Histamine
- source
- actions
- triggers
Source: mast cells, basophils, platelets Actions: vasodilation, increase vascular permeability, endothelial activaton Triggers - physical stimuli - antibodies binding to mast cells - C3a and C5a - neuropeptides (substance P)
Prostaglandins
- source
- actions
Source: mast cells, leukocytes
Actions: vasodilation, pain, fever
What are the key cytokines that act as mediators of inflammation. What are their local and systemic responses?
TNF, IL-1, IL-6
LOCAL: endothelial activation (expression of adhesion molecules)
SYSTEMIC: fever, metabolic derangements, hypotension
What are two inflammatory mediators produced by the lier?
Complement
Kinins
What are the 4 key actions of complement?
o ↑vascular permeability and vasodilation by inducing mast cells to release histamine (anaphylatoxins)
o Leukocyte activation, adhesion and chemotaxis(C5a) (chemotactic agent for PMN, monocytes, eosinophils and basophils)
o Coats microbes for phagocytosis and destruction (augments phagocytosis by PMN and macrophages)
o Generates MAC which punches holes in microbial membranes and haemolysis
What are the 3 ways of activating the complement system?
CLEAVAGE OF C3
• immune complex -> IgG or IgM -> classical starting from C1 -> C9
• endotoxin or anaesthetic agents-> alternate skip C1; starts at C3
• lectin -> plasma mannose binding lectin binds to carbohydrates on microbes and directly activates C1.
Which of the following are synthesised by cells at the site of injury vs are present in plasma in an inactive state and become activated?
NO Complement Cytokines Factor XII Kinins PGs and LTs PAF
CELL SYNTHESISED
PAF, PG, LTs –> phospholipids, damaged cells esp. WBC, endothelium, platelets Cytokines (IL, TNF) –> WBC, endothelium
Nitric oxide –> endothelium, macrophages
PLASMA
C3a, C5a –> anaphylotoxins, chemokines
C5b-C9 –> membrane attack complex
FXII (Hagemen factor) –> bradykinin, fibrin, plasmin
What are the 3 stages of fibrogenesis in wound healing? What are some of the cytokines related to these stages?
o Migration (eg. chemotaxis)
o Proliferation = PDGF, FGF, TNF, EGF
o Collagen deposition
o Collagenases to convert collagen III to collagen I
PDGF, FGF, TNF, TGFB, IL-1, EGF
What are the major causes of increased vascular permeability in acute inflammation?
- endothelial cell contraction
- endothelial cell damage
- leukocyte mediated endothelial injury
- transcytosis of proteins
- angiogenesis and leakage from new vessels
Describe type I hypersensitivity reactions
Type I (anaphylactic type)
- rapid IgE-related release of chemical mediators from mast cells and basophils (IgE crosslinked by Ag)
- influx of esinophils amplify and perpetuate the reaction
Describe type II hypersensitivity reactions
Type II (cytotoxic type)
- Characterised by production of IgG or IgM Ab against body tissue
- Examples
incompatible transfusion reactions
Acquired haemolytic anaemia
Hyperacute graft rejection (antibody mediated)
Goodpasture’s syndrome (caused by anti-glomerular basement membrane antibodies)
Anti-receptor antibodies, eg. thyrotoxicosis
Describe type III hypersensitivity reactions
Type III (immune complex disease)
- Characterised by formation of in situ or circulating antibody-antigen immune complexes
- ICs are not cleared and remain circulating in the body
- Effects are due to release of vasoactive amines, acute inflammation and platelet aggregation
- If fluid component of inflammatory exudates predominate, leads to serum sickness (fever, rash, joint symtoms)
- If cellular component dominate, will lead to polymorph infiltration in Arthus type reactions (fibrinoid necrosis)
Describe type IV hypersensitivity reactions
Type IV (cell-mediated type)
- Mediated by sensitized T-lymphocytes, esp. TH1 (CD4); takes about 24-72 hours, hence delayed type
- Examples include mycobacteria, fungi, parasites, tuberculin test, contact dermatitis, skin allograft rejection, TB
What are some of the substances produced by activated macrophages?
Acid and neutral proteases
Plasminogen activator (amplifies the generation of proinflammatory substances)
ROS and NOAA metabolites
Cytokines eg. IL-1 and TNF
Growth factors (influence proliferation of smooth muscle cells and fibroblasts and production of ECM)
What are the factors produced by intact endothelium
- inhibitors of platelet aggregation
- anticoagulants
- fibrinolytics
Inhibition of platelet aggregation
- PGI2
- NO
- ADPase
Anticoagulant (inhibition of thrombin)
- Anti-thrombin III acceleration by heparin-like molecules
- Thrombomodulin inhibition of thrombin and activation of protein C/S
- Alpha-2-macroglobulin
Fibrinolysis
- Tissue plasminogen activator (t-PA)
What are the chemicals with direct leukocyte chemotactic effects? (5)
o Leukotriene B4 – most potent chemotactic agent for granulocytes by far o C5a o TNF o IL-8 o Kalikrein
How do reactive oxygen species cause bacterial damage?
o Lipid peroxidation of membranes
- Double bonds in membrane lipids are vulnerable to attack by oxygen-derived free radicals
- These interactions yield peroxides, which are unstable and reactive, & can lead to an autocatalytic chain reaction
o Cross-linking and other changes in proteins
- Promote sulfhydryl-mediated protein cross-linking, resulting in loss of enzyme activity
- Free radical reactions may also directly cause polypeptide fragmentation
o DNA damage
- Free radical reactions with thymine in nuclear and mitochondrial DNA produce single-strand breaks
What are the mechanisms by which NK T cells kill other cells?
Perforin = membrane-puncturing, pore-forming molecules (causes lysis)
Granzymes = enzymes that damage the target cell
Cytokines = IFN-γ and TNF-β induce metabolic changes that lead to apoptosis
Fas and Fas ligand = expressed on activated CTL; causes apoptosis of infected cell
