Delong P, O'Sullivan M G, Huggins E, Hubbard C L, McCall C
Section on Infectious Diseases, Department of Medicine, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157-1042, USA.
Am J Respir Cell Mol Biol. 1999 Mar;20(3):493-9. doi: 10.1165/ajrcmb.20.3.3409.
Two genes encode proteins with prostaglandin G/H synthase (PGHS) activity. PGHS-1 is primarily a constitutively expressed gene, whereas inflammatory agents such as bacterial lipopolysaccharide (LPS) endotoxin rapidly induce the PGHS-2 gene in leukocytes. Both PGHS-1 and PGHS-2 are rate-limiting enzymes for the production of prostaglandins and thromboxane following release of arachidonic acid by phospholipases. We previously reported that LPS perfusion into the circulation of isolated perfused rabbit lung (IPL) results in thromboxane-dependent pulmonary hypertension and lung edema when the LPS-primed lung is subsequently stimulated with platelet activating factor (PAF) (J. Clin. Invest. 1990;85:1135). In this study, we showed that the mechanism by which LPS primes IPL for enhanced production of thromboxane and pulmonary hypertension in response to PAF depends on specific upregulation of the PGHS-2 gene in the rabbit lung. LPS perfusion of IPL induced PGHS-2 gene expression, which correlated with the conversion of free arachidonic acid to thromboxane-B2 (TXB2) and the onset of pulmonary hypertension. LPS-induced PGHS-2 expression, TXB2 release, and pulmonary hypertension were inhibited by actinomycin D (an inhibitor of transcription) and cycloheximide (an inhibitor of protein synthesis). The constitutively expressed PGHS-1 remained unchanged with LPS perfusion, and did not convert free arachidonic acid to TXB2, suggesting that PGHS-1 does not contribute to the induction of pulmonary hypertension by LPS. These studies reveal a pathogenic role for induction of PGHS-2 in lung injury.
有两个基因编码具有前列腺素G/H合酶（PGHS）活性的蛋白质。PGHS-1主要是一个组成型表达基因，而诸如细菌脂多糖（LPS）内毒素等炎症因子可在白细胞中快速诱导PGHS-2基因。PGHS-1和PGHS-2都是磷脂酶释放花生四烯酸后前列腺素和血栓素生成的限速酶。我们先前报道，当用血小板活化因子（PAF）刺激预先用LPS处理过的离体灌注兔肺（IPL）时，将LPS灌注到IPL循环中会导致血栓素依赖性肺动脉高压和肺水肿（《临床研究杂志》1990年；85:1135）。在本研究中，我们表明LPS使IPL对PAF诱导的血栓素生成增加和肺动脉高压致敏的机制取决于兔肺中PGHS-2基因的特异性上调。IPL的LPS灌注诱导了PGHS-2基因表达，这与游离花生四烯酸向血栓素B2（TXB2）的转化以及肺动脉高压的发生相关。放线菌素D（一种转录抑制剂）和环己酰亚胺（一种蛋白质合成抑制剂）可抑制LPS诱导的PGHS-2表达、TXB2释放和肺动脉高压。组成型表达的PGHS-1在LPS灌注后保持不变，并且不会将游离花生四烯酸转化为TXB2，这表明PGHS-1对LPS诱导的肺动脉高压没有作用。这些研究揭示了PGHS-2的诱导在肺损伤中的致病作用。
