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This Article Full Text Full Text (PDF) All Versions of this Article: 288/3/L523    most recent 00199.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Offer, S. Articles by Shoseyov, D. Search for Related Content PubMed PubMed Citation Articles by Offer, S. Articles by Shoseyov, D.

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

¹Institute of Biochemistry, Faculty of Agriculture, The Hebrew University, and ⁴Pulmonary Unit, Kaplan Hospital, Rehovot; ²Department of Biochemistry, Hebrew University-Hadassah Medical School, and ⁵Department of Pediatrics, Hadassah University Hospital, Mount Scopus, Jerusalem; and ³Department of Pediatrics, Barzilai Medical Center, Ashkelon, Israel

Submitted 28 May 2004 ; accepted in final form 14 November 2004

Phospholipase A₂ (PLA₂) hydrolyzes cell membrane phospholipids (PL) to produce arachidonic acid and lyso-PL. 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 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 sPLA₂ 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 sPLA₂ 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.

asthma; cysteinyl leukotrienes; prostaglandin E₂; secretory phospholipase A₂ inhibitors

This article has been cited by other articles:

				D Shoseyov, H Bibi, S Offer, O Schwob, M Krimsky, M Kleiman, and S Yedgar Treatment of ovalbumin-induced experimental allergic bronchitis in rats by inhaled inhibitor of secretory phospholipase A2 Thorax, September 1, 2005; 60(9): 747 - 753. [Abstract] [Full Text] [PDF]