FPP MSS First Exam (Midterm)

Neutrophils

"Polys"= polymorphonuclear leukocytes (PMNs) some pink cytoplasm variably shaped nucleus usually forms three lobes From hematopoietic stem cells in the marrow Life span= 1-2 days Rapid and short lived response to stimuli

Apoptosis

"controlled" mitochondrial dysfunction cells activate enzymes that degrade DNA and proteins plasma membrane is intact no leakage of cell contents fragments of cell are "pinched" off = APOPTOTIC BODIES" no inflammation cell fragments are consumed by macrophages Physiological or Pathological Apoptosis

Physiological Causes of Apoptosis

1. During EMBRYOGENESIS 2. involution of HORMONE DEPENDENT TISSUE after hormone deprivation (ex: breast in pregnancy) 3. Turnover of PROLIFERATIVE tissues (ex: GI epithelium) 4. death of LEUKOCYTES (neutrophils, lymphocytes after completion of inflammatory response) after completion of INFLAMMATORY RESPONSE 5. elimination of self-reactive lymphocytes

Pathological Causes of Apoptosis

1. ELIMINATES CELLS WITH DNA DAMAGE (ex- secondary to radiation, chemo etc) - if repair fails--> apoptosis activated and cells die - radiation/chemo drugs work via apoptosis 2. Accumulation of misfiled proteins (Alzheimers) 3. Cell injury induced by viral infections (ex. HIV) induced by the virus or the host

Nuclear changes associated with Cell Necrosis

1. pyknosis (shrinkage and increased basophilia) 2. karyorrhexis (fragmentation of pyknotic nucleus) 3. karyolysis (nuclear basophilia disappears due to digestion (DNASE)

Microscopic Morphology Evaluation Characteristics

1. type of cells present 2. cellularity (high or low compared to normal) 3. architectural pattern (normal or altered) 4. necrosis and mitosis? (present or absent?

Lymphocytes

19-53% mononuclear cell one lobed nucleus amplify and propagate chronic inflammation T and B lymphocytes migrate to site Plasma cells: from activated B - immunoglobulin production against persistent antigens bidirectional interactions with macrophages - subset of helper T cells elicit specific types of Inflammation

Methods of disease classification

Based on: 1. Etiology (genetic/infectious/iatrogenic/nutritional/toxic(or chemical)/physical 2. pathogenetic mechanisms 3. Organ systems affected

Factors affecting cell injury and death

Cell response depends upon: 1. cause of injury 2. duration/severity of insult Outcome depends upon: 1. cell type 2. nutritional/hormonal status (abundant glycogen- last longer) 3. genetic makeup--> metabolism/cytochrome P450 system

56-year-old man who died after a 24-hour hospitalization for severe "crushing" chest pain complicated by hypotension and pulmonary edema. The type of necrosis shown is best described as:

Coagulative necrosis! MI- ischemic attack notice the intact outlines

Death Receptor Pathway

Extrinsic Apoptosis Pathway Cells expressing Fas ligand or TNF bind to cell surface of "death receptors" and trigger caspase activation

Light Microscopy

FROZEN SECTIONS= performed while patient is in surgery under anesthesia to determine: 1. preliminary diagnosis (can guide surgery) 2. margins of resection 3. tissue is frozen/firm= thin sections may be removed "PERMANENT SECTIONS"= prepared after tissue fixation and processing when tissues is embedded in wax (paraffin) that allows thin sections hematoxylin & eosin (H&E) staining

What is an accurate descriptions of the morphologic changes of REVERSIBLE cell injury?

