Chapter 3 Part 2 Flashcards
Histamine
Source: mast cells, basophils, platelets
Action: vasodilation, increased vascular permeability, endothelial activation
Prostaglandins
Source: mast cells, leukocytes
Action: vasodilation, pain, fever
Leukotrienes
Source: mast cells, leukocytes
Action: increased vascular permeability, chemotaxis, leukocyte adhesion, and activation
Cytokines (TNF, IL-6, IL-1)
Source: macrophages, endothelial cells, mast cells
Local Action: endothelial activation (expression of adhesion molecules)
Systemic Action: fever, metabolic abnormalities, hypotension (shock)
Chemokines
Source: leukocytes, activated macrophages
Action: chemotaxis, leukocyte activation
Platelet-activating Factor
Source: leukocytes, mast cells
Action: vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst
Complement
Source: plasma (produced in liver)
Action: leukocyte chemotaxis and activation, fireteams target killing (membrane attack complex), vasodilation (mast cell stimulation)
Kinins
Source: plasma (produced in liver)
Action: increased vascular permeability, smooth muscle contraction, vasodilation, pain
What are the most important mediators of acute inflammation?
vasoactive amines, lipid products (prostaglandins and leukotrienes), cytokines (including chemokines), products of complement activation
Cell-derived mediators
sequestered in intracellular granules and can be rapidly secreted by granule exocytosis or are synthesized de novo
ex) histamine in mast cell granules
Major cell types that produce mediators of acute inflammation
macrophages, dendritic cells, mast cells
Plasma-derived mediators
produced mainly in the liver and are present in circulation as inactive precursors that must be activated
ex) complement proteins
2 major vasoactive amines
histamine
serotonin
Histamine: storage, release, and action
Storage: mast cell granules
Release: mast cell degranulation in response to 1) physical injury; 2) binding of antibodies to mast cell; 3) products of complement (C3a and C5a); 4) neuropeptides, cytokine (IL-1, IL-8)
Action: dilation of arterioles and increased permeability of venules via H1 receptor binding
Serotonin: storage, release, action
Storage: preformed in platelets and neuroendocrine cells
Action: neurotransmitter in GI tract, vasoconstrictor
What two lipid mediators are produced from Arachidonic Acid?
Prostaglandins
Leukotrienes
What is AA made of?
20-carbon unsaturated fatty acid from diet or essential fatty acid linoleum acid esterified in membrane phospholipids
Release of AA
mechanical, chemical, physical mediators release AA from membrane phospholipids via action of phospholipase A2
What two major classes of enzymes do eicosanoids (AA-derived mediators) synthesize?
Cyclooxygenases: generate prostaglandins
Lipoxygenases: produce leukotrienes and lipoxins
What do steroids inhibit?
phospholipase (inhibit release of AA)
What do COX-1 and COX-2 inhibitors, aspirin, and indomethacin inhibit?
cyclooxygenase (production of prostaglandins)
Prostacyclin PGI2 action
vasodilation, inhibits platelet aggregation
Thromboxane A2 (TXA2) action
vasoconstriction, promotes platelet aggregation
PGD2, PGE2 actions
vasodilation, increased vascular permeability
5-HETE action
chemotaxis
Leukotriene C4, D4, E4 (LTC4, LTD4, LTE4) actions
bronchospasm, increased vascular permeability
Lipoxin A4, B4 (LXA4, LXB4) actions
inhibition of inflammation
What do leukotriene receptor antagonists inhibit?
bronchospasm produced by LTC4, LTD4, LTE4
Which eicosanoids cause vasodilation?
Prostaglandins PGI2, PGE1, PGE2, PGD2
Which eicosanoids cause vasocontriction?
Thromboxane A2, Leukotrienes C4, D4, E4
Which eicosanoids cause increased vascular permeability?
Leukotrienes C4, D4, E4
Which eicosanoids cause chemotaxis and leukocyte adhesion?
Leukotriene B4, HETE
COX-1
produced in response to inflammatory stimuli and constitutively expressed in most tissues, where it may serve a homeostatic function
COX-2
produced by inflammatory stimuli, but low or absent in most tissues
What has a thromboxane-prostacyclin imbalance been implicated as an early event in?
thrombus formation in coronary and cerebral vessels
Systemic effects of prostaglandins
fever, pain
Leukotriene: source and action
Source: produced by leukocytes and mast cells by lipoxygenase action
Action: vascular and smooth muscle reactions and leukocyte recruitment
Role of 5-lipoxygenase
predominant lipoxygenase in neutrophils; converts AA to 5-HPETE, which is precursor for leukotrienes and chemotactic for neutrophils
Which are more potent in increasing vascular permeability and causing bronchospasm, histamine or leukotrienes?
