Patho Exam 1

What are some key characteristics of neutrophils?

- 65% of all WBCs - First immune cell to respond to injury/infection - non-specific phagocytosis via PRR (bind to PAMPs); O2 dependent and independent pathways via intracellular lysosomes. - move to site of injury via chemotaxis/extravasation *** Pathogen opsonization via complement or Ab can increase the specificity of neutrophils phagocytosis b/c neutrophils have Ab and complement receptors. *** Neutrophils have difficulty recognizing viral pathogens unless opsonized

Innate immunity can be broken down into 3 main categories:

- Anatomical/physiological barriers - Phagocytosis - Acute inflammation

What is the difference between phagocytosis and endocytosis?

- Endocytosis occurs in almost every cell, it is non-specific and concentration dependent. Movement of small particles from the external environment into the cell. - Phagocytosis is specific/intentional ingestion of large particles from the external environment. It usually requires microfilaments and/or receptor interaction.

What are the 5 critical signs of acute inflammation?

- Erythema d/t increased blood flow - Heat d/t increased metabolic activity (and blood flow) - Swelling d/t fluid shift from other compartments of the body - Pain d/t chemical release at injured tissue stimulating C-fibers (pressure of edema can also be painful) - Loss of function

How do ice and capsaicin affect the inflammatory response?

- Ice can stop C-fiber neurons from firing, therefore stopping the release of substance P. - Capsaicin stops the release of substance P by depleting substance P from the C-fiber neuron.

Which leukocytes are agranulocytes?

- Monocytes (macrophages) - B cells - T cells (Th, Tc, Treg) - NK cells

What are some of the common sources of inflammatory mediators (cytokines) released during an inflammatory response?

- damaged endothelial cells - Immune cells (PMNs, MØ, mast cells) - Nerve cells

Humoral immunity requires ____________ lymphocytes.

B cells

The COX pathway can be further divided into COX-1 and COX-2 pathways. Which of these pathways is physiological and which is inducible?

COX-1 is physiological and COX-2 is inducible

What are effector cells?

Cells that destroy or play a role in destroying the antigen or cells infected by that antigen.

What is a stable cell?

Cells that may undergo mitosis with extra stimulation (ex. liver hepatocytes)

Where do classic NSAIDs work in the AA pathway? What is a potential side effect of these drugs?

Classic NSAIDs will block both the COX-1 and COX-2 pathways. This inhibits the physiologic COX-1 pathway and therefore can make a person more susceptible to developing gastric ulcers.

What system is important in both regeneration and repair mechanisms?

Clotting system; helps to stop bleeding, prevent spread of infection, and keeps inflammatory response localized/compartmentalized.

What is another name for oncotic pressure?

Colloid pressure

Where do corticosteroids act on the AA pathway? Are corticosteroid more or less potent that NSAIDs?

Corticosteroids block both the lipooxygenase and cyclooxygenase pathways therefore they are more potent than NSAIDs which only block the COX 1/2 pathways.

Hydrostatic pressure PUSHES/PULLS while oncotic pressure PUSHES/PULLS.

Hydrostatic pressure pushes. Oncotic pressure pulls.

Water is store in what 2 main fluid compartments of the body?

INTRAcellular EXTRAcellular

What is the difference between total vs partial necrosis?

In total necrosis ALL parenchymal cells are destroyed, only option is repair via scar tissue formation (ex. burns). In partial necroses there is a sufficient number of parenchymal cells remaining, therefore regeneration is possible for labile and stable cells (if connective tissue framework is still intact for stable cells).

What is the overall result of the vascular response?

Increase blood flow to injured site

During vasodilation there is a(n) INCREASE/DECREASE in blood flow, and a(n) INCREASE/DECREASE in blood velocity.

Increase in blood flow, decrease in velocity. Therefore more cells are being brought to the area, but they have more time to move out of the vasculature into the interstitial fluid.

Describe the vascular response:

Inflammatory mediators (cytokines) released at the time of injury lead to smooth muscle relaxation which opens the capillary sphincters and increases blood flow to the injured area. This occurs within minutes of initial injury.

