Negative feedback between secretory and cytosolic phospholipase A₂ and their opposing roles in ovalbumin-induced bronchoconstriction in rats

Abstract

Negative feedback between secretory and cytosolic phospholipase A2 and their opposing roles in ovalbumin-induced bronchoconstriction in rats. Am J Physiol Lung Cell Mol Physiol 288: L523-L529, 2005. First published November 19, 2004 doi:10.1152/ajplung.00199.2004.-Phospholipase A2 (PLA2) hydrolyzes cell membrane phospholipids (PL) to produce arachidonic acid and lyso-PL. The PLA 2 enzymes include the secretory (sPLA 2) 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 bronchoconstrictor cysteinyl leukotrienes (CysLT) is linked exclusively to sPLA2, whereas the bronchodilator prostaglandin PGE 2 is produced by cPLA 2. It has been further reported that the capacity of airway epithelial cells to produce CysLT is inversely proportional to PGE 2 production. This seems to suggest that sPLA2 and cPLA2 play opposing roles in asthma pathophysiology and the possibility of a negative feedback between the two isoenzymes. To test this hypothesis, we examined the effect of a cell-impermeable extracellular sPLA2 inhibitor on bronchoconstriction and PLA2 expression in rats with ovalbumin (OVA)-induced asthma. It was found that OVAinduced bronchoconstriction 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 sPLA 2 inhibitor, resulting in amelioration of bronchoconstriction and reduced CysLT production and sPLA2 expression, concomitantly with enhanced PGE2 production and cPLA 2 expression. This study demonstrates, for the first time in vivo, a negative feedback between sPLA 2 and cPLA2 and assigns opposing roles for these enzymes in asthma pathophysiology: sPLA 2 activation induces production of the bronchoconstrictor CysLT and suppresses cPLA2 expression and the subsequent production of the bronchodilator PGE 2.

Treatment of ovalbumin-induced experimental allergic bronchitis in rats by inhaled inhibitor of secretory phospholipase A2

“…This hypothesis was strongly supported by our recent study with an experimental allergic bronchitis model in rats 15 which showed that ovalbumin (OVA) induced bronchoconstriction is associated with an increase in sPLA 2 and CysLT levels and suppression of cPLA 2 and PGE 2 levels. Furthermore, these processes were reversed by treatment with an extracellular sPLA 2 inhibitor (ExPLI), suggesting a pivotal role for sPLA 2 in the pathophysiology of allergy.…”

Secretory phospholipases A2 in inflammatory and allergic diseases: Not just enzymes

“…Recently, using an extracellular inhibitor of sPLA 2 s in a murine model of asthma, Offer et al 50 showed that sPLA 2 s induce primarily cysteinyl leukotriene generation, whereas cPLA 2 is mainly responsible for prostaglandin E 2 production. These results suggest that cPLA 2 s and sPLA 2 s might have opposing roles in asthma and that their selective inhibition could be a novel pharmacologic approach to modulate eicosanoid formation.…”

Diverse Functions of Secretory Phospholipases A2

“…Using specific inhibitors, it has been demonstrated that sPLA 2 and cPLA 2 play opposing roles in asthma pathophysiology with sPLA 2 s linked to the production of the bronchoconstrictor Cys-LT whereas cPLA 2 promotes the production of the bronchodilator PGE2. In cells that play a key role in asthma, namely, human eosinophils and basophils, PGE2 is produced from a cPLA 2 -linked pool [20,[22][23][24]. sPLA 2 s are found at high levels in bronchoalveolar lavage (BAL) fluid and bronchotracheal smooth muscle cells [25,26].…”

“…In contrast, 12/15-lipoxygenase products are generally considered protective [18,19]. PGD2; thromboxane A2 (TXA2) and cysteinyl leukotrienes (cys-LTs) are reported to function as bronchoconstrictors while PGE2 is considered to act as bronchodilator [20].…”