Role of endogenous carbon monoxide/heme oxygenase (CO/HO) system in the development of hypoxic pulmonary hypertension

Objective To explore the changing regularity of endogenous CO/HO system under chronic hypoxic condition, and the role of CO/HO on the development of hypoxic pulmonary hypertension. Methods The first forty-two Wistar rats were randomly divided into five groups, hypoxia 0, 1, 3, 7, 14 days respectively. The second eighteen Wistar rats were randomly divided into control group, hypoxic group and hypoxic with ZnPP group. Pulmonary artery mean pressure(mPAP) of each rat was evaluated using right cardiac catheterization. The heart was excised and weighed, and the right-to-left heart weight ratio was determined. The indirect production of CO in plasma and pulmonary tissue homogenates was detected by the double-wavelength spectrophotometer. The lung tissue of the first rats were inflation fixed, and the expressions and localization of HO-1 were studied by immunohistochemistry. Results Steady pulmonary hypertension and right ventricular hypertrophy were detected after 7 to 14 days of hypoxia compared with control (P<0.01). The production of CO in the lung tissue homogenates and plasma significantly increased after exposure to hypoxic condition 1 day and 14 days, respectively(P<0.01). In control rat lungs, HO-1 staining was primarily detected in alveolar macrophages. After 1 and 3 days of hypoxia, increased numbers of inflammatory cells were present in the lung and the macrophages stained intensely for HO-1. After 7 and 14 days of hypoxia, HO-1 staining presented in the thickened smooth muscle layer in many small pulmonary arteries was increased significantly(F=8.72, P<0.001). Treatment with ZnPP, an inhibitor of HO, decreased the production of CO in the lung tissue homogenates and plasma and enhanced the mPAP compared with rats exposed to hypoxic condition alone(P<0.01). Conclusion The endogenous CO/HO system in pulmonary arteries under chronic hypoxic condition increased in a time-dependent two-peak manner, the second increase having a very intimate correlation with the pulmonary artery pressure. Endogenous CO/HO serves as an important regulatory system in hypoxic pulmonary hypertension. The mechanisms underlying this effect might involve a direct vasodilating and antiproliferative action of endogenous CO, as well as an indirect effect of CO on the production of vasoconstrictors. Key words: Carbon monoxide; Heme oxygenase (decyclizing); Hypertension, pulmonary; Anoxia