Ch. 1 Inflammatory Response Flashcards
What are the macroscopic signs of acute infllamtion
rubor
calor
dolor
tumor
What induces vasoconstriction immediately upon injury
catecholamines
serotonin
bradykinin
prostaglandins
all released from local tissues
what induces vasodilation
what induces vasodilation
vascular smooth muscle changes that are mediated by nitric oxide, histamine, leukotrienes, prostaglandins, and complement factors
how is permeability of vasodilation mediated?
histamine and serotonin mediate an increase in the number and size of intracellular endothelial gaps in the venules called transcytoplasmic channels or vesiculovacuolar organelles
Interendothelial gaps also form
Why does edema occur in early inflammation
increased permeability = serum protein loss = decreased intravascular osmotic pressure and increased blood viscosity –> inreases in hydrostatic pressure means edema fluid accumulation
Edema is advantageous because it facilitates delivery of antibodies and acute phase proteins to the site of inflammation
What is Sialyl Lewis X complex
weak transient interactions between selectins (glycoprotein cell adhesion molecules on endothelial cells) and ligands their leukocytes occur
Sialyl Lewis X is one with a carbohydrate ligand
What are the three most commonly described endothelial selectins?
E, P, and L selectins
What are integrins
proteins on the leukocytes that have alpha (CD11a, CD11b, CD11c) and beta (CD18) subunits that bind to corresponding proteins on the endothelium
What does Integrin ligand ICAM-1 interact with
interacts with integrins called lymphocyte associated antigen 1 (LFA-1 which is also CD11a/CD18) and macrophage antigen 1 (Mac 1 which is also known as CD11b/CD18)
How does diapedesis occur
- adhesion molecules like ICAM 1 is expressed more near interendothelial junctions and facilitate migration
- platelet endothelial cell adhesion molecules like PECAM 1 also facilitate leukocyte transendothelial migration and transmigration through the basement membrane
What are the four processes of acute vascular response
vasodilation
increased permeability
stasis
leukocyte extravasation
How do neutrophils kill bacteria
phagocytosis
release of superoxide radicals
formation of neutrophil extracellular traps
what are neutrophil extracellular traps
cell free DNA and other antimicrobial peptides including histones ensure a local high concentration of granule enzymes
WHat is azurophil
this is the primary neutrophil granule
contains microbicidal polypeptides such as myeloperoxidase, defensins, lysosome hydrolases, neutral proteases
what are examples of secondary neutrophil granules
metalloproteases
what are examples of tertiary neutrophil granules
gelatinase
what are the primary cytokines released by neutrophils
Interleukin 1 alpha - IL-1a
Interleukin 1 beta - IL-1b
interleukin 6 - IL-6
tumor necrosis factor alpha - TNF a
How do neutrophils go from a resting state to primed
two stage process
within minutes of stimulation by bacterial products or cyto/chemokines, mobilization of tertiary granules and secretory vesicles increase neutrophil cell surface receptors
At the same time, new expression of receptors and cytokines are induced
This allows primed neutrophils to release reactive oxygen species and other inflammatory mediators as well as increase their life span
What chemical signals will macrophages respond to to cause extravasation
fibronectin elastin complment factors C3a and C5a thrombin PDGF TGF beta (transforming growth factor)
What is the main macrophage type in inflammatory conditions
monocyte derived macrophages (remember, macrophages either come from monocytes or they start as tissue resident marophages)
What is macrophage polarization
macrophages will assume two functional phenotypes: M1 or M2
Describe the characteristics of M1 macrophages
activated by infectious agents or proinflammatory cytokines like interferon gamma (IFN-y) or TNF alpha
Debride the affected site by phagocytosis
Secrete IL-1b, IL-6, TNF alpha, prostaglandins
secrete collagenases and elastases
Describe the characteristics of M2 macrophages
activated in response to ANTI inflammatory cytokines like IL4, IL13, IL10
aid in wound repair and healing by releasing PDGF and TGF beta
secrete collagenases and elastases
Toll like receptors, scavenger receptors, mannose receptors, c type lectin like domain containing receptors, peptidoglycan recognition receptors and nucleotide binding site leucine rich repeat receptors are all part of what group
pattern recognition receptors, many will bind to more than one alarm signal molecule
What does toll like receptor 4 (TLR4) respond to?
it is a major receptor for lipopolysaccharide, an endotoxin
in concert with receptor CD14, TLR4 will activate expression of numerous proinflammatory mediators and expression of more TLRs
Responds to the following PAMP/DAMP: lipopolysaccharide, mannan, heparan sulfate, heat shock protein 60
what is nuclear factor kappa B?
NF-κB is one of the main type 1 transmembrane proteins that alter gene expression to lead to more reactive oxygen species, NO, and eicosanoids. It is activated in a macrophage wtih TLR activation
The same cytokine may act at different receptors and the same receptor may accept multiple cytokines. This is a promiscuity in receptor affinity. What is the benefit?
