to a loss of mitochonrial membrane potential, results in failure of oxidative phosphorylation and depletion of ATP, will lead to necrosis of cell

How do free radicals promote oxidative modifications of proteins?

oxidation of amino acid side chains formation of protein-protein ross-linkages (ex: disulfide bonds) oxidation of the protein backbone

How does ischemia affect oxidative phosphorylation?

oxidative phosphorylation ceases without O2, decrease in cellular ATP, increase in adenosine monophosphate, and glycogen stores are rapidly depleted

What is hypoxia?

oxygen deprivation

List the sequence of events in a post-hypoxic or ischemic cell

oxygen tension within the cell decreases: leads to loss of Ox-phos and ATP influx of Ca2+ progressive loss of glycogen decreased protein synthesis

What three characteristics will be seen in regards to an organ undergoing cellular swelling?

pallor, turgor, and increase in weight of the organ

How does NO signal?

paracrine signalling, acts only on cells in close proximity to where it is produced, short half life

In what type of patient will excessive intracellular glycogen be seen?

patients with an abnormality in either glucose or glycogen metabolism

What is the function of atrial natriuretic factor?

peptide hormone that causes salt secretion by the kidney, decreases BV and BP, and reduces hemodynamic load

What cavities can potentially fill with serous fluid in serous inflammation?

peritoneal, pleural. or pericardial cavities this accumulation of fluid is called effusion

How long will coagulative necrosis persist and how is it removed?

persist for days or weeks, cellular debris removed by phagocytosis by infiltrating leukocytes digestion of the dead cells by the action of lysosomal enzymes and leukocytes

What are the two main events that will lead to transition from acute to chronic inflammation?

persistence of the injurious agent interference with normal healing process (Focus of acute inflammation (pneumonia) Extensive tissue destruction Formation of a cavity Chronic lung abscess)

What are the possible causes of infection?

persistent infections by microorganisms immune-mediated inflammatory diseases Autoimmune diseases Atherosclerosis

What happens to pigments inoculated during tattooing?

phagocytosed by dermal macrophages

What will happen to myelin figures within an injured cell?

phagocytosed by leukocytes and degraded further into fatty acids

What will happen to phospholipid precipitates (myelin figures) in cells that have died from necrosis?

phagocytosed by other cells and further degraded into fatty acids

What type of mediator is PAF?

phospholipid derived mediator that causes platelet aggregation

What type of lipids are part of myelin figures found in necrotic cells?

phospholipids

What usually causes reversible functional and structural responses?

physiologic stresses and pathologic stimuli

What is the fluid in serous inflammation derived from?

plasma and secretions of mesothelial cells

What remains intact in an apoptotic cell?

plasma membrane of apoptotic cell and bodies remain intact (target for phagocytes)

What forms the vesicles seen in phagocytosis and what do these vesicles fuse with?

plasma membrane pinches off to form vesicle: phagosome this will fuse with the lysossomal granule forming the phagolysosome

What type of cell produces serotonin?

platelet

What cell produces serotonin?

platelets

What cells aggregation and adhesion is reduced by NO?

platelets

What cells is serotonin present in?

platelets also found in certain neuroendocrine cells in the GI tract

Where are PAFR present?

platelets, leukocytes, and endothelial cells

What is the benefit of taking fish oil?

polyunsaturated fats in fish oil are poor substrates for conversion to active metabolites excellent substrates for production of anti-inflammatory lipid products

What kind of molecule is arachidonic acid?

polyunsaturated fatty acid

What do apoptotic bodies contain?

portions of the cytoplasm and nucleus

Where does diapedesis occur?

post capillary venules

What is the marker for cells undergoing apoptosis?

presence of cleaved, active caspases

What is autophagy and what is a marked characteristic?

process by which starved cell eats its own components to survive marked by increased autophagic vacuoles

What is the role of plasma cells?

produce antibodies to protect against foreign or self antigen

What is the function of lipoxygenases?

produce leukotrienes and lipoxins from arachidonic acid

Where are reactive oxygen species made within cells?

produced normally in cells during mitochondrial respiration and energy generation, also produced in large amounts by leukocytes (neutrophils and macrophages)

What are endogenous abnormal substances?

