Henderson William R
School of Medicine, University of Washington, Seattle, Washington, USA.
J Asthma. 2008;45 Suppl 1:10-2. doi: 10.1080/02770900802569751.
Phospholipases mediate the release of arachidonic acid from membrane phospholipids, enabling the subsequent metabolism to potent inflammatory mediator products of cyclooxygenase and lipoxygenase enzymes, such as prostaglandins and leukotrienes. Cytosolic phospholipase A₂ has long been recognized as important, but newly characterized are secreted A₂ isoenzymes. These secretory phospholipases are released into the extracellular compartment on cell activation. Elevated levels have been found in allergic patients after allergen challenge. Earlier investigations in a mouse asthma model utilizing airway challenges with allergen showed an important role for cysteinyl leukotrienes in the airway remodeling process. Utilizing secretory phospholipase knockout mice, group X deficiency significantly diminished the airway goblet cell metaplasia, mucus hypersecretion, increased airway smooth muscle mass, and subepithelial fibrosis observed in wild type mice after allergen challenge. The mechanism is likely through impaired generation of cysteinyl leukotrienes in the knockout mice. Recent human investigation in patients with exercise induced bronchoconstriction is supportive of a role of secretory phospholipase, directing attention to these enzymes as particularly attractive pharmacologic targets in asthma.
磷脂酶介导花生四烯酸从膜磷脂中释放出来，使得花生四烯酸随后能够被环氧合酶和脂氧合酶代谢为强效的炎症介质产物，如前列腺素和白三烯。胞质磷脂酶A₂长期以来一直被认为很重要，但新发现的分泌型A₂同工酶也具有特征。这些分泌型磷脂酶在细胞活化时被释放到细胞外区室。在变应原激发后的过敏患者中发现其水平升高。早期在小鼠哮喘模型中利用变应原进行气道激发的研究表明，半胱氨酰白三烯在气道重塑过程中起重要作用。利用分泌型磷脂酶基因敲除小鼠，X组缺乏显著减少了变应原激发后野生型小鼠中观察到的气道杯状细胞化生、黏液分泌过多、气道平滑肌质量增加和上皮下纤维化。其机制可能是基因敲除小鼠中半胱氨酰白三烯的生成受损。最近对运动诱发性支气管收缩患者的人体研究支持分泌型磷脂酶的作用，这使得人们将注意力转向这些酶，认为它们是哮喘中特别有吸引力的药物靶点。
