CHAPTER 13- INFLAMMATION AND CYTOKINES.txt

• Injury-
• leads to exposed collagen, platelet-activating factor release, tissue factor release from endothelium.

• Platelets bind-
• release important growth factors (platelet-derived growth factor PDGF) and cytokines (IL-1 and TNF-alpha)

• Macrophages-
• dominant role in wound healing, release important growth factors (PDGF) and cytokines (IL-1 and TNF-alpha)

Establishment of a provisional wound matrix:

• 1) platelets bind to the exposed wound matrix through interaction of beta-1 and beta-3 integrins and collagen, laminin, and fibronectin receptors
• 2) after wounding, the coagulation cascade is activated, generating thrombin, which activates platelet glycoprotein gpIIb/IIIa and increases platelet aggregation.
• 3) A provisional wound matrix is formed, made up of platelets, fibrin, fibrinogen, and fibronectin. The activated platelets in the wound generate transforming growth factor beta (TGF-beta), PDGF, and thrombin.
• 4) TGF-beta is strongly chemotactic for neutrophils, macrophages, and fibrobrasts, recruiting these cells into the provisional wound matrix, where they are also subsequently activated by TGF-beta.
• 5) Increasting concentrations of TGF-beta results in macrophage activation, producing increased amounts of tumor necrosis factor-alpha (TGF-alpha) and interleukin-1 (IL-1). TGF-beta also stimulates fibroblast production of extracellular matrix proteins. These reactions further enhance migration of macrophages and fibroblasts into the wound, facilitating repair.

• 1) similar effects as TGF-beta
• 2) chemotactic and activates inflammatory cells (PMN and macrophages)
• 3) chemotactic and activates fibroblasts --> collagen and ECM proteins
• 4) angiogenesis
• 5) epithelialization
• 6) chemotactic for smooth muscle cells
• 7) has been shown to accelerate wound healing

• 1) acts on similar receptors as TGF-beta
• 2) less potent
• 3) chemotactic and activates fibroblasts --> collagen and ECM proteins
• 4) angiogenesis- V-EGF stimulates angiogenesis and is involved in tumor metastasis
• 5) epithelialization

• 1) chemotactic and activates fibroblasts --> collagen and ECM proteins
• 2) angiogenesis
• 3) epithelialization

• 1) not stored
• 2) generated by phospholipase in endothelium and other cells
• 3) stimulates many types of inflammatory cells chemotactic; increases adhesion molecules

• For inflammatory cells:
• 1- TGF-beta
• 2- PDGF
• 3- PAF
• 4- IL-8
• 5- LTB-4
• 6- C5a and C3a

• For Fibroblasts:
• 1- TGF-beta
• 2- PDGF
• 3- EGF
• 4- FGF

• 1) TGF-alpha
• 2) TGF-beta
• 3) EGF
• 4) FGF
• 5) IL-8
• 6) hypoxia

• 1) TGF-alpha
• 2) TGF-beta
• 3) EGF
• 4) FGF
• 5) PDGF

last 1-2 days in tissues (7 days in blood)

platelets last 7-10 days

1) involved in chronic inflammation (T cells) and antibody production (B-cells)

• 1) have IgE receptors that bind to allergen
• 2) release major basic protein, which stimulates basophils and mast cells to release histamine
• 3) eosinophils increased in parasitic infections

• 1) have IgE receptor
• 2) main source of histamine in blood
• 3) not found in tissues

• 1) primary cell type in type I hypersensitivity reactions
• 2) main source of histamine in tissues other than stomach

• 1) vasodilation
• 2) tissue edema
• 3) postcapillary leakage
• 4) primary effectors in type I hypersensitivity reactions (allergic reactions)

• 1) vasodilation
• 2) increased permeability
• 3) pain
• 4) contraction of pulmonary arterioles

inactivates bradykinin

• 1) has arginine precursor
• 2) Activates guanylate cyclase and increases cGMP, resulting in vascular smooth muscle dilation
• 3) is also called endothelium-derived relaxing factor (EDRF)

vascular smooth muscle constriction

TNF-alpha and IL-1

• 1) macrophages- largest producers of TNF
• 2) increases adhesion molecules
• 3) overall, a procoagulant
• 4) causes cachexia in patients with cancer
• 5) activates neutrophils and macrophages--> more cytokine production, cell recruitment
• 6) can cause myocardial depression
• 7) fever, hypothermia, tachycardia, increased cardiac output, decreased SVRI --> high concentration can cause circulatory collapse and multisystem organ failure