product of abnormal synthesis or metabolism

What does necroptosis resemble mechanistically and why?

programmed cell death (considered hallmark of apoptosis), triggered by genetically programmed signal transduction events

What are other terms for necroptosis?

programmed necrosis or "caspase-independent" necrosis

What is cellular aging?

progressive decline in cellular function and viability caused by genetic abnormalities

Give an example of hormonal hyperplasia

proliferation of the glandular epithelium of female breast during pregnancy and puberty note this is usually accompanied by hypertrophy

Give an example of a cell-derived mediator of inflammation that is synthesized de novo

prostaglandins and cytokines synthesized in response to stimulus

What are the metabolites of arachidonic acid?

prostaglandins, leukotrienes, and lipoxins

What biologically active compounds are synthesized from arachidonic acid?

prostaglandins, leukotrienes, and thromboxanes

What will be released when there are increased cytosolic Ca2+ levels?

proteases: break down both membrane and cytoskeletal proteins endonucleases: responsible for DNA and chromatin fragmentation ATPases: speed up ATP depletion

List nutritional imbalances that may cause cellular injury

protein-calorie deficiencies vitamin deficiencies anorexia nutritional excess

What type of fluid will leave the blood as a result of increased permeability?

protein-rich exudate

What may be the result of oxygen or glucose deprivation within a cell?

proteins may become misfolded which will trigger a cellular reaction leading to cell injury or death

What is the critical step in complement activation?

proteolysis of the third component C3

What type of stain is used to visualize iron pigments?

prussian blue stain

What is pus and what does it contain?

purulent exudate that contains neutrophils, debris of dead cells, and microbes

What is seen in suppurative inflammation?

purulent exudates and pus (neutrophils and necrotic cells) large amounts of pus seen

What occurs in karyorrhexis?

pyknotic nucleus undergoes fragmentation nucleus of the necrotic cell will totally disappear in 1-2 days

What sets the enzymatic death program in motion?

rapid and sequential activation of the executioner caspases (3 and 6) part of execution phase of apoptosis

What are biochemical mechanisms that cause membrane damage?

reactive O2 species, decreased phospholipid synthesis, increased phospholipid breakdown, and cytoskeletal abnormalities

How will microbes within phagocytes be killed?

reactive oxygen species

What must most toxic chemical be converted to to interact with target cells?

reactive toxic metabolites

How will depletion of ATP affect the sodium potassium pump?

reduced activity of sodium potassium pump, sodium accumulates within the cell, water will enter leading to cell swelling and dilation of the ER

What is ischemia?

reduced blood flow

What are possible causes of hypoxia?

reduced blood flow (ischemia) inadequate oxygenation of the blood (cardiorespiratory failure) decreased oxygen-carrying capacity of blood

How can hypothermia help treat ichemia?

reduced metabolic demands of the stressed cells, decreases cell swelling, suppresses the formation of free radicals, and inhibits host inflammatory response

What is hypoxia?

reduced oxygen availability

What are the major causes of depletion of ATP?

reduced supply of oxygen and nutrients, mitochondrial damage, and actions of toxins (ex: cyanide)

How will TNF lead to cachexia?

reduces appetite leading to weight loss and anorexia

What results from oxidative phosphorylation and where does this occur?

reduction of oxygen through electron transfer system of mitochondria

How is fibrinous inflammation cleared?

removed by fibrinolysis and clearing of debris by marophages

What contributes to tissue damage in ischemia reperfusion injury?

reperfused tissued may sustain loss of cells in addition to the cells that are irreversibly damaged at the end of ischemia Think myocardial and cerebral infarct following therapies to restore blood

What are the limitation of morphology?

require molecular analysis

What are the possible outcomes of acute inflammation?

resolution repair supparation chronic inflammation

What is the mechanism of metaplasia?

result of *reprogramming*, NOT a result of a change in phenotype of already differentiated cells, precursor cells (stem cells) differentiate along a new pathway

What causes the morphologic appearance of necrosis?

result of denaturation of intracellular proteins and enzymatic digestion of lethally injured cell, may take hours to develop

What is the mechanism that causes hypertrophy?

result of increased production of cellular proteins

How does ROS affect endothelial cells?

results in damage and increased vascular permeability

What will be the result of endothelial injury?

