Inflammatory Mediators Flashcards
effect of histamine release
dilation of arterioles and increased permeability of venules by producing interendothelial gaps due to retraction of endothelial cell
how is histamine mediated?
binding to H1 receptors on microvascular endothelial cells
what does production of histamine induce
induces synthesis of prostacyclin and nitric oxide (smooth muscle relaxants and vasodilation)
what are things that stimulate release of histamine from mast cells
trauma, cold, heat, binding of Ab to mast cell, C3a and C5a, IL-1, IL-8, substance P, histamine releasing proteins from WBC
where are histamines stored
preformed and stored in granules and released immediately
what is the source of serotonin?
platelets and some neuroendocrine cells
when is serotonin released?
released with histamine during platelet aggregation
what does serotonin do
vasoconstrictor and is a neurotransmitter in the GI tract
what do steroids do
inhibits phospholiases that are needed for the arachidonic acid pathway. reduce transcription of genes encoding COX-2, phospholipase A2, proinflammatory cytokines and iNOS
what is produced in the arachidonic acid pathway
- cylooxygenases
2. 5-lipooxygenase
what does prostacyclin do (PGI2)
vasodilation, inhibit platelet aggregation
what does thromboxane A2 do?
vasoconstriction, promote platelet aggregation
what does PGE/PGD do
vasodilation, increased vascular permeability
what pathway makes prostaglandins and thromboxanes?
cyclooxygenase (COX)
what do aspirin, indomethacin do?
inhibit COX1 and COX2 (inhibit making of prostaglandins and thromboxanes)
how is leukotriene B4 made?
5-lipooxygenase makes 5-HETE which makes leukotriene B4
what makes leukotriene C4, D4, and E4
5-lipooxygenase
what do leukotrienes C4, D4, and E4 do
bronchospasm and increased vascular permeability
what does PGE2 do?
pain and fever
what are the main causes of pain in inflammation
PGE2 and bradykinin
what are ecosinoids
arachidonic acid metabolites (lipid products)
how are ecosinoids made
membrane amino acids are rapidly converted by enzymes into prostaglandins and leukotrienes when cells are activated by diverse stimuli
what do phosphoplipases do
release membrane amino acids into cell cytoplasm to be metabolized by 1 of 2 enzymatic pathways
what do steroids do
inhibit phospholipases that release membrane AA into cell cytoplasm to enter lipooxygenase or cyclooxygenase pathways
what does the cyclooxygenase pathway produce?
prostaglandins and thromboxane
what does the lipooxygenase pathway produce?
leukotrienes and lipoxins
what do PGD2, PGE2, PGF2 do
- vasodilation
2. potentiate edema by enhancing vascular permeability effects of other mediators
what does PGE2 do specifically
mediates pain and is involved in cytokine induced fever with infections
what does PGI2 do? prostacyclin
is released from endothelium and vasodilates and inhibits platelet aggregation
what does thromboxane A2 do
released from platelets and vasoconstricts and promotes platelet aggregation
cyclooxygenase pathway products
- PGI2 prostacyclin
- thromboxane A2
- PGD2, PGE2, PGF2
lipooxygenase pathway products
- leukotriene B4 (LTB4)
- leukotriene C4, D4, E4
- lipoxins A4 and B4
what does leukotriene B4 do
neutrophil chemotaxis
what does leukotriene C4, D4, and E4 do
increase vascular permeability by endothelial cell contraction, vasoconstriction, bronchospasm
what do lipoxins A4 and B4 do
inhibitors of inflammation
what 2 cells are required for lipoxin synthesis
- leukocytes (neutrophils) produce intermediates in lipoxin synthesis
- platelets convert these intermediates to lipoxins
what do lipoxins actually do
inhibit neutrophil adhesion and chemotaxis, play role in resolution of inflammation
what eicosanoids do vasodilation
prostaglandins PGI2 (prostacyclin), PGE1, PGE2, PGD2
what eicosanoids do vasoconstriction
thromboxane A2 and leukotrienes C4, D4, E4
what eicosanoids do increased vascular permeability
leukotrienes C4, D4, E4
what eicosanoids do chemotaxis and leukocyte adhesion
leukotrienes B4 and HETE
what eicosanoid causes bronchospasm?
leukotrienes C4, D4, E4
what do cytokines do
mediate and regulate immune and inflammatory reactions
what cells make cytokines
activated leukocytes, endothelial epithelial cells, and connective tissue cells
what do IL-1 and TNF do
- endothelial activation
- activation of leukocytes and other cells
- systemic acute phase response
what is the systemic acute phase response
fever, cachexia (TNF), and sepsis syndrome
how does IL-1 and TNF help with endothelial activation
increased adhesion molecules, increased procoagulant activity, increased mediators like cytokines, chemokines, GF, eicosanoids
what is the critical step in complement activation
proteolysis of C3 by one of 3 different pathways (classical, alternative, lectin)
what do the complement pathways lead to
formation of C3 convertase which splits C3 into C3a and C3b
what forms the membrane attach complex
C5b - C9
what is C3b
opsonin
what is C3a and C5a
anaphylatoxins, stimulate release of histamine
what is C5a
leukocyte chemotactic factor
what are the important regulatory proteins of complement
- C1 inhibitor
- delay accelerating factor (DAF)
- CD59
what does CD59 do
inhibits formation of membrane attack complex
what is deficient in paroxysmal nocturnal hemoglobinuria
CD55 and CD59 are deficient on red cells, red cells prone to lysis
what does DAF do
is CD55
prevents formation of C3 convertase
what does C1 inhibitor do
block activation of C1
what causes hereditary angioedema
inherited deficiency of C1 inhibitor
what does platelet activating factor do
- vasoconstriction, bronchoconstriction
- increased leukocyte adhesion to endothelium, chemotaxis, degranulation, oxidative burst
- boost synthesis of other mediators esp eicosanoids
what does PAF do in low concentration
causes vasodilation and increased venular permeability with a greater potency than histamine
what cells make PAF
platelets, basophils, mast cells, neutrophils, macrophages, endothelial cells
when does clotting cascade occur
clotting and inflammation occur together
tissue injury that leads to clotting will lead to inflammation.
what is kinin
vasoactive peptides derived from plasma proteins called kininogens
what converts kininogen to kinin
killikrein protease
what does killikrein do
cleaves high molecular weight kininogen (HMWK) into bradykinin
what activates kinin cascade
activated factor XII in the clotting system (hageman factor)
effects of bradykinin
- vasodilation and increased vascular permeability
- major contributor to pain that accompanies inflammation
- bronchoconstriction
what secretes neuropeptides
sensory nerves and some WBC
what neuropeptides are secreted in the peripheral and central nervous system
substance P and neurokinin A
where is substance P prominent
GI and lungs
what does substance P do
transmits pain signals, regulate BP, stimulate endocrine gland hormone secretion, increase vascular permeability
what substance may help initiate and regulate inflammation
neuropeptides
what major mediators are responsible for vasodilation?
- prostaglandins
- histamine
- kinins
- PAF
what major mediators cause increased vascular permeability?
- leukotrienes
- histamine
- kinins
- PAF
what major mediators cause fever?
- IL-1
- TNF
- prostaglandins
- systemic cytokines
what major mediators cause pain?
- bradykinin
2. PGE2/prostaglandins
what major mediators cause tissue damage?
- PAF
- complement (C5a, C3a)
- granulocytes
- cytokines
what major mediators cause chemotaxis
- C5a
- interleukins
- TNF
- leukotrieneB4
- HETE
- cytokines