This phase of tissue repair begins immediately with injury and involves the formation of granulation tissue.

Inflammatory phase

What cytokines do macrophages and lymphocytes secrete?

Interleukins and TNFa - Cause fever d/t affects on the hypothalamus and vasodilation.

Extracellular fluid can be further broken down into what 3 subgroups.

Interstitial, blood, transcellular

What happens to the excess fluid in the interstitial space that is not reabsorbed by the capillary?

It gets absorbed into the lymph system and returned to venous blood flow.

How would an ACE compression wrapping affect starling forces under inflammatory conditions?

It would affect the hydrostatic pressure gradient by increasing the pressure in the interstitial space, which would ideally decrease the amount of fluid that is pushed out of the capillary beds.

What is amplification as it pertains to innate immunity?

Non-specific, positive feedback mechanism that helps mount an immune response. No self/non-self differentiation, no memory. *** Described as a "stereotypical response" because it will be the same response every time ***

Free radicals are part of the O2 DEPENDENT/INDEPENDENT pathway. How do they function to cause destruction?

O2 DEPENDENT; unpaired electron with react with anything that can donate an electron.

What is a superoxide ion?

O2 that has been reduced (gained an e-) and is now highly reactive.

What did Elie Metchnikoff discover?

Observed ingestion (phagocytosis) of fungal spores by leukocytes. Also observed that phagocytosis seemed to be more active in immunized animals than un-immunized. ***started the theory of cell-mediated immunity***

What is another way to refer to neutrophils?

PMNs; polymorphonuclear cells

Define acquired (adaptive) immunity.

Part of the immune system that develops after birth. It is highly specific and is capable of forming pathogen memory.

What is innate immunity?

Part of the immune system you are born with, provided non-specific protection against pathogens.

Where are the complement proteins found in the body?

Plasma

Under inflammatory conditions, what happens to the endothelial barrier in the capillary beds?

Their permeability increases

In general, how can NSAIDS help reduce swelling under inflammatory conditions.

They can decrease vascular permeability and therefore help maintain the oncotic pressure gradient across the capillary bed which will reduce fluid build up in the tissues.

TRUE/FLASE: COX-1 (physiologic) pathway is considered the "good" pathway and functions to protect mucosal linings of the GI tract, regulate renal blood flow, and regulate platelet function.

True.

TRUE/FLASE: Hydrogen peroxide (H2O2) is stable but can be be broken down to form either a hydroxyl radical or hypochlorite. Which of the two products is a powerful oxidant?

True; hypochlorite is a powerful oxidant

TRUE/FALSE: There would be histological differences between tissue in tendinitis and tendinosis.

True; neutrophils tend to be present in tendinITIS because it is due to ACUTE inflammation.

What is a labile cell?

cell that is constantly undergoing mitosis (ex. squamous cells in the mouth)

Fluid movement from vasculature to the interstitium is called:

filtration

Neutrophils, basophils and eosinophils are all:

granulocytes

Mast cells release _______________ which causes _______________ and _________________.

histamine; causes vasodilation and increase in vascular permeability

What cytokine do mast cells secrete?

histamines and serotonin; cause vasodilation and increased vascular permeability

What does the lipooxygenase pathway produce? What are the effects of this product?

leukotrines; promote increased microvascular permeability (also cause smooth muscle contraction and constriction of pulmonary airways)

Is the lipooxygenase pathway affected by NSAIDs?

no

Exudation is the movement of fluid out of the vasculature and into the tissues due to INCREASED vascular permeability and changes in ONCOTIC pressure. This can also be referred to as _________________________ edema.

permeability edema

Increased _________________ of capillaries and venules allows for cells to pass between the _________________ cell lining to the injured site.

permeability, endothelial

Macrophages and Neutrophils cells are examples of:

phagocytes

Neutrophils and macrophages are examples of ________________.

phagocytes

What is serum?

plasma minus cells, platelets, and clotting factors

All blood cells begin as undifferentiated ___________________.

pluripotent stem cells

Transudation is the movement of fluid out of the vasculature and into the surrounding tissues due to INCREASES in plasma HYDROSTATIC pressure. This can also be referred to as ______________________ edema.

