Horie Masafumi, Saito Akira, Yamauchi Yasuhiro, Mikami Yu, Sakamoto Makiko, Jo Taisuke, Nakajima Jun, Takizawa Hajime, Nagase Takahide, Kohyama Tadashi
1Department of Respiratory Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
Exp Lung Res. 2014 Jun;40(5):222-36. doi: 10.3109/01902148.2014.900155.
Airway remodeling is implicated in irreversible airflow limitation of refractory asthma, which includes increased smooth muscle mass and subepithelial fibrosis. Activated fibroblasts acquire contractile phenotype to participate in tissue contraction and structural alteration of extracellular matrices. Histamine is a potent mediator of allergic inflammation, substantially involved in asthmatic pathophysiology.
We hypothesized that histamine might play a role in airway remodeling, and investigated its effect on fibroblast-mediated collagen gel contraction.
Fibroblast-mediated collagen gel contraction was studied. Histamine's regulation of collagen gel contraction was characterized by using specific histamine-receptor antagonists, an IP3 receptor antagonist and a PKC inhibitor.
Histamine induced contraction of collagen gels embedded with human lung fibroblasts, in a time-dependent manner, and at the concentration more than 10(-6) M, both in four primary cultured adult lung fibroblasts and three fetal lung fibroblast cell lines. This effect was attenuated by H1 receptor antagonist, whereas those for H2 to H4 receptors failed to show an inhibitory effect. Furthermore, IP3 receptor-mediated Ca(2+) mobilization was implicated in histamine's action on collagen gel contraction.
Our results suggest that histamine is involved in airway remodeling through its action on lung fibroblasts, and antihistamine drugs, especially H1 receptor antagonists, might be potentially beneficial for a subset of asthmatic patients.
气道重塑与难治性哮喘的不可逆气流受限有关，包括平滑肌质量增加和上皮下纤维化。活化的成纤维细胞获得收缩表型以参与组织收缩和细胞外基质的结构改变。组胺是变应性炎症的强效介质，在哮喘病理生理学中起重要作用。
我们假设组胺可能在气道重塑中起作用，并研究其对成纤维细胞介导的胶原凝胶收缩的影响。
研究成纤维细胞介导的胶原凝胶收缩。通过使用特异性组胺受体拮抗剂、肌醇三磷酸（IP3）受体拮抗剂和蛋白激酶C（PKC）抑制剂来表征组胺对胶原凝胶收缩的调节作用。
组胺以时间依赖性方式诱导包埋有人肺成纤维细胞的胶原凝胶收缩，在浓度超过10^(-6) M时，对4种原代培养的成人肺成纤维细胞和3种胎儿肺成纤维细胞系均有此作用。H1受体拮抗剂可减弱这种作用，而H2至H4受体拮抗剂则未显示出抑制作用。此外，IP3受体介导的钙离子动员与组胺对胶原凝胶收缩的作用有关。
我们的结果表明，组胺通过对肺成纤维细胞的作用参与气道重塑，抗组胺药物，尤其是H1受体拮抗剂，可能对一部分哮喘患者有益。
