Inflammation Flashcards
What are the three functions of inflammation/
remove pathogenic insults
remove injured tissue
institute wound healing
What are the four cardial signs of inflammation
Erythema
Edema
Heat
Pain
What are the three major components of acute inflammation?
- Dilation of smal lblood vessels
- Inreased vascular permeability
- Accumulation/activation of leukocytes at the site in infection/injury
What are the four possible outcomes of inflammation?
- Resolution
- Abscess
- scarring
- chronic inflammation
What is chronic inflammation?
a prolonged response (weeks or months) in which inflammation, tissue injury and attempts at repair coexist.
What are the leukocytes that are at epithelial barriers?
macrophages
dendritic cells
mast cells
innate lymphoid cells
What are the mediators of vasodilation? (3)
Protaglandins
Nitric oxide
Histamine
What are the mediators of increased vascular permeability? (4)
Histamine
Bradykinin
Leukotrienes
PAF
What are the mediatiors of chemotaxis and leukocyte recruitment/activation? (3)
IL-1
TNF
Prostaglandins
What are the mediators of fever?
IL-1
TNF
Prostaglandins
What are the mediators of pain? (2)
Prostaglandins
Bradykinin
What are the mediators of tissue damage? (3)
Lysosomal enzymes of leukocytes
ROS
NO
What is the first step (in inflammation) that the macrophages/mast cells/dendritic cells/innate lymphoid cells take when the encounter an antigen?
Release inflammatory mediators
Mast cells are activated by C5a to produce what?
Histamine and prostaglandins
What is histamine? How is it released so quickly?
It is a vasoactive amine that is preformed and stored in mast cell granules, and therefore it is released immediately following mast cell activation
What is histamine the principle mediator of?
Vascular permeability
What do anti-histamines block?
H1 receptors located on mast cells which, when activated, would release histamine
What does histamine stimulate?
It stimulate the EC to synthesize NO, which cause vasodilation and subsequent increased blood flow
What are prostaglandins? What specific chemical are they produced from?
Lipid mediators (like PGD2) that are produced from arachiodonic acid
What produced prostaglandins?
Mast cells
What are the two effects of prostaglandins?
vasoilation (edema)
Pain
What is Hageman factor (factor XII) and what activates it?
A protein that leads to the activation of anaphylatoxins and the clotting cascade, including bradykinin
Injury to the basement membrane activates it
What is bradykinin?
It is an inflammatory mediator (specifically a vasoactive peptide) that is generated by a protease called kallikrein (which is activated by Hageman factor).
What is the effect of bradykinin?
It increases vascular permeability and causes contraction of smooth muscle, dilation of blood vessels, and pain (same thing as histamine)
What are the three major proinflammatory cytokines of acute inflammation?
TNFα
IL-1
IL-6
What activates TNFα, IL-1 and IL-6?
monocytes/macrophages/dendritic cells following activation with pathogen associated molecular patterns (PAMPS) that bind to PRR (pattern recognition receptors).
What is the effect of TNF, IL1, (and also histamine) on epithelial cells?
upregulate expression of adhesion molecules
What is the effect of the upregulation of adhesion molecules by TNF, IL1, and histamine?
Adhesion molecules act as stop signs for circulating leukocytes and allow them to slow down, roll, adhere and extravasate
What are the chemokines that promote leukocyte migration to the site of injury/infection?
C5a and C3a
How do chemokines lead leukocytes to were they need to go?
Complement cascade starts on the surface of microbe, and gradient is produced
What are the three major chemical that are released by lyososomes that are toxic to both microbe and host?
Lysosomal enzymes
ROS
NO
What are the first leukocytes to migrate out to the site of infection/injury? What is the time scale of this?
PMN (neutrophils) arrived within hours
How do neutrophils localize to the sites of injury?
Adhesion molecules expressed by epithelial cells cause rolling
What are the five steps of leukocyte extravasation?