Fatty change and vacuolar degeneration

Bone Marrow

Generative Immune Organ almost everything comes out of here - hematopoietic progenitor, lymphocyte development B cells are educated/matured into naive B cells here too

Thymus

Generative Immune Organ where T cells are educated

Causes of Cell Injury

Hypoxia Ischemia Toxins Infectious Agents Immunologic Reactions (autoimmune/allergies) Genetic Derangements Nutritional Imbalances Physical Agents Aging

Coagulative Necrosis

Hypoxia/anoxia due to ischemia (infarct) persistence of dead cells with INTACT OUTLINE but LOSS of CELLULAR DETAIL -injury denatures both cellular proteins and enzymes but no proteolysis occurs all solid organs EXCEPT the brain

Liquefactive Necrosis

INFLAMMATORY Processes- stimulates leukocytes Complete digestion of dead cells- tissue is semi-piqued as it has been dissolved by HYDROLYTIC ENZYMES (from lysosomes in WBCs) commonly seen in bacterial and fungal infections microbes stim WBC accumulation--> WBC release digestive enzymes Necrotic cells+ Acute inflammatory cells= PUS soft to touch! (yellow and raised) abscesses

Innate Immunity

INHERENT protection against organisms that are permanent from birth response immediately- primary response - does not require previous exposure PRRs recognize PAMP on bacteria, virus, fungal, or parasitic pathogens (Toll-Like Receptors) 1. epithelial barriers 2. Phagocytic leukocytes: MACROPHAGES AND NEUTORPHILS 3. NATURAL KILLER CELLS 4. Dendritic Cells . 5. plasma proteins such as COMPLEMENT (alternative and lectin pathways) enhance phagocytosis or form membrane attack complex NO MEMORY

Elastic Lamina

In Arteries Only (adds thickness) internal between the intima and media external between media and adventitia VEINS DO NOT HAVE THIS

Fibrinoid Necrosis

In Vasculitis syndromes (polyarteritis nodosa, giant cell arteriis, etc) Deposition of immune complexes (antigens and antibodies) in vascular wall "fibrin-like" (OLD) = bright pink amorphous appearance Only in vessel walls

Macrophages

In tissue= histiocytes small peripheral nucleus with abundant FOAMY cytoplasm WBC that engulfs and digests cellular debris, foreign substances, microbes, etc circulating monocytes the become macrophage after TLR and IFN-y participate in acute inflammation and chronic inflammation - persist - steady release of dead cells, stimulated by activated T-cells, secrete products that result in continued tissue injury, stimulated by other cytokines to perform reparative function

Fat Necrosis

Injury to the PANCREAS or Fatty Tissue leads to release of LIPASE which liquifies fat and splits triglycerides fatty acids combine with calcium to form a white chalky material (saponification) "Smudgy purple" also in the breast

Mitochondrial Pathway

Intrinsic Apoptosis Pathway 1. BH3 sensors activated 2. Bak and Bax released (regulated by Bcl-2 and x) 3. Cytochrome C leaks from mitochondria 4. Activates Caspases

Hypoxic death of brain cells is usually characterized by which type of necrosis?

Liquefactive (we do not necessarily know why!)

Brain infarcts result in what kind of necrosis?

Liquefactive! inflammatory with complete digestion of dead cells later: mostly macrophages -- little debris leads to EMPTY SPACE do not know reason why

Peripheral Immune Organs

Lymph Nodes and Spleen MALT, GALT, SULT, Wandeyers ring

MHC

Major histocompatibility complex (I or II)

Barrett's esophagus and myositis ossificans are examples of?

Metaplasia Barrets= squamous--> Glandular epithelial Myositis ossifcans=mesenchymal

Irreversible Injury leads to?

Necrosis or Apoptosis

INNATE Specificity

PATTERN RECOGNITION RECEPTORs - LIMITED diversity - toll like receptors - complement proteins - recognize PMPS

Kate is now 57 and she has not had a menstrual period for 4 years. Shown below is what her endometrium would look like if it were to be biopsied. What is the illustrated process?

