THE ACUTE-PHASE RESPONSE IN THE PATHOGENESIS OF INFLAMMATORY DISEASE - PROSPECTS FOR PHARMACOTHERAPY

Trauma and many diseases are followed or accompanied by a sequence of cellular and molecular reparative reactions known as the acute phase response. The early, or local, part of the acute phase response is initiated by release of proinflammatory cytokines at site(s) of tissue injury and cell necrosis, and is amplified by the formation of chemotactic peptides (chemokines) that cause leucocyte infiltration. The late, systemic, part of the acute phase response is characterised by a second wave of cytokine production that initiates cellular and cytokine cascades that temporarily alter metabolism in nearly all organ systems of the body. If tissue injury and cell necrosis are massive or recurrent, chronic inflammation ensues, with self-propagating tissue remodelling and fibrosis. Knowledge of the acute phase response can be applied to pharmacotherapy in various ways: (a) anticytokine strategies can be applied to diseases with either acute or chronic inflammatory components to ameliorate the disease process; (b) interpretation of standard clinical measurements, such as plasma lipid concentrations as indicators of coronary artery disease, is subject to the confounding influences of early and late acute phase reactants; and (c) acute phase reactants can be used as surrogate markers of proinflammatory cytokines in clinical monitoring of disease therapy. Treatment of diseases with a chronic inflammatory component, such as arthritis, can be expected to require different intervention strategies from those with an acute inflammatory component, such as sepsis and septic shock. However, characterisation of cells and cytokines at each stage of either acute or chronic inflammation will be necessary for adequate definition of intervention strategies.