- Rolling or tethering via selectins and selectin ligands
- Leukocyte activation via chemokines
- Tight adhesion via integrins and integrin ligands
- Transendothelial migration (mediated by PECAM and others)
- Migration along a chemokine gradient
What are addressins, and what are the three cell types that use them?
Cell adhesion molecules that direct either lymphocytes, monocytes, or neutrophils to extravasate
What is the chemical that causes neutrophil extravasation? How is it release so quickly?
P-selectin, which is stored in Weibel-Palade bodies
What does P-selectin bind to on the surface of neutrophils? When is this expressed?
P selection glycolipid 1 (PSGL-1), which is constitutively expressed by neutrophils
What is the effect of P-selectin/PSGL-1 binding?
Rolling and extravasation of neutrophils
Is the affinity between P-selectin and PSGL-1 high or low?
Low (relatively)
What is the next chemical to be upregulated on the surface of epithelial cells after neutrophils have bound to P-selectin? What does it do?
ICAM-1, which binds to LFA-1 o the surface of neutrophils
What state is LFA-1? What is the different between its active state and inactive state? What activates it?
LFA-1 is an integrin consisting of an α and β chain that is found in a low affinity state until the cell is activated by a chemokine such as C5a
What is the chemical interaction between epithelium and neutrophils that stop the rolling process?
ICAM-1 on epithelial surface
LFA-1 on neutrophil
Is the affinity between LFA and ICAM-1 high or low?
High
What is the chemical that is constitutively expressed by neutrophils and the tight junctions of epithelial cells? What does this do?
PECAM-1, which allows neutrophils to squeeze between epithelial cells and basement membrane
How are neutrophils influenced to migrate toward the site of inflammation?
By a gradient of chemotactic substances
What are the chemcials released by neutrophils that kill bacteria? What else do they do to bacteria?
ROS
Enzymes
They also phagocytose them
What is the cell type that replaced neutrophils/come in next? When does this occur?
Monocytes (macrophages), which come in 24-48 hours after infection
What are M1 and M2 macrophages?
M1-classically induced macrophages that produce proinflammatory ROS and NO
M2- produce anti-inflammatory cytokines (IL-10 and TGFβ)
What is the function of the TGFβ produced by M2 macrophages?
Initiate the process of wound healing by stimulating fibroblasts and collagen synthesis
What are the systemic effects of inflammation?
Fever
Neutrophilia
Acute phase response
Shock
What are the two routes by which a systemic infection may be initiated?
- Pathogen gains entry into blood
2. Inflammatory mediators released into blood
What are the chemicals that initiate the fever response? How do they exert their effects?
Pyrogens, which stimulate prostaglandin synthesis in the vascular and perivascular cells of the hypothalamus
What is the effect of upregulation of PGE2 by pyrogens and leukocytes on the hypothalamus?
Upregulate neurotransmitters, like cAMP, which will reset the temperature base point
What is the mechanism by which NSAIDs reduce fever?
Inhibit prostaglandin synthesis
What is neutrophilia?
Increased peripheral blood neutrophils that commonly accompanies acute inflammation
What are the two specific chemicals that bring about neutrophilia?
Proinflammatory cytokines IL-1 and TNF stimulate accelerated release of PMN’s from the bone marrow
What is the form of neutrophils that are released from granulocyte colony stimulating factor.
Band form
What are band cells?
Immature leukocytes
What is the acute phase response?
Increase in CRP and ESR due to the release of interleukin 6
What is interleukin-6, and what are its effects?
It is a chemical released by macrophages that acs on hepatocytes to synthesize and release acute phase proteins (like CRP)
What CRP and what are its effects?
C-reactive protein which acts as an opsonin to facilitate phagocytosis
What is the chemical that causes septic shock? How does this work?
TNF, which stimulates vasodilation and low heart output
Systemic activation of the coagulation system (“DIC”) resulting from systemic inflammation leads to what?
a cut-off of blood supply to organs and organ failure