Physiologic Glandular atrophy

Gangrenous Necrosis

Severe Necrosis (Bowel, appendix, gallbladder) Type of Ischemic Coagulative Necrosis of upper and lower extremities When bacterial infection is also present, the necrosis has liquefactive characteristics= WET GANGRENE can be associated with a history of insulin dependent diabetes

Decreased Immunogenicity

Small (<2kD) high or low dose intravenous or intragastric (normal route) simple composition no or few bacteria adjuvants ineffective interaction of MHC complex

Reversible Cell Injury

Stage of cell injury at which the injured cell can return to normal if damaging stimulus is removed ex: failure of the membrane pumps to maintain homeostasis and accumulation of degenerated organelles and lipids--> Cell swelling (intracellular organelles take on water) results in enlargement of entire organ Microscopic: hydronic change/vacuolar degeneration in cells and fatty change

Morphology

Structural alterations induced in the organs or cells helps to discover and understand disease mechanism can be gross or microscopic Analyzed in biopsies and resections

Antigen

a molecule that binds to and is recognized by adaptive immune mediators (Antibody or TCR) RECOGNIZED BY A LYMPHOCYTE

Immunogen

a molecule that induces an immune response

Tolerogen

a molecule that induces immune UNRESPONSIVENESS to subsequent doses of the molecule ex: response to self antigens

Necrosis vs Apoptosis

a specific case of injury may trigger multiple and overlapping biochemical pathways that may be active simultaneously Mitochondrial dysfunction in both necrosis and apoptotic cell death defects in membrane permeability occur in NECROTIC CELL DEATH

Latent Toxins

activation results in toxic metabolite often by P450 oxidases in liver smooth ER examples: - acetaminophen (tylenol) - carbon tetrachloride converted to toxic free radical which breaks down ER Membranes necrotic cell death

Extrinsic

aka acquired discussing etiology Infectious Iatrogenic Nutritional Toxic Physical (trauma)

Immunohistochemistry

antibodies used to identify a specific epitopes (proteins) in tissues used for neoplasms a lot can help determine if something is a carcinoma too

ADAPTIVE Specificity

antigen receptors - T Cell Receptor (TCR)- protein peptide antigens - B Cell Receptors (BCR) --- recognize large complex molecules in their native state

Clearance of Apoptotic Cells

apoptotic cells express ligands for phagocyte cell receptors and secrete factors that attract phagocytes

Direct Toxins

cause necrotic cell death bind to cellular organelle or molecular component ex: mercuric chloride binds to cell membrane proteins - results in decreased membrane transport and increased membrane permeability

Etiology

cause- can be intrinsic, extrinsic or idiopathic

Oxidative Stress

cellular abnormalities induced by ROS generation of ROS increased with: absorption of radiant energy (UV, XR or light), selected exogenous toxins (carbon tetrachloride), and reperfusion of ischemic tissues

Adventitia

collagenous tissue that blends with the connective tissue surrounding the vessels Most external

Morphology of Cell Necrosis

cytoplasmic changes: - increased eosinophilia, homogenous cytoplasms and vacuolation Nuclear changes - pyknosis (shrinkage and increased basophilia) - karyorrhexis (fragmentation of pyknotic nucleus) - karyolysis (nuclear basophilia disappears due to digestion (DNASE) Dead cells - may be completely digested and disappear - debris may be phagocytes and further degraded - results in fatty acids that may calcify

Morphology of Apoptosis

cytoplasmic eosinophilia chromatin condensation and aggregation eventual karyohexis (fragmentation of nucleus and breakup of chromatin into granules) cell shrinkage with cytoplasmic blebs and apoptotic bodies phagocytosis without inflammation

Surgical Pathology

diagnostic biopsies (neoplasms) determines treatment

Intrinsic

discussing etiology genetic ex: cystic fibrosis, SCA, huntingtons

Capillaries

do not have media (middle) layer formed by endothelial cells

Adaptive Immunity

dynamic protection results from specific immune components CHANGING or adapting to unique features of the pathogen or foreign agent normally silent- activated to adapt and neutralize responds slowly at first MEMORY- faster response to subsequent exposure T-CELLS B-CELLS

Blood Vessels

each vessel has 3 layers: intima- endothelial cells and sub endothelial tissue (fibroconnective tissue) media- smooth muscle cells and connective tissue adventitia- collagenous tissue that blends with the connective tissue surrounding the vessels

