Cathcart Mary-Clare, Tamosiuniene Rasa, Chen Gang, Neilan Tomas G, Bradford Aidan, O'Byrne Kenneth J, Fitzgerald Desmond J, Pidgeon Graham P
Department of Molecular and Cellular Therapeutics, Royal College of Surgeons Ireland, Dublin, Ireland.
J Pharmacol Exp Ther. 2008 Jul;326(1):51-8. doi: 10.1124/jpet.107.134221. Epub 2008 Mar 28.
Exogenous prostacyclin is effective in reducing pulmonary vascular resistance in some forms of human pulmonary hypertension (PH). To explore whether endogenous prostaglandins played a similar role in pulmonary hypertension, we examined the effect of deleting cyclooxygenase (COX)-gene isoforms in a chronic hypoxia model of PH. Pulmonary hypertension, examined by direct measurement of right ventricular end systolic pressure (RVESP), right ventricular hypertrophy (n = 8), and hematocrit (n = 3), was induced by 3 weeks of hypobaric-hypoxia in wild-type and COX-knockout (KO) mice. RVESP was increased in wild-type hypoxic mice compared with normoxic controls (24.4 +/- 1.4 versus 13.8 +/- 1.9 mm Hg; n = 8; p < 0.05). COX-2 KO mice showed a greater increase in RVESP following hypoxia (36.8 +/- 2.7 mm Hg; p < 0.05). Urinary thromboxane (TX)B(2) excretion increased following hypoxia (44.6 +/- 11.1 versus 14.7 +/- 1.8 ng/ml; n = 6; p < 0.05), an effect that was exacerbated by COX-2 gene disruption (54.5 +/- 10.8 ng/ml; n = 6). In contrast, the increase in 6-keto-prostacyclin(1alpha) excretion following hypoxia was reduced by COX-2 gene disruption (29 +/- 3 versus 52 +/- 4.6 ng/ml; p < 0.01). Tail cut bleed times were lower following hypoxia, and there was evidence of intravascular thrombosis in lung vessels that was exacerbated by disruption of COX-2 and reduced by deletion of COX-1. The TXA(2)/endoperoxide receptor antagonist ifetroban (50 mg/kg/day) offset the effect of deleting the COX-2 gene, attenuating the hypoxia-induced rise in RVESP and intravascular thrombosis. COX-2 gene deletion exacerbates pulmonary hypertension, enhances sensitivity to TXA(2), and induces intravascular thrombosis in response to hypoxia. The data provide evidence that endogenous prostaglandins modulate the pulmonary response to hypoxia.
外源性前列环素对某些类型的人类肺动脉高压（PH）有效，可降低肺血管阻力。为探究内源性前列腺素在肺动脉高压中是否发挥类似作用，我们在慢性低氧性肺动脉高压模型中研究了环氧化酶（COX）基因亚型缺失的影响。通过直接测量右心室收缩末期压力（RVESP）、右心室肥厚（n = 8）和血细胞比容（n = 3）来评估肺动脉高压，野生型和COX基因敲除（KO）小鼠经3周低压低氧诱导产生肺动脉高压。与常氧对照组相比，野生型低氧小鼠的RVESP升高（24.4±1.4对13.8±1.9 mmHg；n = 8；p < 0.05）。COX - 2基因敲除小鼠在低氧后RVESP升高幅度更大（36.8±2.7 mmHg；p < 0.05）。低氧后尿血栓素（TX）B2排泄增加（44.6±11.1对14.7±1.8 ng/ml；n = 6；p < 0.05），COX - 2基因破坏使该效应加剧（54.5±10.8 ng/ml；n = 6）。相反，COX - 2基因破坏降低了低氧后6 - 酮 - 前列环素（1α）排泄的增加（29±3对52±4.6 ng/ml；p < 0.01）。低氧后断尾出血时间缩短，且有证据表明肺血管内有血栓形成，COX - 2破坏使其加剧，COX - 1缺失使其减轻。血栓素A2/内过氧化物受体拮抗剂伊非曲班（50 mg/kg/天）抵消了COX - 2基因缺失的影响，减轻了低氧诱导的RVESP升高和血管内血栓形成。COX - 2基因缺失加剧了肺动脉高压，增强了对血栓素A2的敏感性，并在低氧时诱导血管内血栓形成。这些数据提供了内源性前列腺素调节肺对低氧反应的证据。
