Gong Li-min, Du Jun-bao, Shi Lin, Shi Yun, Tang Chao-shu
Department of Pediatrics, First Hospital of Peking University, Xi An Men Street No. 1, Beijing 100034, PR China.
Life Sci. 2004 Jan 23;74(10):1225-41. doi: 10.1016/j.lfs.2003.07.046.
To study the role of endogenous carbon monoxide (CO) in collagen metabolism during hypoxic pulmonary vascular remodeling, a total of 18 Wistar rats were used in the study and they were randomly divided into three groups: hypoxia group (n = 6), hypoxia with zinc protoporphyrin-IX (ZnPP-IX) group (n = 6) and control group (n = 6). The measurement of mean pulmonary artery pressure (mPAP) and carboxyhemoglobin (HbCO) formation in lung tissue homogenates was measured. A morphometric analysis of pulmonary vessels was performed, in which the percentage of muscularized arteries (MA); partially muscularized arteries (PMA) and nonmuscularized arteries (NMV) in small and median pulmonary vessels, relative medial thickness (RMT) and relative medial area (RMA) of pulmonary arteries were analyzed. Collagen type I and III and transforming growth factor-beta3 (TGF-beta3) expressions were detected by immunohistochemical assay. The expressions of procollagen type I and III and TGF-beta3 mRNA were detected by in situ hybridization. The results showed that ZnPP-IX significantly increased mPAP and markedly decreased HbCO formation in lung tissue homogenates in rats under hypoxia (P < 0.01). In the hypoxia rats treated with ZnPP-IX, the percentage of muscularized arteries of small and median pulmonary vessels was obviously increased, and RMT and RMA of intra-acinar muscularized pulmonary arteries were markedly increased compared with hypoxic rats. Ultrastructural changes, such as hyperplasia and hypertrophy of endothelial cells (ECs) and smooth muscle cells (SMCs) and the increased number of SMCs in synthetic phenotype were found in intra-acinar pulmonary muscularized arteries of hypoxic rats treated with ZnPP-IX. Meanwhile, ZnPP-IX promoted the expression of collagen type I and III and TGF-beta3 protein in pulmonary arteries of rats under hypoxia (P < 0.01). Furthermore, ZnPP-IX elevated obviously the expressions of procollagen type I and III mRNA, and TGF-beta3 mRNA in pulmonary arteries of rats under hypoxia (P < 0.01). The results of this study suggested that ZnPP-IX played an important role in promoting collagen synthesis in pulmonary arteries of rats with hypoxic pulmonary structural remodeling by increasing the expression of TGF-beta3. The above findings also suggested a possible role of endogenous CO in the pathogenesis of chronic hypoxic pulmonary hypertension.
为研究内源性一氧化碳（CO）在缺氧性肺血管重塑过程中胶原代谢的作用，本研究共使用18只Wistar大鼠，将其随机分为三组：缺氧组（n = 6）、缺氧加锌原卟啉-IX（ZnPP-IX）组（n = 6）和对照组（n = 6）。测量平均肺动脉压（mPAP）以及肺组织匀浆中碳氧血红蛋白（HbCO）的生成量。对肺血管进行形态计量分析，分析中小肺血管中肌化动脉（MA）、部分肌化动脉（PMA）和非肌化动脉（NMV）的百分比，以及肺动脉的相对中膜厚度（RMT）和相对中膜面积（RMA）。采用免疫组织化学法检测I型和III型胶原蛋白以及转化生长因子-β3（TGF-β3）的表达。采用原位杂交法检测I型和III型前胶原蛋白以及TGF-β3 mRNA的表达。结果显示，ZnPP-IX显著升高了缺氧大鼠肺组织匀浆中的mPAP，并明显降低了HbCO的生成量（P < 0.01）。在接受ZnPP-IX治疗的缺氧大鼠中，中小肺血管的肌化动脉百分比明显增加，与缺氧大鼠相比，腺泡内肌化肺动脉的RMT和RMA显著增加。在接受ZnPP-IX治疗的缺氧大鼠的腺泡内肺肌化动脉中发现了超微结构变化，如内皮细胞（ECs）和平滑肌细胞（SMCs）的增生和肥大以及合成表型的SMC数量增加。同时，ZnPP-IX促进了缺氧大鼠肺动脉中I型和III型胶原蛋白以及TGF-β3蛋白的表达（P < 0.01）。此外，ZnPP-IX明显提高了缺氧大鼠肺动脉中I型和III型前胶原蛋白mRNA以及TGF-β3 mRNA的表达（P < 0.01）。本研究结果表明，ZnPP-IX通过增加TGF-β3的表达在促进缺氧性肺结构重塑大鼠肺动脉胶原合成中起重要作用。上述发现还提示内源性CO在慢性缺氧性肺动脉高压发病机制中可能发挥作用。
