Corl C M, Contreras G A, Sordillo L M
Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA.
Vet Immunol Immunopathol. 2010 Jul;136(1-2):98-107. doi: 10.1016/j.vetimm.2010.03.003. Epub 2010 Mar 11.
Endotoxin promotes the production of potent pro-inflammatory lipid mediators, such as platelet activating factor (PAF) and eicosanoids, which contribute to the pathophysiology of endotoxic shock. Endothelial cells are both a target for and producers of these lipid mediators so it is vital to understand the pathways leading to their production in these cells. Previous research suggested a positive feedback loop between eicosanoids and PAF during endotoxemia. This study sought to determine if eicosanoids derived from the 15-lipoxygenase (15-LOX1) pathway can modulate the biosynthesis of PAF in cultured bovine aortic endothelial cells (BAEC) following endotoxin stimulation. Endotoxin stimulation increased the production of 15-LOX1-derived eicosanoids prior to PAF in primary BAEC. Exogenous addition of specific 15-LOX1 eicosanoids, as well as overexpression of 15-LOX1 in endotoxin-stimulated BAEC, further increased the endotoxin-induced production of PAF. Whereas increased expression of 15-LOX1 activity can further exacerbate endotoxin-induced PAF biosynthesis, inhibition of 15-LOX1 activity is not capable of abrogating the initial onset of endotoxin-induced PAF production. The results indicate that 15-LOX1 activity is not necessary for the initial induction of PAF following endotoxin stimulation. There may exist, however, a role for elevated 15-LOX1 activity in further escalating the extent of PAF biosynthesis in BAEC during endotoxic shock. Determining factors that can potentiate endotoxin-induced vascular dysfunction may lead to the development of novel therapeutic targets to diminish the pathophysiological effects of endotoxic shock.
内毒素可促进强效促炎脂质介质的产生，如血小板活化因子（PAF）和类花生酸，这些介质参与了内毒素休克的病理生理过程。内皮细胞既是这些脂质介质的作用靶点，也是其产生者，因此了解这些细胞中导致其产生的途径至关重要。先前的研究表明，在内毒素血症期间，类花生酸和PAF之间存在正反馈回路。本研究旨在确定源自15-脂氧合酶（15-LOX1）途径的类花生酸是否能在内毒素刺激后调节培养的牛主动脉内皮细胞（BAEC）中PAF的生物合成。在内毒素刺激初级BAEC后，内毒素刺激先于PAF增加了15-LOX1衍生的类花生酸的产生。外源性添加特定的15-LOX1类花生酸，以及在内毒素刺激的BAEC中过表达15-LOX1，进一步增加了内毒素诱导的PAF产生。虽然15-LOX1活性的增加可进一步加剧内毒素诱导的PAF生物合成，但抑制15-LOX1活性并不能消除内毒素诱导的PAF产生的初始发作。结果表明，15-LOX1活性对于内毒素刺激后PAF的初始诱导并非必需。然而，在感染性休克期间，升高的15-LOX1活性可能在进一步扩大BAEC中PAF生物合成的程度方面发挥作用。确定可增强内毒素诱导的血管功能障碍的因素可能会导致开发新的治疗靶点，以减轻内毒素休克的病理生理效应。
