Inflammation and Cytokines Flashcards
Injury
- leads to exposed collagen, platelet activating factor release, tissue factor release from endothelium
- platelets bind - release important growth factors (PDGF); leads to PMN, macrophage recruitment
- macrophages play dominant role in wound healing, release important growth factors (PDGF) and cytokines (IL-1 and TNF-alpha)
PDGF
- similar effect as TGF-B
- chemotactic and activates inflammatory cells (PMNs and macrophages)
- chemotactic and activates fibroblasts –> collagen and ECM proteins
- angiogenesis
- epithelialization
- chemotactic for smooth muscle cells
- has been shown to accelerate wound healing
EGF (epidermal growth factor)
- acts on similar receptors as TGF-B; less potent
- chemotactic and activates fibroblasts –> collagen and ECM proteins
- angiogenesis –> VEGF stimulates angiogenesis and is involved in tumor mets
- epithelialization
Fibroblastic growth factor (FGF)
- chemotactic and activates fibroblasts –> collagen and ECM proteins
- angiogenesis
- epithelialization
PAF (platelet activating factor)
- not stored, generated by phospholipase in endothelium and other cells
- stimulates many types of inflammatory cells; chemotactic; increase adhesion molecules
Chemotactic factors
- for inflammatory cells: TGF-B, PDGF, IL-8, LTB-4, C5a and C3a, PAF
- for fibroblasts: TGF-B, PDGF, EGF, FGF
Angiogenesis Factors
TGF-B, EGF, FGF, TGF-alpha, IL-8, hypoxia
Epithelialization factors
TGF-B, PDGF, EGF, FGF, TGF-aplha
PMNs
last 1-2 days in tissues (7 days in blood)
Platelets
last 7-10 days
Lymphocytes
involved in chronic inflammation (T cells) and antibody production (B cells)
Eosinophils
- involved in type I hypersensitivity rxn
- have IgE receptors that bind to allergen
- release major basic protein, which stimulates basophils and mast cells to release histmaine
- increased in parasitic infections
Basophils
- involved in type I hypersensitivity rxn
- have IgE receptors
- main source of histamine in blood; not found in tissue
Mast cells
- primary cell in type I hypersensitivity rxn
* main source of histamine in tissues other than stomach
Histamine
- vasodilation, tissue edema, postcapillary leakage
* primary effectors in type I hypersensitivity rxs (allergic reactions)
Bradykinin
- vasodilation, increased permeability, pain, contraction of pulmonary arterioles
- Angiotensin converting enzyme (ACE) - inactivates bradykinin
Nitric oxide
- has arginine precursor
- activates guanylate cyclase and increases cGMP, resulting in vascular smooth muscle dilation
- is also called endothelium-derived relaxing factor
Endothelin
vascular smooth muscle contraction
Initial cytokine response to injury and infection
TNF-alpha and IL-1
Tumor necrosis factor alpha (TNF-alpha
- macrophages - largest producers of TNF
- increases adhesion molecules
- overall a procoagulant
- causes cachexia in patients with cancer
- activates neutrophils and macrophages –> more cytokine production, cell recruitment; can also cause myocardial depression
- fever, hypothermia, tachycardia, increase cardiac output, decrease SVRI –> high concentrations can cause circulatory collapse and multisystem organ failure
IL-1
- main source also macrophages; effects similar to TNF and synergizes TNF
- responsible for fever (PGE2 mediated in hypothalamus) –> raises thermal set point, causing fever; NSAIDs decrease fever, reducing PGE2 synthesis
- alveolar macrophages –> cause fever with atelectasis by releasing IL-1
- IL-1 also increases IL-6 production
IL-6
- increase hepatic acute phase proteins (CRP, amyloid A)
* lymphocyte activation
Interferons
- released by lymphocytes in response to viral infection or other stimulates
- activate macrophages, NK cells, and cytotoxic T cells
- inhibit viral replication
Hepatic Acute Phase Response Proteins
- IL-6 most potent stimulus
- increased: CRP (an opsonin, activates complement), amyloid A and P, fibrinogen, haptoglobin, ceruloplasmin, alpha-1 antitrypsin, alpha-1 antichymotrypsin and C3 (complement)
- decreased: albumin and transferrin
Selectins
*L-selectins, located on leukocytes, bind to E-(endothelial) and P-(platelets) selectins; rolling adhesion
Beta-2 integrins
CD 11/18 molecules - on leukocytes; bind ICAMs, anchoring adhesion
ICAM, VCAM, PECAM, ELAM
*on endothelial cells, bind beta-2 integrin molecules located on leukocytes and platelets; these are also involved in transendothelial migration
Classic pathway
- IgG or IgM - antigen-antibody complex activates
- factors C1, C2 and C4 - found only in classic pathway
- C3 - common to and is the convergence point for both pathways
- Mg required for both pathways
- Membrane attack complex - C5b-C9b
Alternative pathway
- endotoxin, bacteria, other stimuli activate
- factors B, D, and P (properdin) - found only in alternate pathway
- C3 - common to and is the convergence point for both pathways
- Mg required for both pathways
C3b
opsonization
C3a and C5a
chemotaxis
PGI2 and PGE2
vasodilation, bronchodilation, increase permeability, inhibit platelets
PGD2
vasodilation, bronchoconstriction, increase permeability
NSAIDs
inhibit cyclooxygenase (reversible)
Aspirin
inhibits cyclooxygenase (irreversible), inhibits platelet adhesion by decreasing TXA2
Steroids
inhibit phospholipase, which converts phospholipids to arachidonic acid –> inhibits inflammation
Leukotrienes: LTC4, LTD4, LTE4
*slow reacting substances of anaphylaxis; bronchoconstriction, vasoconstriction followed by increased permeability (wheal and flare)
LTB4
chemotactic
Cathecholamines
- peak 24-48 hours after injury
- norepinephrine released from sympathetic postganglionic neurons
- epinephrine and norepinephrine released from adrenal medulla (neural response to injury)
Neuroendocrine response to injury
afferent nerves from site of injury stimulate CRF, ACTH, ADH, growth hormone, epinephrine and NE release
*thyroid hormone does NOT play a major role in injury
CXC chemokines
- chemotaxis, angiogenesis, wound healing
- IL-8 and platelet factor 4 are CXC chemokines
- C = cysteine X –> another amino acid
Red blood cells
*have some antioxidant properties (superoxide dismutase and catalase)
Reperfusion injury
PMNs are primary mediator
Chronic granulomatous disease
NADPH-oxidase system enzyme defect in PMNs; results in decrease superoxide radical (O2-) formation