results in endothelial cell necrosis and detachment direct damage to the endothelium

How will hyperplasia affect an organ/tissue?

results in increased mass of the organ/tissue (pathologic or physiologic)

What type of change is metaplasia?

reversible change

What is an adaptation?

reversible changes of cells in response to changes in their environment Ex: size, number, phenotype, metabolic activity, and functions

How will intracellular accumulations of proteins appear?

rounded, eosinophilic droplets, vacuoles, or aggregates in the cytoplasm Ex: reabsorption droplets in proximal renal tubules, associated with protein loss in urine

What is lymphagitis?

secondarily inflamed lymph vessels

What is the function of a1 antitrypsin?

secreted from the liver to counteract the effects of neutrophil elastase

What is pyroptosis?

seperate form of cell death that resembles apoptosis, accompanied by the release of fever inducing cytokine IL-1

What type of inflammation is seen in a blister?

serous inflammation, thin exudate

What type of inflammation is shown in the following image?

serous inflammation: blisters, accumulation of thin fluid

What are the 4 types of acute inflammation?

serous, fibrinous, suppurative, and hemorrhagic

What are activated during apoptosis?

several members of a family of cystein proteases called caspases

What occurs to the cell during necrosis?

severe membrane damage, lysosomal enzymes enter the cytoplasm and digest the cell, cellular contents leak out

What will happen to a cell that is undergoing irreversible injury?

severe swelling of the mitochondria, extensive damage to plasma membranes (giving rise to myelin figures), swelling of lysosomes, and large flocculent amorphous densities develop in the mitochondrial matrix

WHat is the life span of mediators after they are activated?

short lived

In what ways can free radicals form lesions in DNA?

single and double strand breaks in DNA cross-linking of strands formation of adducts oxidative DNA damage

Give an example of the difference between skeletal and cardiac muscle in terms of cell injury

skeletal muscle deprived of it's blood supply can be placed at rest and preserved while cardiac muscle cannot

How are ulcers formed?

sloughing of inflamed necrotic tissue

What will be seen on the microscopic level in cells undergoing cellular swelling?

small clear cytoplasmic vacuoles caused by *hydropic change (accumulation of H2O) or vacuolar degeneration*, cells may also show increased eosinophilic staining

Where are cytochrome P-450 mixed-function oxidases found?

smooth ER of the liver and other organs

What cells are involved in atherosclerotic plaques?

smooth muscle cells and macrophages

What layer do atherosclerotic plaques aggregate in?

smooth muscle cells and macrophages in the intimal layer of aorta and large arteries leading to yellow cholesterol-laden atheromas

What is fibrinoid necrosis?

special form of necrosis seen in immune reaction involving blood vessels

What is the role of chemokines?

stimulate cells to migrate through interendothelial spaces towards site of injury or infection where the chemokines are produced

What will be the downstream effects if fibrin cannot be removed in fibrinous inflammation?

stimulated the growth of fibroblasts and blood vessels leads to scarring conversion of fibrinous exudate to scar tissue

What is the function of PGF2a?

stimulates contraction of uterine, bronchial smooth muscle, and small arterioles

List examples of neuropeptides

substance P and neurokinin A

What is shown in the attached image?

suppurative inflammation within abscess notice neutrophils

What type of inflammation is shown?

suppurative inflammation: large amounts of neutrophils present (will produce pus)

What will be seen on the surface of apoptotic cells?

surface blebbing and fragmentation into membrane-bound apoptotic bodies

What mitochondrial changes will be seen in reversible injury?

swelling and small amorphous densities

How might contractile proteins behave during hypertrophy?

switch from adult to fetal/neonate forms Ex: muscle hypertrophy, alpha myosin heavy chain replaced by beta isoform

What type of changes may first manifest in acute inflammation of internal organs?

systemic changes :fever

What does elastase target and what does it cause?

targets elastic tissue seen commonly in blood vessels and lung leads to emphysema

What is the clinical use of lipfuschin?

telltale sign of free radical injury and lipid peroxidation, seen in cells undergoing slow regressive changes

What concept did Rudolf Virchow put forth in pathology?

that diease starts with molecular and structural alterations in cells, injury to cells and ECM leads to tissue and organ injury (determines morphologic and clinical patterns of disease)

What is a frequent target of drug toxicity?

the liver, many drugs are metabolized here

What is opsonization?

the process by which a foreign particle, particularly a microbe, is coated with plasma proteins (opsonins) so as to facilitate the attachment and internalization of that particle by the phagocytic cell.