pressure edema

What is the end result of the cycloogygenase (COX) pathway?

production of prostaglandins that induce vasodilation

What cytokine do neutrophils release?

proteases --> cause endothelial cell damage which leads to increased vascular permeability

Movement of fluid from the interstitium to the vasculature is called:

reabsorption

What did Emil von Behring and Shibasaburo Kitasto discover?

showed that serum (non-cellular) portion of blood transferred from an immunized to non-immunized animal also transferred the immune state. ***showed that there were more than just cells involved (AKA humoral immunity)***

Another name for ultrafiltrate is:

transudate

What cytokine do nerve cells release?

Substance P; causes vasodilation and vascular permeability by triggering histamine release from mast cells

Cell-mediated immunity requires ____________ lymphocytes.

T cells

TRUE/FALSE: RBCs can move into tissue spaces during the inflammatory response.

TRUE. Passive movement of RBCs occurs due to changes in vascular permeability. This is how bruising occurs.

What are some benefits of an acute inflammatory response?

Take advantage of the vascular system to bring immune cells to site of damaged tissue/infection.

What is the difference between tendinopathy, tendinitis, and tendinosis?

Tendinopathy = general term to describe injury to a tendon. Tendinitis = acute inflammation of a tendon Tendinosis = degenerative condition of tendon without evidence of acute inflammation. (also referred to as "chronic tendinitis")

Why is interstitial fluid under normal conditions considered an ultrafiltrate?

because no large proteins or cells can move through the endothelial gaps.

What factors can affect wound healing?

blood flow, oxygen levels, nutrients, NSAIDS and corticosteroid drugs

What are the 3 possible end results of acute inflammation?

1. Repair (scar tissue) 2. Regeneration (restoration of normal function) 3. Chronic inflammation (delayed healing, no regeneration or repair)

What are the benefits of vasodilation and increased vascular permeability in inflammation?

- dilute the offending agent/microbe. - wash out offending agent and expose it to lymph nodes where cells of adaptive immunity are present. - flood injured area with defense proteins and cells (ex. complement, phagocytes) - bring oxygen and nutrients to help repair damaged tissue

What are some key characteristics of eosinophils?

- phagocytic - play a role in secretion - granulocyte

What are some key characteristics of basophils?

- secrete substances that act on other cells - granulocyte

What is the time course of extravasation for neutrophils, macrophages, and lymphocytes?

0-24 hours: neutrophils dominate 3hr-weeks: Monocytes (macrophages) move in and peak around 48hr. Lymphocytes are seen at greatest concentrations after 48 hours.

What are the two pathways for breakdown of AA?

1. Cyclooygenase (COX) pathway 2. Lipooxygenase pathway

Complement plays a role in both innate and adaptive immunity. What are the 3 major functions of complement proteins?

1. Direct cell lysis via MAC 2. Opsonization to enhance phagocytosis 3. Regulate the inflammatory response by promoting chemotaxis and vasodilation

What are the 3 phases of tissue repair?

1. Inflammatory phase 2. Proliferative phase 3. Remodeling phase

What are the three stages of extravasation? Describe each step.

1. Margination: leukocytes move to the sides of the blood vessels near the endothelial walls. 2. Pavementation: leukocytes and endothelial cells adhere to one another via cell adhesion molecules (CAMs). 3. Emigration: leukocytes move through the gaps in between endothelial cells out into the tissue. (towards site of injury via chemotaxis)

Describe the process of phagocytosis:

1. Phagocytes bind to foreign/damaged tissue via pseudopodia and membrane receptor interactions. 2. Phagocytic cell engulfs the foreign/damaged tissue creating a membrane-bound vacuole called a "phagosome". 3. Once inside the cell the phagosome fuses with a lysosome creating a "phagolysosome". 4. Lysosome releases into contents into the phagolysosome to destroy the foreign/damaged tissue.

What are the three main mechanisms of cell injury?

1. Physical injury 2. Free radical injury 3. Hypoxic injury

What pressure system does the change in endothelial lining permeability affect? Why?

Affects the oncotic pressure systems because albumin proteins leak out into the interstitial space--lose the concentration gradient across the vessel lining.

