Yamada Takehiro
Department of Hospital Pharmacy & Pharmacology, Asahikawa Medical College, Asahikawa, Hokkaido, Japan.
Yakugaku Zasshi. 2009 Oct;129(10):1211-4. doi: 10.1248/yakushi.129.1211.
Circulatory failure in septic shock is due to vascular hyporesponsiveness, in which a massive amounts of nitric oxide (NO) derived from inducible NO synthase (iNOS) plays a major role. In response to various inflammatory stimuli, prostanoids are also derived from inducible isoform of cyclooxygenase-2 (COX-2). Several reports on the cross talk between NO and prostanoids have been published; vasodilator prostanoids such as prostacyclin (PGI(2)) and prostaglandin E(2) enhance iNOS expression in cultured cells. However, the details of the cross talk between prostanoids and the iNOS-NO system remains unknown. We examined inflammatory cytokine-induced iNOS expression and NO production in cultured vascular smooth muscle cells (VSMCs) and cytokine-induced hyporesponsiveness of the aorta from mice lacking the thromboxane A(2) (TXA(2)) receptor (TP(-/-) mice). The cytokine-induced iNOS expression and NO production were significantly augmented in TP(-/-) VSMCs. Furthermore, U-46619, a TP agonist, inhibited the cytokine-induced iNOS expression and NO production. The cytokine-induced hyporesponsiveness of aortas to vasoconstrictor was significantly augmented in TP(-/-) aorta. Finally, U-46619 significantly suppressed lipopolysaccharide-induced NO production in vivo in wild-type mice, however, this effect was not observed in TP(-/-) mice. These results suggest that TXA(2) has a protective role against the development of the vascular hyporesponsiveness via its inhibitory action on iNOS-NO system under pathological conditions such as sepsis. Thus, it seems that the cross-talk between PG and NO works to maintain the vascular homeostasis in the systemic inflammatory reactions such as sepsis.
脓毒性休克中的循环衰竭是由于血管反应性降低，其中诱导型一氧化氮合酶（iNOS）产生的大量一氧化氮（NO）起主要作用。响应各种炎症刺激，前列腺素也来源于环氧化酶-2（COX-2）的诱导型同工型。已经发表了几篇关于NO与前列腺素之间相互作用的报道；血管舒张性前列腺素如前列环素（PGI₂）和前列腺素E₂增强培养细胞中iNOS的表达。然而，前列腺素与iNOS-NO系统之间相互作用的细节仍不清楚。我们研究了炎症细胞因子诱导的培养血管平滑肌细胞（VSMC）中iNOS的表达和NO的产生，以及缺乏血栓素A₂（TXA₂）受体的小鼠（TP⁻/⁻小鼠）的细胞因子诱导的主动脉反应性降低。细胞因子诱导的iNOS表达和NO产生在TP⁻/⁻ VSMC中显著增强。此外，TP激动剂U-46619抑制细胞因子诱导的iNOS表达和NO产生。细胞因子诱导的主动脉对血管收缩剂的反应性降低在TP⁻/⁻主动脉中显著增强。最后，U-46619在野生型小鼠体内显著抑制脂多糖诱导的NO产生，然而，在TP⁻/⁻小鼠中未观察到这种作用。这些结果表明，在脓毒症等病理条件下，TXA₂通过对iNOS-NO系统的抑制作用，对血管反应性降低的发展具有保护作用。因此，PG和NO之间的相互作用似乎在脓毒症等全身炎症反应中维持血管稳态。
