The Inflammatory Response

The inflammatory response occurs in vascularised tissues in response to injury; it is part of the innate (nonspecific) immune response. Inflammatory responses require activation of leukocytes: neutrophils, eosinophils, basophils, mast cells, monocytes and lymphocytes, although not all cell types need be involved in an inflammatory episode. The cells migrate to the area of tissue damage from the circulation and become activated.

Inflammatory mediators

Activated leukocytes at a site of inflammation release compounds which enhance the inflammatory response. The account below focuses on cytokines and eicosanoids (arachidonic acid metabolites) because of their therapeutic implications. Nevertheless, the complexity of the response, and its involvement of other systems, is indicated by the range of mediators, which include:

Complement products, especially C3b and C5-9 (the membrane attack complex); kinins and the related proteins, bradykinin and the contact system (coagulation factors XI and XII, pre-kallikrein, high molecular weight kininogen); nitric oxide and vasoactive amines (histamine, serotonin and adenosine); activated forms of oxygen; platelet activating factor (PAF); proteinases (collagenses, gelatinases and proteoglycanase).

Cytokines

Cytokines are peptides that regulate cell growth, differentiation and activation, and some have therapeutic value:

• Interleukins produced by a variety of cells including T cells, monocytes and macrophages. Recombinant interleukin-2 (aldesleukin) is used to treat metastatic renal cell carcinoma and malignant melanoma. Interleukin-1 may play a part in conditions such as the sepsis syndrome and rheumatoid arthritis, and successful blockade of its receptor offers a therapeutic approach for these conditions.

• Cytotoxic factors include tumour necrosis factor (TNF) which is similar to interleukin-1. Biological agents that block TNF, e.g. etanercept, infliximab are finding their place amongst drugs that modify the course of rheumatoid disease (and Crohn's disease, see p. 65).

• Interferons are so named because they were found to interfere with replication of live virus in tissue culture. Interferon alfa is used for a variety of neoplastic conditions (see Table 30.3) and for chronic active hepatitis.

• Colony-stimulating factors have been developed to treat neutropenic conditions, e.g. filgrastim (recombinant human granulocyte colony stimulating factor, G-CSF) and molgramostim (recombinant human granulocyte macrophage-colony stimulating factor, GM-CSF) (see Ch. 30).

Eicosanoids

Eicosanoids (prostaglandins, thromboxanes, leuko-trienes, lipoxins) is the name given to a group of 20-carbon1 unsaturated fatty acids derived principally from arachidonic acid in cell walls. They are shortlived, extremely potent and formed in almost every tissue in the body. Eicosanoids are involved in most types of inflammation and it is on manipulation of their biosynthesis that most present anti-inflammatory therapy is based. Their bio-synthetic paths appear in Figure 15.1 and are amplified by the following account.

• Arachidonic acid is stored mainly in phospholipids of cell walls, from which it is mobilised largely by the action of phospholipase. Glucocorticoids prevent the formation of arachidonic acid by inducing the synthesis of an inhibitory polypeptide called lipocortin-1; the capacity to inhibit the subsequent formation of both prostaglandins and leukotrienes, explains part of the powerful anti-inflammatory effect of glucocorticoids (for other actions, see p. 664).

• Arachidonic acid is further metabolised by cyclo-oxygenase (COX, also called PGH synthase), which changes the linear fatty acids into the cyclical structures of the prostaglandins. Nonsteroidal anti-inflammatory drugs (NSAIDs) act exert their anti-inflammatory effects by inhibiting COX.

• COX exists as two different types, COX-1 and COX-2. The isoform COX-1 is predominantly constitutive2 (although activity is increased 2-4-fold by inflammatory stimuli); it is present in

1 The Greek word for 20 is eicosa, hence the term eisocanoid.

2 Constantly produced by the cell regardless of growth conditions.

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