Intima

endothelial cells and sub endothelial tissue (fibroconnective/elastic tissue) appears more as a black line most internal

Pleomorphism

enlarged, irregularly shaped nuclei

Idiopathic

etiology not determined yet ex: alzheimers

Molecular Pathology

evaluation and screening of cells for disease causing mutations or polymorphisms

Cytopathology

evaluation of cells removed from organ or fluid (needle) pap smears diagnosis

Active Immunity

exposure to a foreign antigen slow protection long duration--> memory lymphocytes flu shot

Karyorrhexis

fragments of nuclei in necrosis

Clinical Significance

functional derangements (symptoms) may be explained by understanding morphological changes/pathophysiology ex: CF thick lung secretion--> obstruction

A 65-year-old man comes to ER complaining of chest pain. He says it has been present for the past two hours. He is diagnosed with heart ischemia most likely due to a coronary artery occlusion. He is taken for angiography and possible stenting of coronary artery. At angiography, he is found to have a thrombus occluding his left main coronary artery. This is removed and a metallic stent is placed in the vessel (overlying/compressing the atherosclerotic plaque). An echocardiogram shows decreased movement of the anterior wall of the left ventricle and he is found to have elevated cardiac enzymes (troponins).

he has had a myocardial infarct because his heart muscle was ischemic for a prolonged time before the stenting occurred

What is a classic example of physiologic hyperplasia?

hormonal hyperplasia of female breast at puberty and in pregnancy and compensatory hyperplasia of liver after partial resection

Cytoplasmic changes associated with cell necrosis

increased eosinophilia homogenous cytoplasm vacuolation

Iatrogenic

induced by medical care hospital-acquired infections, errors/toxicity

Memory

innate: NONE adaptive: MEMORY T AND B CELLS

Increase immunogenicity

large intermediate dose (Goldie Locks= just right) sub Q or intraperitoneal (abnormal route complex composition bacterial adjuvants effective interaction of MHC complex

Pathology

logos= study pathos= suffering devoted study of the structural and functional alterations in cells, tissues and organs that underlie DISEASE essential for understanding and practice of medicine BRIDGES basic sciences and clinical sciences helps us UNDERSTAND The underlying mechanism of diseases and practice medicine

Caseous Necrosis

looks similar to coagulated cells associated with tuberculosis infections Gross appearance is crumbly (friable) resembling cheese Fragmented and coagulated cells with loss of tissue architecture (no cell outlines) Usually surrouneded by a border of inflammatory cells forming a distinctive pattern (granuloma)

Collagen

made up of fibrous tissues with fibroblasts

Necrosis

major pathway of cell death uncontrolled "accidental" - inevitable result of damage that is too severe to be repaired occurs in response to: - ischemia - toxin exposure - infection - trauma what happens: 1. membrane falls apart 2. enzymes leak out of lysosomes and cells 3. induces inflammation 4 cell is digested by the enzymes or recruited inflammatory cells (leukocytes) leads to mitochondrial dysfunction AND defects in membrane permeability (plasma and lysosomal membranes)

Chemical/Toxic Injury

many drugs are metabolized in the liver-- drug toxicity Necrotic Cell Death Direct: bind to cellular organelle or molecular component ex: mercuric chloride binds to cell membrane proteins--> decreased membrane transport and increased membrane permeability Latent: activation results in toxic metabolite- often by P450 oxidases in liver smooth ER ex: acetaminophen (tylenol), carbon tetrachloride converted to toxic free radical which breaks down ER Membranes

Pathogenesis

mechanism of disease development: Sequence of events that occur in cells or tissues in response to the injury by an etiologic agent Often dictates the appearance of signs and symptoms often must be understood to develop effective therapy

Live Attenuated Vaccine

micro-organism is modified to decrease pathogenicity limited growth after injection mainly induces CELLULAR RESPONSE (T CELLS) pros- strong and life long immunity cons- may revert to virulent form