What is the main protein found in the blood? What role does it play in Starling Forces?

Albumin. Generates ONCOTIC pressure in the blood.

Skin and mucous membranes are examples of what type of barrier?

Anatomical barriers

What is an antigen?

Any structure recognized as foreign by the immune system that elicits an immune response.

What is arachidonic acid (AA) and what role does it play in the inflammatory response?

Arachidonic acid is a fatty acid found in all cell membranes that is released when cell membranes are damaged. It can be broken down via 2 different pathways to produce either prostaglandins or leukotrines which ultimately play a role in vasodilation and vascular permeability.

Damaged cells (most commonly damaged endothelium cells) secrete what cytokine?

Arachidonic acid metabolites

What are some examples of physical cell injury?

Burns, frostbite, mechanical stress/trauma

What are the two methods of vasodilation stimulated by inflammatory mediators/cytokines?

Direct: Cytokines act directly on local smooth muscle. Indirect: Cytokines act on local nerve endings (ex. C-fibers) which cause a reflex arc in the CNS ultimately stimulating autonomic efferents which will affect smooth muscle and cause vasodilation.

What is found inside a lysosome?

Enzymes (ex. proteases) and reactive oxygen species (ex. free radicals)

What was Edward Jenner's role in the development of immunology? (late 1700s)

Experimented with cowpox lesions as a "vaccine" for smallpox. Observed that milkmaids that were exposed to cowpox did not contract smallpox.

Explain Louis Pasteur's role in the development of immunology? (late 19th and 20th centuries)

Experiments with cholera bacteria and anthrax. Used old cholera as a form of immunization against fresh batch of cholera in chickens. Used attenuated (heat treated) form of anthrax as a vaccination in sheep. Ultimately extended these findings to other diseases like polio and rabies.

TRUE/FALSE: The lymph system can always accommodate for the excess fluid build up in the interstitial space under inflammatory conditions.

FALSE, this is how we develop swelling In the tissues.

TRUE/FLASE: Innate and acquired immunity do not happen simultaneously.

False, innate and acquired immunity can occur simultaneously.

TRUE/FALSE: Inflammation is never harmful.

False, key example would be anaphylaxis.

TRUE/FALSE: Enzymes need oxygen to function, therefore they would be considered part of the oxygen dependent pathway.

False. Enzymes DO NOT need oxygen to destroy foreign or damaged tissue and are therefore part of the O2 INDEPENDENT pathway.

COX-2 (inducible) pathway is considered the "bad" pathway and leads to:

Fever and inflammation

In a normal capillary, ___________________ is favored at the arterial end, and __________________ is favored at the venous end.

Filtration is favored at the arterial end. Reabsorption is favored at the venous end.

Under inflammatory conditions, is filtration or reabsorption favored at the venous end of the capillary? What is the result?

Filtration is favored, therefore there is a build up of fluid in the interstitial space.

Leukocytes can be broken down into two major classes:

Granulocytes and agranulocytes

How do free radicals cause cell injury?

Highly reactive chemical species with an unpaired electron in outer orbit will react non-specifically with cellular molecules such as proteins, fats, carbohydrates to damage cell membranes, DNA and enzymes. (ex. H2O2, superoxide)

Where are kinins found in the body and what is their role in the inflammatory response?

Kinins are found in the plasma (same as complement) and help amplify the inflammatory response by: - promoting vasodilation and increase in vascular permeability - stimulate C-fibers (pain fibers) to release substance P

Which cell types are more likely to regenerate? Which cells types are more likely to be repaired via scar tissue formation?

Labile and stable cells are more likely to regenerate. Damage to permanent cells often results in scar tissue formation.

What is inflammation?

Localized response to injury/infection where the affected part of the body becomes red, swollen, hot and often painful in effort to get rid of the pathogen and necrotic (damaged) tissue

What is an exudate?

Material that has escaped from blood vessels during the inflammatory process, can include cells, protein, and debris from infection.

When a B or T cell is activated they proliferate and differentiate into what two cell types?

Memory and effector cells

Where do blood cells mature?

