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首页> 外文期刊>American Journal of Physiology >Negative feedback between secretory and cytosolic phospholipase A2 and their opposing roles in ovalbumin-induced bronchoconstriction in rats.
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Negative feedback between secretory and cytosolic phospholipase A2 and their opposing roles in ovalbumin-induced bronchoconstriction in rats.

机译：分泌和胞质磷脂酶A2之间的负反馈及其在大鼠卵白蛋白引起的支气管收缩中的相反作用。

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摘要

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.
机译：磷脂酶A2（PLA2）水解细胞膜磷脂（PL），生成花生四烯酸和溶血PL。 PLA2酶包括分泌型（sPLA2）和胞质型（cPLA2）同工型，假定它们在涉及炎症过程的类花生酸的生产中具有协同作用。然而，越来越多的证据提出在气道和哮喘相关的炎症细胞（嗜酸性粒细胞，嗜碱性粒细胞）中，支气管收缩半胱氨酸白三烯（CysLT）的产生仅与sPLA2相关，而支气管扩张剂前列腺素PGE2由cPLA2产生。进一步报道，气道上皮细胞产生CysLT的能力与PGE 2产生成反比。这似乎表明sPLA2和cPLA2在哮喘的病理生理中起相反的作用，并且两种同工酶之间可能产生负反馈。为了验证该假设，我们检查了卵白蛋白（OVA）诱发的哮喘大鼠中细胞不可渗透的细胞外sPLA2抑制剂对支气管收缩和PLA2表达的影响。发现OVA诱导的支气管收缩与肺sPLA2表达和CysLT产生的升高有关，同时与cPLA2表达和PGE2产生的抑制有关。通过用sPLA2抑制剂治疗可以逆转这些症状，从而改善支气管收缩，减少CysLT产生和sPLA2表达，同时增加PGE2产生和cPLA2表达。这项研究首次证明了sPLA2和cPLA2之间的负反馈，并为这些酶在哮喘病理生理学中赋予了相反的作用：sPLA2激活诱导了支气管收缩剂CysLT的产生并抑制了cPLA2的表达以及随后的支气管扩张剂PGE2的产生。

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