13- Inflammation

What triggers inflammation and what is its function

• It is a tissue response to injury or trauma e.g. infection or wound

• Part of the innate immune system, may be acute or chronic

• Injury caused by replicating infectious agents, non replicating agents (heat, cold, radiation), inert materials (foreign bodies e.g. splinter), auto immune reactions

• Functions include destroying and removing pathogens, if not possible limiting tissue damage e.g TB, repairing and replacing damaged tissue

5 Cardinal signs of inflammation

• Pain- dolor

• Heat- calor

• Redness- rubor

• Swelling- tumor

• Loss of function- funcio laesa

Steps in inflammatory response

• Damaged tissue releases histamines which increase blood vessel permeability which increases blood flow to the area and causes capillaries to leak, releasing phagocytes and clotting factors into the wound

• Phagocytes engulf bacteria, dead cells, cellular debris

• Complement becomes activated

• Macrophages release cytokines for signalling and tissue repair

• Platelets move out of capillary to seal wounded area

• Phospholipids enter the arachidonic pathway

• Cell junctions between epithelium open to allow plasma proteins to exit circulation

Three major events in inflammation

• Increase in vascular diameter (vasodilation)- increased blood volume in affected area (heat, redness)

• Increase in capillary permeability- large molecules and cells that do not normally move out of capillaries can reach affected site (oedema)

• Influx of phagocytic cells- monocytes and neutrophils are attracted to site of infection by chemotaxis and move out of capillaries (extravastion)

• Destroy pathogen, may recruit other immune cells, can cause collateral tissue damage

Chemotaxis mechanism

• Movement of cells towards a chemical stimulus e.g. neutrophils move from peripheral blood to site of infection

• Tissue releases those chemical signals causingincreased capillary permeability

• Neutrophils migrate by rolling, activation, adhesion and extravasation

• Chemoattractants include chemokines (cytokines released by immune cells) and complement components released during inflammation

Cells involved in inflammation

• Mast cells- release histamine which increases vascular permeability, induces smooth muscle contraction, mucuous secretion and causes pain by irritating nerve endings

• Basophils- secrete histamine

• Macrophages- APC’s, phagocytosis, wound healing, removal of certain cells

• Neutrophils- migrate to site, respond to chemoattractants e.g. C5a, C3a, IL8 and IFNy, phagocytosis

• Endothelial cells- become activated when exposed to IL1 and TNF, display increased adhesiveness for monocytes and neutrophils

Mediators in inflammation

• Histamine derived from mast cells and basophils

• Serotonin derived from nerve cells- controls blood flow

• Bradykinin from the kinin system- causes vasodilation, increased permeability, chemotactic molecule

• Lipid derived mediators derived from membrane phospholipids and arachidonic acid, include prostaglandins, leukotrienes, prostacylin whcih induce vasodilation, histamine release, permeability, platelet aggregation

• Cytokines- TNF, IL1, IL6 which are pyrogens, acute phase respondants, chemokines, anti-inflammatory

Mediators from plasma enzyme systems

• Clotting factors from the clotting system are involved in the coagulation process

• Bradykinin from the kinin system is a plasma protein involved in the inflammatory response, coagulation and blood pressure

• Fibrin degredation products from the fibrinolytic system are plasma proteins involved in the breakdown of blood clots

• Split products from the complement system are plasma proteins involved in cell lysis, C5a and C3a are also chemotatic factors and cause mast cell degranulation (histamine)

Acute inflammation

• Rapid onset (seconds to minutes) of inflammation of short duration lasting from minutes to several days

• Presents with exudation of fluid and plasma proteins (oedema) and migration of neutrophils

• The outcomes are either resolution (tissue healing) or chronic inflammation

Chronic inflammation

• Longer duration, active inflammation, tissue injury and healing can occur simultaneously

• Associated with the presence of lymphocytes and macrophages, proliferation of blood vessels (angiogenesis), fibrosis and tissue necrosis

• Caused by persistance of injurious agent, recurrent attacks of actuew inflammation e.g. UTI’s, chronic inflmmation starting de novo e.g. M tuberculosis

Acute phase response

• Neutrophils and macrophages secrete cytokines like L1, IL6, IL8 and TNF-a

• Liver responds by producing a large number of acute phase proteins, increase dramatically in acute inflammation

• Pentraxins- C reactive protein, serum amyloid P (opsonins)

• Collectins- MBL (activates complement)

• Serpins- a-1-antitrypsin (downregulates inflammation)

• Haptoglobin- binds haemoglobin, prevents iron uptake by microbes

• Fibrinogen- coagulation factor

Stages of tissue healing

• Collagenation- macrophages clear damaged area, after a number of days fibroblasts begin to construct a new collagen matrix which will act as the framework for new tissue cells

• Angiogenesis- generation of new capillaries, when blood flow is reestablished tissue cells e.g. muscle will begin to grow

• Proliferation- lasts up to 4 weeks, affected area composed of specific tissue cells and granulation tissue, if not removed it will lead to formation of scar tissue which can decrease the overall tissue function

•Remodelling- new cells and proteins fibres arrange in surroundings to produce functioning tissue, can take months