What is pathology?

the scientific study of disease: cells, tissues, and organs that underlie disease

Where does serous inflammation most commonly occur?

the skin, outpouring of thin fluid into the cavities

What induces apoptosis in viral infections?

the virus (adenovirus and HIV) Host will display immune response (viral hepatitis)

What is fibrinous inflammation characterized by?

thick exudates (bread and butter) fibrin normally found only within the blood vessels

What is serous inflammation characterized by?

thin exudate

How will abscesses be formed in suppurative inflammation?

through liquefactive necrosis

How is the energy in free radicals released?

through reactions with adjacent molecules Ex: inorganic or organic chemicals/proteins, lipids, carbs, and nucleic acids q

How is arachidonic acid released from membrane phospholipids?

through the action of phospholipases (PLA2)

what is the most frequent reason for terminating therapeutic use or developmental drugs?

toxic liver injury

What are causes of steatosis?

toxins, protein malnutrition, diabetes mellitus, and obesity

What is liquefactive necrosis?

transformation of tissue into a liquid viscous mass (characterized by digestion of the dead cells)

What is the most useful strategy in ischemic brain and spinal cord injury?

transient induction of hypothermia (core body temp lower than 92)

What is the immediate hemodynamic change in response to injury and what vessels are involved?

transient vasoconstirction involving mainly arterioles mild injury: 3-5 seconds severe injury: about 5 minutes

What type of fluid will be seen in protein wasting diseases of the liver and kidney?

transudate: low protein fluid

What is the most common cause of granulomatous inflammation?

tuberculosis!!! super high yield, know this!!

What is the execution phase of apoptosis?

two initiating pathways converge to a cascade of caspase activation that mediates final phase of apoptosis

What type of necrosis would be seen in a gangrenous situation in which there was not bacteria?

typically coagulative necrosis involving multiple tissue planes think dry gangrene

what pathway is responsible for accelerated proteolysis?

ubiquitin-proteasome pathway (think cancer cachexia)

How are free radicals removed?

unstable and decay spontaneously multiple nonenzymatic and enzymatic mechanisms in cells remove free radicals iron and copper minimize levels by binding ions to storage and transport proteins (transferrin, ferritin, lactoferrin, and ceruloplasmin) enzymes act as free radical-scavenging systems

is permeability involved in transudate?

usually not, usually found in patients losing alot of protein through liver or kidney disease

What type of tissues are most actively involved in inflammation?

vascular tissue: dilation and permeability allow cells to enter Connective tissue

What physiologic effects does PAF have?

vasoconstriction and bronchoconstriction at extremely low concentrations: vasodilation and increased venule permeability

What is the function of nitric oxide?

vasodilation

What is the earliest sign of inflammation?

vasodilation (from histamine)

What leads to the redness and warmth in areas of inflammation?

vasodilation: increased blood flow in capillary beds (microvasculature)

What is the earliest manifestation of acute inflammation?

vasodilation: starts in arterioles and leads to opening of new capillary beds note this occurs after the transient vasoconstriction of arterioles

What is the function of prostacyclin?

vasodilator inhibitor of platelet aggregation (potent) increases permeability of vessels and chemotactic effects of other mediators

What are normal cellular constituents?

water, lipids, proteins, and carbohydrates that accumulate in excess

What are the sequential morphologic alterations associated with reversible cell injury?

Decreased generation of ATP Loss of cell membrane integrity Defects in protein synthesis Cytoskeletal damage DNA damage

What is defective in chediak higashi?

Defective fusion of phagosomes & lysosomes in phagocytes causing increase susceptibility to infections

Chart the formation of lipoxins, leukotrienes, and prostaglandins

Note that pharmaceuticals will target enzymes in this pathway to prevent inflammation

Draw how ischemia will affect the mitochondria and it's functions

Note that these changes indicate reversible injury, further depletion will lead to cell death

Draw the process of leukocyte extravasation including the markers at each stage

Note this is not the same as transcytosis as VEGF isn't involved KNOW MOLECULES INVOLVED!!

