Negative feedback between secretory and cytosolic phospholipase A 2 and their opposing roles in ovalbumin-induced bronchoconstriction in rats

Sarit Offer, Saul Yedgar, Ouri Schwob, Miron Krimsky, Haim Bibi, Abraham Eliraz, Zecharia Madar, David Shoseyov

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Phospholipase A2 (PLA2) hydrolyzes cell membrane phospholipids (PL) to produce arachidonic acid and lyso-PL. The PLA2 enzymes include the secretory (sPLA2) and cytosolic (cPLA 2) 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 PGE2 is produced by cPLA2. It has been further reported that the capacity of airway epithelial cells to produce CysLT is inversely proportional to PGE2 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 OVA-induced 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 cPLA2 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: sPLA2 activation induces production of the bronchoconstrictor CysLT and suppresses cPLA2 expression and the subsequent production of the bronchodilator PGE2.

Original languageEnglish
Pages (from-to)L523-L529
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume288
Issue number3 32-3
DOIs
StatePublished - 1 Mar 2005
Externally publishedYes

Keywords

  • Asthma
  • Cysteinyl leukotrienes
  • Prostaglandin E
  • Secretory phospholipase A inhibitors

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