Mio T, Liu X, Toews M L, Adachi Y, Romberger D J, Spurzem J R, Rennard S I
Pulmonary and Critical Care Medicine Section, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198-5125, USA.
Am J Physiol Lung Cell Mol Physiol. 2001 Jul;281(1):L164-71. doi: 10.1152/ajplung.2001.281.1.L164.
Bradykinin is a multifunctional mediator of inflammation believed to have a role in asthma, a disorder associated with remodeling of extracellular connective tissue. Using contraction of collagen gels as an in vitro model of wound contraction, we assessed the effects of bradykinin tissue on remodeling. Human fetal lung fibroblasts were embedded in type I collagen gels and cultured for 5 days. After release, the floating gels were cultured in the presence of bradykinin. Bradykinin significantly stimulated contraction in a concentration- and time-dependent manner. Coincubation with phosphoramidon augmented the effect of 10(-9) and 10(-8) M bradykinin. A B2 receptor antagonist attenuated the effect of bradykinin, whereas a B1 receptor antagonist had no effect, suggesting that the effect is mediated by the B2 receptor. An inhibitor of intracellular Ca2+ mobilization abolished the response; addition of EGTA to the culture medium attenuated the contraction of control gels but did not modulate the response to bradykinin. In contrast, the phospholipase C inhibitor U-73122 and the protein kinase C inhibitors staurosporine and GF-109203X attenuated the responses. These data suggest that by augmenting the contractility of fibroblasts, bradykinin may have an important role in remodeling of extracellular matrix that may result in tissue dysfunction in chronic inflammatory diseases, such as asthma.
缓激肽是一种多功能炎症介质，被认为在哮喘中起作用，哮喘是一种与细胞外结缔组织重塑相关的疾病。我们使用胶原蛋白凝胶收缩作为伤口收缩的体外模型，评估了缓激肽对重塑的影响。将人胎儿肺成纤维细胞包埋在I型胶原蛋白凝胶中并培养5天。释放后，将漂浮的凝胶在缓激肽存在下培养。缓激肽以浓度和时间依赖性方式显著刺激收缩。与磷酰胺共同孵育增强了10(-9)和10(-8)M缓激肽的作用。B2受体拮抗剂减弱了缓激肽的作用，而B1受体拮抗剂则无作用，这表明该作用是由B2受体介导的。细胞内Ca2+动员抑制剂消除了反应；向培养基中添加EGTA减弱了对照凝胶的收缩，但未调节对缓激肽的反应。相反，磷脂酶C抑制剂U-73122以及蛋白激酶C抑制剂星形孢菌素和GF-109203X减弱了反应。这些数据表明，通过增强成纤维细胞的收缩性，缓激肽可能在细胞外基质重塑中起重要作用，并可能导致慢性炎症性疾病（如哮喘）中的组织功能障碍。