• 1) main source also macrophages
• 2) effects similar to TNF and synergizes TNF
• 3) Responsible for fever (PGE₂ mediated in hypothalamus)
• 1- raises thermal set point, causing fever
• 2- NSAIDs- decrease fever, reducing PGE₂ synthesis
• 4) alveolar macrophages- cause fever with atelectasis by releasing IL-1
• 5) IL-1 also increases IL-6 production

• 1) increased hepatic acute phase proteins (C-reactive protein, amyloid A)
• 2) lymphocyte activation

• 1) released by lymphocytes in response to viral infection or other stimulants
• 2) activate macrophages, natural killer cells, and cytotoxic T cells
• 3) inhibit viral replication

• 1) IL-6 is most postent stimulus
• 2) Increased:
• 1- C-reactive protein (an opsonin, activates complement)
• 2- amyloid A and P
• 3- fibrinogen
• 4- haptoglobin
• 5- ceruloplasmin
• 6- alpha-1 antitrypsin
• 7- alpha-1 antichymotrypsin
• 8- C3 (complement)
• 3) Decreased:
• 1- albumin
• 2- transferrin

L-selectins, located on leukocytes, bind to E- (endothelial) and P-(platelets) selectins; rolling adhesion

Beta-2 integrins (CD11/18 molecules)- on leukocytes, bind ICAMS etc. anchoring adhesion

on endothelial cells, bind beta-2 integrin molecules located on leukocytes and platelets. These are also involved in transendothelial migration

• 1) circulating leukocytes express integrins in a low-affinity conformation
• 2) exposure to activated endothelium leads to rolling, which is mediated by L-selectin and P-selectin on the neutrophil and E-selectin on the endothelium
• 3) leukocye exposure to cytokines released by macrophages phagocytosing pathogens induces a high affinity integrin conformation. Tight leukocyte-endothelial adhesion involves integrin engagement with counter-ligand expressed on endothelium
• 4) subsequent exposure to chemokines leads to diapedesis, which is further mediated by the family of beta-1 and beta-2 integrins

• Classic pathway (IgG or IgM)- antigen-antibody complex activates
• 1- factors C1, C2, and C4- foudn only in the classic pathway

• Alternative pathway- endotoxin, bacteria, other stimuli activate
• 1- factors B, D, and P (properdine) found only in the alternate pathway

C3- common to and is the convergence point for both pathways

Mg- required for both pathways

• Anaphylatoxins- C3a, C4a, C5a;
• 1- increases vascular permeability
• 2- smooth muscle contraction (bronchi)
• 3- activate mast cells and basophils

• Alternative pathway:
• 1) C3 is cleaved to C3b
• 2) C3b binds and cleaves B to Bb to form C3 convertase (C3bBb)
• 3) another C3b binds C3 convertase to form C5 convertase (C3bBbC3b)

• Classical pathway:
• 1) C1 binds immunoglobulin
• 2) C1 binds and cleaves C4 and C2 to C4b and C2a to form C3 convertase (C4b2a)
• 3) C4b2a binds another C3b to generate C5 convertase (C4b2aC3b)

• Late pathway:
• 1) C5 convertase cleaves C5 to form C5b, which integrates into the plasmalemma
• 2) C6-8 are recruited forming the C5b-8 complex
• 3) C5b-8 recruits numerous C9 subunits, which form a pore in the pathogen cell wall

• 1) vasodilation
• 2) bronchodilation
• 3) increased permeability
• 4) inhibit platelets

• 1) vasocilation
• 2) bronchoconstriction
• 3) increased permeability

1) inhibit cyclooxygenase (reversible)

• 1) inhibits cyclooxygenase (irreversible)
• 2) inhibits platelet adhesion by decreasing TXA₂

inhibit phospholipase, which converts phospholipids to arachidonic acid--> inhibits inflammation

LTC₄, LTD₄, LTE₄- slow reacting substances of anaphylaxis; bronchocontriction, vasoconstriction followed by increased permeability (wheal and flare)

LTB₄- chemotactic

24-48 hours

1) norepinephrine released from sympathetic postganglionic neurons

2) epinephrine and norepinephrine released from adrenal medulla (neural response to injury)

• Afferent nerves from site of injury stimulate:
• 1- CRF
• 2- ACTH
• 3- ADH
• 4- growth hormone
• 5- epinephrine
• 6- norepinephrine release

thyroid hormone does not play a major role in injury

• 1) Chemotaxis, angiogenesis, wound healing
• 2) IL-8 and platelet factor 4 are CXC chemokines
• 3) C=cysteine X--> another amino acid

RBCs have some antioxidant properties (superoxide dismutase and catalase)

PMNs are the primary mediator

• 1) NADPH-oxidase system enzyme defect in PMNs
• 2) results in decreased superoxide radical (O₂-) formation