Draw the images depicting the differences between transudate and exudate

Notice transudate is a result of decreased colloid osmotic pressure

What are the cell-derived factors that influence vascular permeability and what is the downstream effect?

*Histamine* serotonin PAF, Prostaglandins, leukotrienes NO leads to edema from increased vascular permeability

What are the biologic functions of substance P and neurokinin A?

*Transmission of pain signals* Regulation of blood pressure Stimulate secretion by endocrine cells Increasing vascular permeability

What is the initial sign of apoptosis?

*cell shrinkage* with tightly packed organelles in a dense cytoplasm (other forms of cell injury an early feature is cell swelling)

Chart the differences between acute and chronic inflammation

*know this one really well for test*

What is the survival duration of CGD and how can it be treated?

20-25 years, but bone marrow transplants can increase success

What are the 3 different lipoxygenases?

5-lipoxygenase LTB4 Cysteinyl-containing leukotrienes

A 19-year-old female gives birth to her first child. She begins breast feeding the infant. She continues breast feeding for almost a year with no difficulties and no complications. Which of the following cellular processes that began in the breast during pregnancy allowed her to nurse the infant for this period of time? OA. Lobular hyperplasia OB. Stromal hypertrophy OC. Epithelial dysplasia OD. Steatocyte atrophy OE. Ductal epithelial metaplasia

A

A study is performed involving the microscopic analysis of tissues obtained from surgical procedures. Some of these tissues have the microscopic appearance of an increased cell size of multiple cells within the tissue, due to an increase in the amount of cytoplasm, with nuclei remaining uniform in size. Which of the following conditions is most likely to have resulted in this finding? OA. Uterine myometrium in pregnancy OB. Liver following partial resection OC. Ovary following menopause OD. Cervix with chronic inflammation

A

A 38-year-old male incurs a traumatic blow to his upper left arm. He continues to have pain and tenderness even after 3 months have passed. A plain film radiograph reveals a 4 cm circumscribed mass in the soft tissue adjacent to the humerus. The mass contains areas of brightness on the x-ray. Over the next year this process gradually resolves. Which of the following terms best describes this process? OA. Dysplasia OB. Hyperplasia OC. Hypertrophy OD. Metaplasia OE. Neoplasia

D

What types of cells are seen in chronic inflammation?

Monocytes/macrophages: *most important* lymphocytes plasma cells eosinophils

Give an example of hypertrophy

Muscle hypertrophy: muscles have limited capacity for division thus will undergo hypertrophy when metabolic demands are increased Think body builders pumping iron, individual muscle fibers will increase in size

What is defective in chronic granulomatous disease and what will this lead to?

NADPH oxidase defective: cannot produce ROS phagocytes ingest microbes but cannot kill them leading to formation of granulomas and recurrent infections

How is NO microbicidal?

NO-derived ROS are toxic to microbial cells

WHere is 5-lipoxygenase found and what is it's function?

Neutrophils Converts AA to 5-hydroxyeicosatetraenoic acid chemotactic to neutrophils, precursor of leukotrienes

How will stasis affect neutrophils?

Neutrophils accumulate along vascular endothelium endothelial cells are activated (express increased adhesion molecules) leukocytes adhere to endothelium and migrate

What types of cells are seen in acute inflammation?

Neutrophils: *most common* Basophils/mast cells Platelets

What two cell populations are required for synthesis of lipoxins?

Neutrophils: produce intermediates of lipoxin synthesis Platelets: interact with leukocytes and convertintermediates to lipoxin

What is shown in the following image?

Suppurative inflammation with abscess note the congested blood vessels in the periphery and the large collection of neutrophils (alot of neutrophils think suppurative!!!)

What family are death receptors part of?

TNF receptor family

How might myocytes appear if they are adapted and if they are irreversibly damaged?