Leukotrienes
Lipotoxins: source and action
Source: generated from AA by lipoxygenase pathway
Action: suppress inflammation by inhibiting the recruitment of leukocytes, inhibits neutrophil chemotaxis and adhesion; require 2 cell populations for transcellular biosynthesis (leukocytes produce intermediates that are converted to lipoxins by platelets)
Actions of COX inhibitors
inhibit prostaglandin synthesis (treat fever and pain); aspirin does this by irreversibly acetylating and inactivating cyclooxygenases
Actions of Lipoxygenase inhibitors
5-lipoxygenase not affects by NSAIDS; inhibit leukotriene production (useful for treating asthma)
Actions of corticosteroids
antiinflammatory; reduce transcription of gene encoding COX-2, phospholipase A2, pro inflammatory cytokines (IL-1 and TNF), and iNOS
Actions of leukotriene receptor antagonists
block and prevent actions of leukotrienes (asthma treatment)
What does consumption of fish oil do?
polyunsaturated fats are poor substrates for conversion to active metabolites by cyclooxygenase and lipoxygeanse pathways, but better for production of anti-inflammatory lipid products
Cytokines: source and action
Source: produced by many cell types and activated by lymphocytes, macrophages, dendritic cells, endothelial and epithelial cells, and connective tissue cells
Actions: mediate and regulate immune and inflammatory reactions
TNF and IL-1: source, stimulation, and actions
Source: produced by activated macrophages and dendritic cells (TNF also produced by T lymphocytes; IL-1 also produced by some epithelial cells)
Stimulation: microbial products, immune complexes, foreign bodies, physical injury; TNF induced by signals through TLRs and microbial sensors; IL-1 activation dependent on inflammasome
Actions: endothelial activation (increased expression of adhesion molecules, increased production of mediators, increased procoagulant activity); activation of leukocytes and other cells (TNF induces production of NO; IL-1 activates fibroblasts, and stimulates Th17 responses); systemic acute-phase response (fever, suppress appetite)
TNF antagonists actions
treatment of chronic inflammatory diseases; patients become susceptible to mycobacterial infection due to reduced ability of macrophages to kill intracellular microbes
IL-6
Source: macrophages
Actions: systemic effects (acute phase response)
Chemokines
Source: macrophages, endothelial cells, T lymphocytes, was cells
Actions: recruitment of leukocytes to sites of inflammation; migration of cells in normal tissues
IL-17
Source: T lymphocytes
Actions: recruitment of neutrophils and monocytes
IL-12
Source: dendritic cells, macrophages
Actions: increased production IFN-y
IFN-y
Source: T-lymphocytes, NK cells
Actions: activation of macrophages
C-X-C chemokines
act on neutrophils
IL-8
induced by IL-1 and TNF
C-C chemokines
MCP-1, eotaxin, MIP-1a, RANTES
attract monocytes, eosinophils, basophils, and lymphocytes
C chemokines
specific for lymphocytes
Cx3C chemokines
fractaline
cell surface bound- promotes strong adhesion of monocytes and T cells
soluble form- chemoattractant activity
Chemokine functions
stimulate leukocyte attachment to endothelium by increasing leukocyte affinity of integrins and stimulate chemotaxis (inflammatory); homeostatic chemokines maintain tissue architecture
What is the complement system a collection of?
soluble proteins and membrane receptions that function mainly in host defense against microbes and in pathologic inflammatory reactions
What is the critical step in complement activation?
proteolysis of C3
Classical Pathway
triggered by fixation of C1 to IgM or IgG antibody that has combined with antigen
Alternative Pathway
triggered by microbial surface molecules, complex polysaccharides, cobra venom, and other substances in absence of antibody
Lectin Pathway
plasma mannose-binding lectin binds to carbohydrates on microbes and directly activates C1
Steps on complement pathway:
1) activation leads to C3 converts formation
2) splits into C3a and C3b
3) C3a released
4) C3b attaches to cell or molecule where complement is being activated
5) more C3b fragments come together to form C5 converts
6) cumulation of steps leading to MAC formation
Main functions of complement system (3)
Inflammation- C3a, C5a, C4a
Opsonization and phagocytosis- C3b
Cell Lysis- MAC deposition
C1 inhibitor (C1 INH)
blocks activation of C1; inherited deficiency is the cause of hereditary angioedema
Decay Accelerating Factor (DAF) and CD59
linked to plasma membrane by glycophosphatidyl anchor; DAF inhibits formation of C3 convertase; CD59 inhibits formation of MAC; deficiency leads to paroxysmal nocturnal hemoglobinuria
PAF
platelet aggregation, inflammatory effects, vasoconstriction and bronchoconstriction (at low concentrations induces vasodilation and increased venular permeability)
PARs
protease activated receptors; activated by thrombin to produce fibrin (form clot), expressed on platelets and leukocytes
Kinins
vasoactive peptides derived from plasma proteins, kininogens, by action of kallikreins (proteases)
Bradykinin
increases vascular permeability and causes contraction of smooth muscle, dilation of blood vessels, and pain when injected into the skin (mediator in some forms of allergic reaction)
Neuropeptides (substance P and neurokinin A)
secreted by sensory nerves and various leukocytes; may play role in initiation and regulation of inflammatory response
Morphologic hallmarks of acute inflammatory reactions
dilation of small blood vessels, accumulation of leukocytes and fluid in extravascular tissue
Serous Inflammation
exudation of cell-poor fluid into spaces created by cell injury or into body cavities lines by peritoneum, pleura, or pericardium (effusion)
Fibrinous Inflammation
fibrinogen leakage out of blood and formation of fibrin deposits in extracellular space; fibrinous exudate develops when vascular leaks are large or there is a local procoagulant stimulus
- formation of scars
- seen in lining of body cavities, such as meninges and pericardium
Purulent (suppurative) Inflammation, Abscess
production of pus, an exudate consisting of neutrophils, the liquefied debris of necrotic cells, and edema fluid (bacterial infection- staph); abscesses are localized collections of purulent inflammatory tissues
Ulcers
local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing of inflamed necrotic tissue
