Inflammation and innate immunity

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Initiation of acute inflammatory responses

Mast cells are important to acute inflammatory process

This is because on stimulation the release histamine and other vasoactive amines that result in vascular changes seen in acute inflammation

There is also pro-inflammatory substances such as cytokines IL-1 and TNF a and other molecules including leukotrienes,PAF and nitric oxide which cause vessel dilation and edema.

These molecules increase adhesion of neutrophils and monocytes to the endothelium.

Vasoactive amines such as histamine also have an effect on smooth muscle contraction which is important in defence against worms in the intestines.

Histamine is released immediately as a result of mast cell degranulation

The pro-inflammatory cytokines are synthesised de novo by mast cells

The tissue macrophages also play a role in generation of pro-inflammatory cytokines

This is done through the pattern recognition receptors , of PAMPs associated with microbes.

Mast cells themselves express PRRs which trigger cytokine production and some PRRs histamine and degranulation release.

Crucial for the elimination of a microbe and the healing process is the production of acute phase proteins by the liver through the release of the pro-inflammatory cytokines during the early stages of inflammation.

Vascular changes

Inflammatory mediators which are released by tissues, mast cells and macrophages cause the dilation of the blood vessels, which increases blood flow and smooth muscle contraction.

These mediators cause rapid alterations in the blood vessel endothelium and induce increased expression of cellular adhesion molecules, which assist in the transfer of blood leukocytes.

Vasodilation and increased blood flow result in redness and heat and edema results in swelling .

Overall mast cells play a major role in acute inflammation initiated by injury and infection by microbes

PMNS leave the bloodstream as a result of their recognition of adhesion molecules displayed on the endothelial cells.

The expression of these adhesion molecules is induced by pro-inflammatory cytokines released from macrophages.

PMNs form weak attachments through their sialyl-Lewis X molecules to E-selectin to the endothelial surface.

Binding to chemokines , for example IL-8 activates the PMN to express an active form of LFA-1 that then binds to ICAM-1 on the endothelial surface.

This leads to the arrest and flatening of PMNs which then extravasates by squeezing between the endothelial cells then PMN migrates into the tissue towards the source of inflammatory mediators.

Termination of response and repair

Once the microbe is removed inhibitors dampen inflammation and tissue repair mechanisms become activated , the inhibitors of the pro-inflammatory cytokines include soluble receptors and anti - inflammatory cytokines and components of the hemostasis and thrombosis and glucocorticoids

Th2 cytokine IL-4 down regulates the production of pro-inflammatory cytokines from Th1 cells and TGFb is a potent inhibitor of many immune functions.

Protein C is a component of hemostasis and thrombosis system which is an anti-inflammatory gent that functions by inhibiting cytokines such as TNFa.

Glucocorticoids are well known anti-inflammatory agents that inhibit the production of nearly all the pro-inflammatory mediators

alpha- melanocyte stimulating hormone reduces fever IL-2 synthesis and prostaglandin production

Corticotropin inhibits macrophage activation and IFN-y synthesis.

Neuropeptides, somatostatin and VIP reduce inflammation by inhibiting T cell proliferation and migration.

As the inflammatory phase is neutralised by these anti-inflammatory molecules the repair to the damage begins.

The various cells such as macrophages and myo-fibroblasts both make collagen and mend tissues.

Macrophage products including epidermal growth factor , platelet- derived growth factor , fibroblast growth factor and transforming growth factor , are all important in the repair process.