The cellular adaptation is myocardial hypertrophy (lower left), caused by increased blood flow requiring greater mechanical effort by myocardial cells. This adaptation leads to thickening of the left ventricular wall to over 2 cm In reversibly injured myocardium (illustrated schematically, right) there are generally only functional effects, without any readily apparent gross or even microscopic changes. In the specimen showing necrosis, a form of cell death (lower right), the light area in the posterolateral left ventricle represents an acute myocardial infarction caused by reduced blood flow (ischemia).

draw and describe the normal and inflamed vasculature seen in acute inflammation

The major local manifestations of acute inflammation, compared with normal, are (1) vascular dilation & increased blood flow (causing erythema and warmth), (2) extravasation of plasma fluid & proteins (edema), & (3) leukocyte (mainly neutrophil) emigration & accumulation

How do caspases exist within the body?

as inactive pro-enzymes or zymogens, will undergo enzymatic cleavage to become active

How are histamine and serotonin stored?

as preformed molecules in cells

What type of illness might lipoxygenase inhibitors be useful in?

asthma, blocks leukotriene receptors (montelukast)

What are aggregates of cholesterol called?

atheromas

What steps must be taken to preserve tissue in order to identify lipids?

avoidance of fat solvents commonly used, prepare frozen tissue sections of either fresh or aqueous formalin-fixed tissue, sections may then be stained with sudan 4 or oil-red o

What is fibrosis?

when functional tissue is replaced by nonfunctional scar tissue, leads to decreased function of the organ

When might oxygen lead to cell injury?

when in high concentrations

When might glucose or salt lead to cell injury?

when in hypertonic concentrations

When will inflammation become harmful?

when injurious stimulus cannot be eliminated

When will hageman factor become activated?

when it comes into contact with negatively charged surfaces

When will a monocyte become a macrophage?

when it leaves the blood and enters the tissue stimuli include: microbial products, cytokines, and other chemical mediators

When will serotonin be released in inflammation?

when platelets aggregate ( after contact with collagen, thrombin, adenosine diphosphate (ADP) & antigen-antibody complexes)

When will arachidonic acid become essential?

when there is a deficiency in linoleic acid

What are myelin figures, what type of cell are they seen in, and how are they disposed of?

whorled phospholipid masses seen in necrotic cells Derived from damages cell membrane: phospholipid precipitates Phagocytosed by other cells and further degraded into FA

Describe how a normal cell will behave

will be confined to a narrow range of structure and function by metabolism/differentiation/specialization, contraints of neighboring cells, and availability of metabolic substrates Maintains homeostasis: steady state

What will happen to plasma derived mediators that are produced by the liver?

will circulate in the blood as inactive precursors must be activated to acquire biological function

How will foreign body granulomas be formed?

will form around material (sutures, talc powder in IV drug abuse) foreign material can be identified in the center of the granuloma

How will ROS affect antiproteases?

will inactivate them Ex: a1-antitrypsin will be inactivated allowing elastase to break down elastic tissue

What will occur if a macrophage cannot remove fibrin in fibrinous inflammation?

will lead to clots outside of the blood vessels, this is manifested by the synthesis of collagen which will lead to scarring!!!!

What will happen if an injury to a cell is to extensive to repair?

will lead to inflammation and eventually fibrosis

How will a cell respond to an accumulation of misfolded proteins?

will lead to mutations in genesed encoding these proteins, free radicals, and ER stress This will cause the cell to undergo apoptosis

What happens to cell debris in autophagic vacuoles that resist digestion?

will persist as membrane-bound residual bodies Ex: lipofuscin granules (brown atrophy)

What might happen to a cell that has DNA damage from radiation, cytotoxic anticancer drugs, or hypoxia?

will produce free radicals leading to apoptosis

How will ischemia affect anaerobic energy generation?

will stop as glycolytic substrates are exhausted and glycolysis is inhibited (will lead to accumulation of metabolites)

What will happen in a cell deprived of growth factor?

will undergo apotosis Ex: hormone sensitive cells: deprived of hormone lymphocytes: not stimulated by antigen or cytokine Neurons: deprived of nerve growth factor

How do chemical mediators work?

work by binding receptor which will cause the release of other mediators (usually short lived, but can be harmful)

What sequence of events will occur in a heart muscle undergoing continued hypoxia?

worsening ATP depletions Further deterioration: cytoskeleton disperses, myelin figures from cell membrane degradation (myelin figures), mitochondria swells, ER dilates, entire cell swells

How will lipofuschin appear

yellow-brown, finely granular cytoplasmic, often perinuclear pigment