Inhibition of calcium-independent phospholipase A2 prevents inflammatory mediator production in pulmonary microvascular endothelium.
Inhibition of calcium-independent phospholipase A2 prevents inflammatory mediator production in pulmonary microvascular endothelium.
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DOI：
10.1016/j.resp.2008.11.006
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发表时间：
2009-02-28
影响因子：
2.3
通讯作者：
McHowat, Jane
中科院分区：
文献类型：
--
作者：
Rastogi, Prerna;McHowat, Jane
关键词：
吸入过敏原会导致肥大细胞脱颗粒，并在肺内释放颗粒内容物，包括类胰蛋白酶。人肺微血管内皮细胞的损伤也可导致凝血级联反应的激活和凝血酶的生成。我们推测这些酶激活血管内皮细胞内钙非依赖性磷脂酶A2(IPLA2)，导致膜磷脂衍生的炎症介质的产生。凝血酶和类胰蛋白酶刺激人脐静脉内皮细胞-L均可增加iPLA2活性，而iPLA2选择性抑制剂溴烯醇内酯(BEL)可抑制这种活性。在类胰蛋白酶和凝血酶刺激的细胞中，花生四烯酸和前列腺素I2(PGI2)的释放也增加，而BEL预处理则抑制。胞内PLA2抑制剂AACOCF3不能抑制类胰蛋白酶或凝血酶诱导的花生四烯酸和前列腺素I2的释放。此外，凝血酶和类胰蛋白酶还可增加血管内皮细胞L血小板激活因子的产生，从而显著促进中性粒细胞在内皮细胞上的募集和初始黏附。类胰蛋白酶或凝血酶刺激的中性粒细胞与内皮细胞黏附的增加可被BEL预处理或PAF受体特异性拮抗剂CV3988预处理。总之，这些数据支持我们的假设，即在HMVEC-L中，iPLA2活性是响应类胰蛋白酶或凝血酶刺激而导致膜磷脂水解的。因此，选择性抑制iPLA2可能是抑制肥大细胞脱颗粒或急性肺损伤所致肺血管早期炎症的药理作用靶点。
Inhalation of allergens can result in mast cell degranulation and release of granule contents, including tryptase, in the lung. Injury to human pulmonary microvascular endothelial cells (HMVEC-L) can also result in activation of the coagulation cascade and thrombin generation. We hypothesize that these proteases activate calcium-independent phospholipase A2 (iPLA2), in HMVEC-L, leading to the production of membrane phospholipids-derived inflammatory mediators. Both thrombin and tryptase stimulation of HMVEC-L increased iPLA2 activity that was inhibited by pretreatment with the iPLA2 selective inhibitor bromoenol lactone (BEL). Arachidonic acid and prostaglandin I2 (PGI2) release were also increased in tryptase and thrombin stimulated cells and inhibited by BEL pretreatment. Pretreating the endothelial cells with AACOCF3 a cytosolic PLA2 inhibitor did not inhibit tryptase or thrombin induced arachidonic acid and PGI2 release. In addition thrombin and tryptase also increased HMVEC-L platelet activating factor (PAF) production that significantly contributes to the recruitment and initial adherence of polymorphonuclear neutrophils (PMN) to the endothelium. Tryptase or thrombin stimulated increase in PMN adherence to the endothelium was inhibited by pretreatment of HMVEC-L with BEL or pretreatment of PMN with CV3988, a PAF receptor specific antagonist. Collectively, these data support our hypothesis that iPLA2 activity is responsible for membrane phospholipid hydrolysis in response to tryptase or thrombin stimulation in HMVEC-L. Therefore selective inhibition of iPLA2 may be a pharmacological target to inhibit the early inflammation in pulmonary vasculature that occurs as a consequence of mast cell degranulation or acute lung injury.
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影响因子：
24.3
作者：
Carroll, NG;Mutavdzic, S;James, AL
通讯作者：
James, AL
DOI：
10.1111/j.1749-6632.1996.tb32563.x
发表时间：
1996-01-01
期刊：
CYTOKINES AND ADHESION MOLECULES IN LUNG INFLAMMATION
影响因子：
--
作者：
Liu, LX;Mul, FPJ;Knol, EF
通讯作者：
Knol, EF
DOI：
10.1164/ajrccm/144.1.83
发表时间：
1991-07-01
期刊：
AMERICAN REVIEW OF RESPIRATORY DISEASE
影响因子：
--
作者：
JARJOUR, NN;CALHOUN, WJ;BUSSE, WW
通讯作者：
BUSSE, WW
影响因子：
64.8
作者：
Coughlin, SR
通讯作者：
Coughlin, SR
影响因子：
82.9
作者：
Göggel, R;Winoto-Morbach, S;Uhlig, S
通讯作者：
Uhlig, S