what three processes occur with endothelial injury?
exposed collagen; platelet-activating factor release; tissue factor release
what substance is released from the endothelium when platelets bind to collagen
PDGF (platelet-derived growth factor) is released
what cells are recruited by endothelial release of PDGF?
recruits PMNs and macrophages
What cell type has the dominant role in wound healing?
macrophages
what three substances are released by macrophages that causes its dominant role in wound healing?
growth factors (PDGF), cytokines (IL-1, TNF-alpha)
what two cell types are attracted by PDGF and what do they cause?
PDGF is chemotactic and activates inflammatory cells (PMNs and macrophages) and fibroblasts (causing collagen and ECM proteins)
what effect does PDGF have on blood vessels?
causes angiogenesis
what effect does PDGF have on epithelial cells?
causes epithelialization
what effect does PDGF have on smooth muscle cells?
chemotactic for smooth muscle cells
what effect does PDGF have on wound healing?
shown to accelerate wound healing
name three effects of epidermal growth factor (EGF)
chemotactic and activates fibroblasts (collagen and ECM proteins); angiogenesis; epithelialization
name three effects of fibroblastic growth factor (FGF)
chemotactic and activates fibroblasts (collagen and ECM proteins), angiogenesis, epithelialization
what type of molecule is platelet-activating factor?
its a phospholipid
where is platelet-activating factor generated?
it is generated by phospholipase in the endothelium
what is the effect of platelet-activating factor (2)?
chemotactic for inflammatory cells; increases adhesion molecules
name six chemotactic factors for inflammatory cells
PDGF, IL8, LTB4, C5a, C3a, PAF
name three chemotactic factors for fibroblasts
PDGF, EGF, FGF
name five angiogenesis factors
PDGF, EGF, FGF, IL8, hypoxia
name three epithelialization factors
PDGF, EGF, FGF
how long do PMNs last in tissues
PMNs last 1-2 days in tissue
how long do PMNs last in blood?
PMNs last 7 days in blood
How long do platelets last in blood?
last 7-10 days in blood
what type of lymphocyte is involved in chronic inflammation?
T-cells
what type of lymphocyte is involved in antibody production?
B cells
Which WBC is involved in type I hypersensitivity reaction
eosinophils
what type of receptors are on eosinophils and how does it affects its ability to take part in allergic reactions / type I hypersensitivity reactions?
IgE receptors that bind to allergen
what chemical is released by eosinophils and how does this stimulate the immune system?
eosinophils release major basic protein, which stimulates basophils and mast cells to release histamine
in what type of infection are eosinophils increased?
increased in parasitic infections
what is the major source of histamine in the blood?
basophils
are basophils present in tissue?
nope
what is the primary cell in type I hypersensitivity reactions?
mast cells
what is the major source of histamine in tissue?
mast cells
name three effects of histamine on tissues and capillaries (3)?
vasodilation, tissue edema, postcapillary leakage
what is the primary effector in type I hypersensitivity reactions?
histamine
Name four systemic effects of bradykinin
peripheral vasodilation, increased permeability, pain, pulmonary vasoconstriction
what is the function of angiotensin-converting enzyme and where is it located?
ACE inactivates bradykinin and is located in the lungs
what is the amino acid precursor for nitric oxide?
arginine
what is the enzyme that catalyzes the synthesis of nitric oxide and what is its substrate?
nitric oxide synthase converts arginine to nitric oxide
name the two reactions that occur in the endothelium that causes nitric oxide to vasodilate
NO activates guanylate cyclase, increases cGMP, resulting in vascular smooth muscle dilation
what is an alternative name for nitric oxide?
endothelium-derived relaxing factor
how does endothelin affect the vascular system?
causes vascular smooth muscle constriction (opposite effect of nitric oxide)
name the two main initial cytokine response to injury and infection
TNF alpha and IL-1
what cell is the largest producer of TNF-alpha
macrophages
what is the effect of TNF alpha on adhesion molecules?
increases adhesion molecules
what is the effect of TNF-alpha on coagulation?
procoagulant
what is the effect of TNF-alpha on cancer patients?
causes cachexia in patients with cancer
what is the effect of TNF alpha on other WBCs?
activates neutrophils and macrophages –> more cytokine production and cell recruitment
name two systemic effects of high levels of TNF-alpha?
causes circulatory collapse and multisystem organ failure
what is the major source of IL-1?
macrophages
what does IL-1 synergize with?
synergizes with TNF-alpha
what are the effects of IL-1? (3)
similar to TNF-alpha: increased adhesion molecules, procoagulant, activates neutrophils and macrophages
which interleukin causes fever?
IL-1
how does IL-1 cause fever?
mediated by PGE2 in the hypothalamus by raising the thermal set point
What is the MOA of antipyretic NSAIDs?
reduces PGE2 synthesis, which is responsible for increasing the thermal set point in the hypothalamus
What is the MOA of fever with atelectasis?
alveolar macrophages cause fever with atelectasis by releasing IL-1
what proteins are stimulated for release by IL-6 (2)?
IL-6 stimulates increased hepatic acute phase proteins (C-reactive protein and amyloid A)
what cell type releases interferons and why?
released by lymphocytes in response to viral infection
what are the three cell types activated by interferons?
activates macrophages, natural killer cells, and cytotoxic T-cells
how do interferons affect viruses?
inhibits viral replication
what is the most potent stimulus for hepatic acute phase response proteins?
