THE IMMUNE RESPONSE
The immune response occurs when immunologically competent cells are activated in response to foreign organisms or antigenic substances liberated during the acute or chronic inflammatory response. The outcome of the immune response for the host may be deleterious if it leads to chronic inflammation without resolu-tion of the underlying injurious process . Chronic inflammation involves the release of a number of mediators that are not prominent in the acute response. One of the most impor-tant conditions involving these mediators is rheumatoid arthritis, in which chronic inflammation results in pain and destruction of bone and cartilage that can lead to severe disability and in which systemic changes occur that can result in shortening of life.
The cell damage associated with inflammation acts on cell membranes to release leukocyte lysosomal enzymes; arachidonic acid is then liberated from precursor compounds, and various eicosanoids are synthesized. As discussed, the cyclooxygenase (COX) pathway of arachidonate metabolism pro-duces prostaglandins, which have a variety of effects on blood vessels, on nerve endings, and on cells involved in inflammation. The lipoxygenase pathway of arachidonate metabolism yields leu-kotrienes, which have a powerful chemotactic effect on eosinophils, neutrophils, and macrophages and promote bronchoconstriction and alterations in vascular permeability.
The discovery of two cyclooxygenase isoforms (COX-1 and COX-2) led to the concept that the constitutive COX-1 isoform tends to be homeostatic, while COX-2 is induced during inflam-mation and facilitates the inflammatory response. On this basis, highly selective COX-2 inhibitors have been developed and mar-keted on the assumption that such selective inhibitors would be safer than nonselective COX-1 inhibitors but without loss of efficacy.
Kinins, neuropeptides, and histamine are also released at the site of tissue injury, as are complement components, cytokines, and other products of leukocytes and platelets. Stimulation of the neutrophil membranes produces oxygen-derived free radicals and other reactive molecules such as hydrogen peroxide and hydroxyl radicals. The interaction of these substances with arachidonic acid results in the generation of chemotactic substances, thus perpetu-ating the inflammatory process.