Inflammatory response

Inflammatory response
Body reacts to infection and tissue damage in the form of inflammation. This is a complicated sequence of overlapping events – aim is to prevent spread of the damaging agents, dispose of cellular debris and pathogens, and initiate the repair process. Key process of inflammation is the movement of proteins, fluids and cells from the blood into the tissues  delivery of agents to combat infection.

Basics of inflammatory response:
Noxious stimulus (bacteria, viral, immune complex, crystals, chemicals, toxins or tissue injury)  recognition systems react to the stimulus (specific immune response)  changes in vascular permeability  cellular responses  removal of the noxious stimulus  healing. Inflammation is a complex process that involves changes in the circulation, changes in vessel wall permeability, a response from the white cells and the release of chemical mediators.

Inflammatory mediators:
• vasoactive agents – histamine (released from mast cells, platelets and basophil granules  increased vascular permeability, smooth muscle contraction, increased glandular mucous secretion – release is stimulated by complement components C3a and C5a and by lysosomal proteins from neutrophils); prostaglandins (long chain fatty acids derived from arachidonic acid  local vasodilation and increase vascular permeability); leukotrienes (synthesised from arachidonic acid, mostly in neutrophils  may increase vascular permeability, smooth muscle contraction, mucous secretion); platelet activating factor; kinins; lysosomal compounds (released from neutrophils  activates complement and may increase vascular permeability); serotonin (5-hydroxytryptamine – in mast cells and platelets  potent vasoconstrictor.
• chemotactic factors – complement products, leukotriene B4, C5a, platelet activating factor, cytokines (eg Interlaken, tumour necrosis factor, lympotoxin)
• proinflammatory cytokines – interleukins, tumour necrosis factor
• enzymes – tryptase, chymase
• fever – prostaglandins
• pain – prostaglandins, bradykinin

Vascular changes:
• after damage  release of inflammatory mediators  vascular response
• initially a very short transient phase of arteriolar constriction  most likely a response to the tissue damage and considered of no importance to inflammatory response (but probably plays a role in preventing blood loss) – lasts 5-10 minutes
• arterioles and precapillaries in non-injured adjacent area dilate  increased blood flow
• endothelial cells swell and partially retract gaps develop between capillary endothelial cells (increases permeability)  cells and fluid escape (exudate)

Cellular response:
• circulating neutrophils initially adhere to the swollen endothelial cells (margination)  then migrate through vessel basement membrane (emigration)  neutrophils accumulate in damaged area  later joined by macrophages
• chemotactic factors attract polymorphonuclear cells
• if chronic, the stimulus cannot be removed  lymphocytes replace neutrophils
• Neutrophils are predominant in acute inflammatory responses – they are attracted to sites of tissue damage by several chemotactic stimuli (C5a, LTB4, bacterial components  bind to surface of neutrophils  activate secondary messenger systems  increased motility). Large numbers are circulating in blood  rapid response to engulf foreign matter – initially they are opsonised (rendered more amenable to phagocytosis) by immunoglobulins or complement proteins
• Macrophages are also effective phagocytic cells
• red blood cells may also enter tissue by diapedesis (passive process that relies on hydrostatic pressure)  indicative of more severe injury (eg tear in vascular wall)

Acute phase response:
• release of proteins (most from liver) in response to infectious and immunologic stimulus  contribute to host defences and healing
• include – C-reactive protein, fibrinogen, haptoglobin, C3, alpha-1-antitrypsin, ceruloplasmin

Systemic effects of acute inflammation:
Pyrexia (endogenous pyrogens from polymorphs and macrophages  act on hypothalamus  thermoregulatory mechanisms set at higher temperatures); malaise; anorexia; nausea; weight loss more common in chronic inflammation; lymph node enlargement; haematological changes (increased ESR, leucocytosis)

Beneficial effects of inflammation:
• toxins produced by bacteria are diluted
• increased vascular permeability  allows antibodies to enter extravascular space
• therapeutic drugs (eg antibiotics) are carried to site of infection
• increased supply of nutrients and oxygen to cells with high metabolic rate (eg neutrophils)
• immune response is stimulated

Detrimental effects of inflammation:
• normal tissues can be destroyed (eg collagenases may digest normal tissue)
• swelling (can be dangerous if in enclosed space)
• inappropriate inflammatory response (eg hypersensitivity)
• fever (but, increased metabolism from increased temperature  speeds up inflammatory response)

Proliferative phase of wound healing:
• this phase normally starts around day 3 and lasts for up to 3 weeks
• epithelisation – proliferation of epithelial cells on margin of superficial wounds reproduce and migrate over injured area
• collagen production – fibroblasts migrate to injured area in response to chemotactic agents  fibroblasts synthesise procollagen  form collagen filaments  form collagen fibres  crosslinking to increase strength
• wound contraction – begins after about 5 days – pulls edges of wound together; mostly due to myofibroblasts (similar to fibroblasts, but possess contractile elements)
• neovascularisation – new blood vessels formed (angiogenesis); macrophages believed to stimulate this; vessels at periphery develop buds that spread into wound area

Maturation phase of wound healing:
• usually begins after 9-10 days – lasts for up to a year
• number of fibroblasts, myofibroblasts, macrophages and capillaries decrease
• synthesis and lysis of collagen is now in balance and the collagen fibres become orientated

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