IL6
what is the function of C-reactive protein?
opsonin, activates complement
name 7 hepatic acute phase response proteins that are increased with IL6
CRP, amyloid A, amyloid P, fibrinogen, haptoglobin, ceruloplasmin, alpha-1 antitrypsin, C3 (complement)
name 3 hepatic acute phase response proteins that are decreased with IL6
albumin, pre-albumin, transferrin
where are L-selectins located?
located on leukocytes
where are E-selectins located?
endothelium
where are P-selectins located?
platelets
how do L-selectins, E-selectins, and P-selectins interact to allow for rolling adhesion
L-selectins on leukocytes bind to E-selectins on endothelium and P-selectins on platelets, causing rolling adhesion
where are beta-2 integrins located?
on leukocytes
what is the function of beta-2 integrins?
bind ICAMs and function in anchoring adhesion
where are ICAM, VCAM, PECAM, and ELAM located?
on endothelial cells
what is the function of ICAM, VCAM, PECAM, and ELAM? (2)
bind to beta-2 integrin molecules located on leukocytes and platelets. Also involved in transendothelial migration.
**PHOTO** describe the four steps of leukocyte recruitment
1) circulating leukocytes express integrins in low-affinity conformation; 2) exposure to activated endothelium leads to rolling mediated by L-selecting/P-selectin on neutrophils and E-selectin on endothelium; 3) leukocyte exposure to cytokines released by macrophages phagocytosing pathogens induces high-affinity integrin conformation –> tight lieukocyte-nedothelial adhesion withintegrin; 4) exposure to chemokines leads to diapedesis mediated by beta1 and beta2 integrins
what are the three complement factors are present only in the classic pathway?
C1, C2, C4
how is the classic complement pathway activated?
IgG or IgM with antigen-antibody complex activation
what are the two stimuli for the alternative complement pathway
endotoxin or bacteria
what are three factors only found in the alternate complement pathway?
factors B, D, and P (properdin)
what is the complement factor that is common to both classic and alternative pathways and functions as its convergence point?
C3
what chemical is required for both classic and alternative complement pathways?
Magnesium
name three complement anaphylatoxins
C3a, C4a, C5a
what are the four systemic effects of complement anaphylatoxins
C3a, C4a, C5a –> increased vascular permeability, bronchoconstriction, activate mast cells, basophils
what complement factors create the membrane attack complex?
C5b-9b
what is the function of the membrane attack complex created by complement?
cell lysis (usually bacteria) by creating a hole in cell membrane
define opsonization
targets antigen for immune response
name two complement factors that act as opsonins
C3b and C4b
name two complement factors that cause chemotaxis for inflammatory cells
C3a and C5a
what is the precursor for prostaglandins
produced from arachidonic precurosrs
name four systemic effects of PGI2
vasodilation, increased vascular permeability, bronchodilation, inhibit platelets
name four systemic effects of PGE2
vasodilation, increased vascular permeability, bronchodilation, inhibit platelets
what is the MOA of NSAIDs anti-inflammatory action?
reversible COX (cyclooxygenase) inhibitor
what is the MOA of aspirin’s anti-inflammatory action
irreversible COX (cyclooxygenase) inhibitor
what is the MOA of platelet inhibition by aspirin?
inhibits platelet adhesion by decreasing TXA2
what is the MOA of steroids’ anti-inflammatory action?
inhibit phospholipase (converts phospholipids to arachidonic acid) –> inhibits inflammation
what is the precursor for leukotrienes?
produced from arachidonic precurosrs
what are the systemic effects of LTC4, LTD4, and LTE4 (leukotrienes) (2)
slow-reacting substances of anaphylaxis; bronchoconstriction, vasoconstriction followed by increased permeability (wheal and flare)
what is the effect of LTB4 (leukotriene)
chemotactic for inflammatory cells
when do catecholamines peak after injury?
peak 24-48 hours after injury
where is norepinephrine released from?
released from sympathetic postganglionic neurons
where are epinephrine and norepinephrine released from?
released from adrenal medulla (neural response to injury)
describe the pathophysiology of the neuroendocrine response to injury (6 hormones)
afferent nerves from site of injury –> stimulate CRF (corticotropin releasing factor), ACTH, ADH, growth hormone, epinephrine, and norepinephrine release
what role do thyroid hormones play in injury/inflammation
no major role in injury or inflammation
what is the role of CXC chemokines in inflammation (3)
chemotaxis, angiogenesis, wound healing
name two CXC chemokines
IL8, platelet factor 4
what does the “C” in CXC chemokines stand for?
cysteine
what does the “X” in CXC chemokines stand for?
another amino acid
what process results in oxidant generation?
inflammation (from main producer oxidase)
what enzyme produces the superoxide anion radical (O2-)
NADPH oxidase
what enzyme produces hydrogen peroxide (H2O2)?
xanthine oxidase
what is the cellular defense against superoxide anion radicals?
superoxide dismutase converts it to hydrogen peroxide
what enzyme protects against hydrogen peroxide
glutathione peroxidase / catalse
what cells are the primary mediator of reperfusion injury?
PMNs
what is the pathophysiology of chronic granulomatous disease?
NADPH-oxidase system enzyme defect in PMNs results in reduced superoxide radical formation