Most cells mature in the bone marrow, T cells mature in the thymus.

What is chemotaxis?

Movement of cells to a site of injury due to a chemical concentration gradient created by chemicals released by cells in the area.

Are macrophages considered PMNs?

NO

How is substance P released and what are its effects on the inflammatory response?

Nerve fibers (C-fibers) are stimulated by cytokines released at site of injury. This causes an "axon reflex" and secretion of substance P from nearby neural dendrites. Substance P is a neuropeptide and causes vasodilation, increased permeability and stimulates mast cells to release histamine (which also increased vasodilation and vascular permeability).

Newer brands of NSAIDs work to block only one of the COX pathways. Which pathway do they block and why might this be beneficial?

Newer NSAIDs only block the COX-2 pathway which ideally would help protect the gastric lining.

Under normal conditions, can albumin move across the endothelial capillary barrier?

No, therefore under normal conditions oncotic pressure stays constant across arterial and venous ends of the capillary.

What are permanent cells?

Static cell population that does not undergo mitosis (ex. neurons). Typically replaced with scar tissue.

What is the difference between a pressure edema and a permeability edema?

Pressure edema is caused by change in HYDROSTATIC pressure, causing more fluid to be pushed out into the interstitial space. - Ex: Right heart failure causes fluid backup in the liver, ultimately leading to fluid being pushed out into the abdominal cavity). Permeability edema is caused by change in ONCOTIC pressure due to changes in vessel permeability and movement of cells and proteins into the interstitial fluid. - Ex: bacterial infection in the abdomen lead to cytokine secretion which will increase vessel permeability and ultimately draw fluid into the interstitial space of the abdominal cavity).

What generates hydrostatic pressure?

Pressure gradient between capillary and interstitial fluid is generated by BP from the heart contracting during systole.

This phase occurs 2-20 days following the injury and involves the emigration of fibroblasts and replacement of granulation tissue with collagen.

Proliferative phase

Describe a hypoxic injury.

Reduction of O2 to a cell --> change from aerobic to anaerobic respiration --> decrease in ATP production and decrease in cell pH ultimately affecting chemical reactions, protein function and can damage DNA. Affects cell transport channels --> cell swelling.

What is the difference between regeneration and repair?

Regeneration restores normal function to the cell/tissue. Repair replaces damaged cells/tissue with scar tissue via fibroblasts.

This phase begins around day 10 after injury and can last up to several months. During this phase scar tissue matures and becomes stiffer/less compliant than surrounding tissue.

Remodeling phase

What is thought to be the cause of chronic inflammation?

Repeated bouts of inflammation or prolonged immune response

What is the function of memory cells?

Reside in LNs and other tissues for months--years to provide memory of a specific antigen to provide a FASTER and STRONGER response to a subsequent exposure. *** Reason why vaccines work! ***

What are pathogen associated molecular patterns (PAMPs)?

Sequence of molecules commonly found on pathogens that can be recognized by the pattern recognition receptors (PRRs) on phagocytic cells.

What is a parenchymal cell?

The functional cell of any tissue or organ

What is extravasation? What is the driving force behind extravasation?

The process of moving cells from one vascular compartment to another. - Ex: mobilizing immune cells from other tissues and moving them to the site of injury. - Occurs via chemotaxis

The functional response of inflammation includes the _______________ response and the _________________ response.

Vascular response and cellular response.

Smooth muscle of the arterioles is controlled by the SYMPATHETIC nervous system, therefore in order to cause relaxation and vasodilation you would need sympathetic stimulation/withdrawal.

Withdrawal

What is an antigen?

a toxin or other foreign substance that induces an immune response in the body, especially the production of antibodies.

Describe the vascular response:

minutes

As scar tissue matures it become MORE/LESS elastic and MORE/LESS compliant.

more elastic, less compliant (AKA "stiffer")

What are a few examples of physiological barriers?

pH, temperature, O2, tension

Approximately how many pattern recognition receptors are there on phagocytic cells of the innate immune response?

~1000; example of innate immunity's limited specificity. (Compare to 10^10s possible combinations for the B and T cell receptors of adaptive immunity)