ensures the maintenance of innate immune responses
What are PAMPs/DAMPs
pathogen associated molecular patterns or
danger associated molecular patterns
What DAMPs/PAMPs does TLR 2 respond to
toll like receptor 2 responds to:
- lipoproteins
- lipopolysaccharides
- heat shock protein 70
What is the archetypal neutrophil chemoattractant
the chemokine IL 8 which is also known as CXCL 8
will attract neutrophils but also upregulates surface adhesion molecules, triggers degranulation of proteases, increases the production of other inflammatory mediators
How does interleukin 10 act as an anti inflammatory cytokine
- inhibits NF-κB which decreases response to TNFa, IL1, IL6, IL8
- degrades mRNA
- downregulates Th-1 helper t cell cytokine production
- promotes shedding of TNF receptors
- inhibits antigen presentation
IL 10 is mostly produced by CD4 Th-2 helper cells, monocytes, and B cells
What is the cell origin and physiologic action of PGE2
many cell types produce it
causes hyperalgesia, potent pyrogenic agent, vasodilation, increases proresolution molecules
What is the cell origin and physiologic action of PGD2
Produced by mast cells and causes vasodilation, chemoattractant, increases proresolution molecules, and causes bronchoconstriction
What is the cell origin and physiologic action of PGF2alpha
produced by endometrial cells and stimulates uterine contraction, bronchoconstriction, and vasodilation
what is the cell origin of PGI2 (prostacyclin) and physiologic action
produced by endothelial cells and causes vasodilation, inhibits platelet aggregation, and causes hyperalgesia
What is the cell origin of TxA2 (thromboxane) and its physiologic action
released by platelets and macrophages and causes platelet aggregation and vasoconstriction
How do proresolution eicosanoids act?
halt neutrophil infiltration
activate macrophage phagocytosis
increase clearance of phagocyts
stimulate expression of molecules involved in anti microbial defense like the lipoxins
What is lipoxin
- a molecule involved in antimicrobial defense
- produced by a transcellular biosynthetic mechanism requiring cell to cell interactions to metabolize arachidonic acid
- Aspirin actually increases the production of some lipozins
- lipoxins block secretion of TNFa from T cells
- inhibit leukotriene induced neutrophil chemotaxis by blocking Beta 2 integrin mediated cell adhesion and decreasing P selectin expression -
How are fish oils anti inflammatory
contain eicosapentaenoic and docosahexaenoic acid which are the precursors for resolvins and protectins (two proresolution mediators) and those then bind to g protein coupled receptors on leukocytes
Eicosapentaenoic acid is also a competitive inhibitor to arachidonic acid
What are the functions of platelet activating factor
- stimulates arachidonic acid release by binding to g protein coupled receptors
- increases affitiny and avidity of surface integrins
- increases platelet aggregation and degranulation
- increases eosinphil degranulation
- increases reactive oxygen species production
- increases vascular permeability, bronchoconstriction, pulmonary vasoconstriction
What degrades platelet activating factor
platelet activating factor acetylhydrolase
What is frustrated phagocytosis
a phagocyte fails to engulf its target and releases damaging agents
What is redox signalling?
non phagocytic cells produce H2O2 in the wound bed and that promotes keratinocyte migration and proliferation
What does carbon monoxide do in the inflammatory process?
has antiinflammatory effects that impair the production, differentiation, and activation of inflammatory cells
WHat is the role of IL 12
serum amyloid A increases IL 12 production which is needed for Th1 cell antimicrobial response
What is the role of IL 23
increased in response to serum amyloid A, will play a role in chronic and autoimmune inflammation in monocytes
How is the classical complement pathway activated?
immune complexes activate the classical pathway
how is the lectin complement pathway activated
Via interaction of hepatically synthesized lectin proteins with surface carbohydrates on pathogens
How is the alternative complement pathway activated
contact with foreign microbes
All three pathways of the complement factors converge to cleave C3 to C3a and C3b, what happens to C3b?
C3b will bind to either classical C3 convertase (C4bC2a) or alternative C3 convertase (C3bBb)
What do classical C3 convertase (C4bC2a) and alternative C3 convertase (C3bBb) do?
Cleave C5 to C5a and C5b
What is C5b’s role in the complement cascade?
Binds to C6, C7, zc8, and C9 in the terminal complement pathway to make the membrane attack complex
What does the membrane attack complex do?
inserts into the lipid bilayer of target cell membranes and creates channels, leading to dysregulation of cellular homeostasis and eventual lysis
This will destroy intracellular pathogens but it will also lead to tissue destruction
What do C3a, C4a, and C5a have in common
they are anaphylatoxins that are cleavage products on the complement cascade
they enhance leukocyte chemotaxis, inflammation and oxygen free radicals
Which complement cleavage product is an activator of eosinophils and mast cells and suppresses the release of IL 6 and TNFa from B cells to decrease the antibody response
C3a
What are opsonins?
phagocytosis by monocytes and neutrophils is enhanced with opsonins
the C opsonins coat target cells and allow for direct interaction and ingestion by phagocytes
What are bradykinin 2 receptors known for?
B2 receptors are ubiquitously and constitutively expressed in healthy tissue
What are bradykinin 1 receptors known for?
B1 receptors are produced in pathologic conditions
Production may be influenced by NF-κB
What does bradykinin do?
- mediator of endothelial prostacyclin synthesis, superoxide formation, and tissue plasminogen activator release
- facilitates migration of polymorphonuclear leukocytes and stimulates cytokine synthesis
- stimulates venous dilation through local NO releases, increases vascular permeability, produces pain response
- inactivated by kininase
What are some theories for the cause of multiple organ failure
- reperfusion mediated oxidative injury to the gut epithelium
- two-hit phenomenon - the initial event primes neutrophils and macrophages for an exaggerated response to subsequent events like secondary infection or prolonged hypotension
endotoxin tolerance
a cell exposed to endotoxin becomes unresponsive to subsequent stimulation
most commonly recognized in monocytes/macrophages possibly due to reprogramming to downregulate inflammatory genes
What is cross tolerance
exposure to another stimulus such as lipoteichoic acid from gram positive bacteria leaves the cell unresponsive to endotoxin
How are fibroblasts involved in chronic inflammation
Express CXCL8 (IL-8), CXCL12 (stromal cell derived factor or SDF-1), and CCL2 (monocyte chemoattractant protein MCP-1) Express CD40 receptor which engages with T cells and promotes expression of IL-6 and COX 2 Differentiates into myofibroblasts and that increases extracellular matrix like collagen and that leads to tissue fibrosis and sometimes granulomatous inflammation
