Mechanisms of Regulation and Implication of Secretory Phospholipase A2 in the Development of Acute Lung Inflammation
Lhousseine Touqui
Abstract
Lung inflammation involves the activation of specific processes leading to the release of a variety of inflammatory mediators in the bronchoalveolar spaces. Some of these mediators are stored in active form in specific granules and released upon appropriate stimulation of their cell sources but other are present as inactive precursors. The latter are converted into active mediators during the initial step of inflammation through an enzymatic cascades catalyzed by specific enzymes. Lipid mediators are the best example of this type of mediators whose synthesis is catalyzed by phospholipase A2 (PLA2). Indeed, this enzyme hydrolyses phospholipids at the sn-2 position leading to concomitant generation of lyso-phospholipids and fatty acids. According to their molecular mass and location in mammalian cells these enzymes are divided into two major classes, the cytosolic form (cPLA2) and the secretory form (sPLA2). The type-II sPLA2 (sPLA2-II) is involved in the pathogenesis of various inflammatory diseases including Acute Respiratory Distress Syndrome (ARDS). This syndrome is characterized by arterial hypoxemia, noncardiogenic pulmonary oedema and alteration of pulmonary surfactant, a surface active film mainly composed by phospholipids that lowers surface tension along the alveolar epithelium. Up to date attempts to modify or to prevent the progressive respiratory deterioration during this disease have failed. Consequently, mortality with ARDS remains unacceptably high at 50 % or more. Recent studies on animal model of « ARDS » showed that sPLA2-II plays a major role in the hydrolysis of surfactant phospholipids, which was prevented by pre-treating animals with specific sPLA2-II inhibitors. These inhibitors also reduced the intensity of lung injury. Thus, the use of sPLA2-II inhibitors may be of a great help in ARDS therapy. Key words: ARDS, surfactant, PLA2, Prostaglandin E2, TNF