Phospholipase A₂ (PLA₂) hydrolyzes cell membrane phospholipids (PL) to produce arachidonic acid (AA) and lyso-phospholipids (LysoPL). The PLA₂ enzymes include the secretory (sPLA₂) and cytosolic (cPLA₂) isoforms, which are assumed to act synergistically in production of eicosanoids that are involved in inflammatory processes. However, growing evidence raises the possibility that in airways and asthma-related inflammatory cells (eosinophils, basophils), the production of the broncho-constrictors cysteinyl-leukotrienes (CysLT) is linked exclusively to sPLA₂, while the bronchodilator prostaglandin PGE₂ is produced by cPLA₂. It has been further reported that the capacity of airway epithelial cells to produce CysLTs is inversely proportional to PGE₂ production. This seems to suggest that sPLA₂ and cPLA₂ play opposing roles in asthma pathophysiology, and possibly a negative feed-back between the two iso-enzymes. To test this hypothesis, we have examined the effect of a cellimpermeable extracellular sPLA₂ inhibitor on broncho-constriction and PLA₂ expression in rats with ovalbumin (OVA)-induced asthma. It was found that OVA-induced broncho-constriction was associated with elevation of lung sPLA₂ expression and CysLT production, concomitantly with suppression of cPLA₂ expression and PGE₂ production. These were reversed by treatment with the sPLA₂ inhibitor, resulting in amelioration of broncho-constriction, reduced CysLT production and sPLA₂ expression, concomitantly with enhanced PGE₂ production and cPLA₂ expression. This study demonstrates, for the first time in vivo, a negative feed-back between sPLA₂ and cPLA₂ and assigns opposing roles for these enzymes in asthma pathophysiology: sPLA₂ activation induces production of the broncho-constrictor CysLTs, and suppresses cPLA₂ expression and the subsequent production of the broncho-dilator PGE₂.