Tozzi Carol A, Poiani George J, McHugh Nansie A, Shakarjian Michael P, Grove Beverly H, Samuel Chrishan S, Unemori Elaine N, Riley David J
Department of Medicine, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854-5635, USA.
Pulm Pharmacol Ther. 2005;18(5):346-53. doi: 10.1016/j.pupt.2005.01.003.
The fibroproliferative changes in pulmonary artery (PA) remodeling are partially prevented by antifibrotic agents. Relaxin (Rlx), a hormone involved in loosening collagen bundles in ligaments during parturition, has antifibrotic and vasodilator properties that may prevent pulmonary vascular remodeling. In the hypoxia model of pulmonary hypertension, two doses of recombinant human relaxin (rhRlx 24 [high] or 5 [low] mg X 10(-2)/kg d(-1)) were administered subcutaneously continuously for 10d to hypoxic (10% O2) rats. At day 11, right ventricular pressure (Pa X 10(2)) was reduced by rhRlx in a dose-dependent manner (15 +/- 1* control; 28 +/- 1 hypoxia; 23 +/- 1* low; 20+/-1* high; n = 10-14/group, *P < 0.05 vs. hypoxia). High rhRlx ameliorated increased collagen accumulation (mug hydroxyproline/vessel) in main PAs (87 +/- 6) vs. untreated hypoxia (102 +/- 2) (n=5/group, P < 0.05). Infusion of rhRlx had no effect on air-breathing rats, and acute administration did not alter blood pressure in hypoxic rats. Fibroblasts cultured from rat PAs spontaneously expressed collagen and fibronectin, and treatment with TGF-beta increased secretion 26- and 25 X 10(-1)-fold, respectively. Addition of rhRlx to transforming growth factor-beta-stimulated fibroblasts inhibited collagen (37%) and fibronectin (38%) secretion vs. vehicle (n = 4 per group, both P < 0.05). We conclude that rhRlx inhibits the early fibroproliferative response in hypoxic pulmonary hypertension and the mechanism may be due in part to suppression of collagen synthesis.
抗纤维化药物可部分预防肺动脉（PA）重塑中的纤维增殖性变化。松弛素（Rlx）是一种在分娩过程中参与韧带中胶原束松弛的激素，具有抗纤维化和血管舒张特性，可能预防肺血管重塑。在肺动脉高压的低氧模型中，连续10天皮下给予两剂量的重组人松弛素（rhRlx 24 [高剂量] 或5 [低剂量] mg×10⁻²/kg d⁻¹）给低氧（10% O₂）大鼠。在第11天，rhRlx以剂量依赖性方式降低右心室压力（Pa×10²）（对照组为15±1；低氧组为28±1；低剂量组为23±1；高剂量组为20±1；每组n = 10 - 14，*与低氧组相比P < 0.05）。高剂量rhRlx改善了主肺动脉中胶原积累增加（微克羟脯氨酸/血管）的情况，与未治疗的低氧组（102±2）相比为（87±6）（每组n = 5，P < 0.05）。rhRlx输注对呼吸空气的大鼠无影响，急性给药也未改变低氧大鼠的血压。从大鼠肺动脉培养的成纤维细胞自发表达胶原蛋白和纤连蛋白，用转化生长因子-β处理分别使分泌增加26倍和25×10⁻¹倍。在转化生长因子-β刺激的成纤维细胞中添加rhRlx可抑制胶原蛋白（37%）和纤连蛋白（38%）的分泌，与溶剂对照组相比（每组n = 4，两者P < 0.05）。我们得出结论，rhRlx抑制低氧性肺动脉高压中的早期纤维增殖反应，其机制可能部分归因于对胶原合成的抑制。