Plasma Cells

mononuclear cells eccentric nucleus pale zone next to nucleus

Secondary immune response

more rapid and stronger response to subsequent exposure to substance

Clinical Pathology

multiple subsidiary sections all blood or fluid tests on a patient LABS

Karyolysis

nuclear basophilia disappears due to digestion by DNase

Hyperchromatic

nuclei with very dark chromatin

Hydronic Change

or vacuolar change cellular swelling first manifestation of many types of cell injury corresponds to distended endoplasmic reticulum; plasma membrane blebs, swollen mitochondria and clumped nuclear chromatin when it effects many cells in an organ- organ weight increases and appears swollen

Hypoxia

oxygen deficiency due to either inadequate oxygenation of blood (lung disease or lack of O2 in air) OR reduced oxygen-carrying capacity of blood (anemia) anaerobic glycolysis can continue 1. leads to reduced production and depletion of intracellular ATP -- reduction of activity for pm ATP-dependent Na+ pumps --> cell swelling -- increase anaerobic glycolysis leads to increase lactic acid and decreased pH--> decreased activity of intracellular enzymes --> disruption of protein synthesis apparatus --> ROS generation? --> eventual irreversible damage to mitochondria and lysosome membranes

Inactivated Vaccine

pathogen is inactivated (heat or chemical) but retains an immunologic epitope on surface mainly induces HUMORAL B CELL RESPONSE - T cell dependent (stronger) (ADD ADJUVANT) - T Cell independent (weaker) Pros- stable and safer than LIVE Cons- weaker immunity and requires booster vaccine

Fatty Change

primarily in cells dependent on fat metabolism usually causes yellow color and "greasiness" steatosis=fat accumulation hepatocytes are injured resulting in an intracellular accumulation of triglycerides, liver enlargements and elevated liver enzymes (leaked from injured hepatocytes) Common causes: toxins (alcohol) obesity, malnutrition, carbon tetrachloride, anoxia, diabetes, viruses can accumulate in heart, skeletal muscle, and kidney as well

Passive Immunity

receiving preformed antibody rapid protection short duration (T1/2 for Ab=3 weeks) maternal milk

Ischemia

reduced blood supply to a site reduces nutrient supply and build up of toxic metabolites more damaging than hypoxia injures tissue faster 1. no delivery of substrates for glycolysis (both aerobic and anaerobic glycolysis stop) 2. no removal of metabolites via blood flow most common cause of cell injury 1. leads to reduced production and depletion of intracellular ATP -- reduction of activity for pm ATP-dependent Na+ pumps --> cell swelling -> decreased activity of intracellular enzymes --> disruption of protein synthesis apparatus --> ROS generation? --> eventual irreversible damage to mitochondria and lysosome membranes

What is the fundamental biochemical abnormality in hypoxic cells that leads to cell injury?

reduced generation of ATP

Primary Immune Response

response to the initial exposure to the substance

Reperfusion injury

restoration of blood flow to ischemic tissue may increase cell injury occurs most frequently in brain and heart Mechanisms: - increased generation of ROS- incomplete reduction of oxygen with ischemia, restoration of oxygen allows production of ROS which increases tissue damage - increased leukoctyes plasma proteins and complement (inflammation)- production of adhesion molecules and cytokines by damaged tissue attract inflammatory cells that increase extent of injury

Pyknosis

shrinkage and increased basophilia

Media

smooth muscle cells and connective tissue

Adjuvant

something that activates the INNATE immune response

Anatomic Pathology

surgical or cytopathology and autopsy

Immunity

the state of being immune to or protected from an organism or foreign agent

Adaptation

to physiological or pathological stimuli/stress to maintain homeostasis

Parkinsons example

we understand the pathogenesis but not as much the etiology degeneration of substantial nigra (midbrain) --> decrease dopamine to basal ganglia--> extrapyramidal syndrome overall cause is not known (etiology) treatment here is based on pathogenesis