Department of Internal Medicine, Member of the German Center for Lung Research, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), Germany.
J Pathol. 2013 Jan;229(2):242-9. doi: 10.1002/path.4127.
Pulmonary fibrosis is a devastating and progressive parenchymal lung disease with an extremely poor prognosis. Patients suffering from idiopathic pulmonary fibrosis (IPF) display a compromised lung function alongside pathophysiological features such as highly increased production of extracellular matrix, alveolar epithelial cell dysfunction, and disordered fibroproliferation - features that are due to a dysregulated response to alveolar injury. Under pathophysiological conditions of IPF, abnormally high concentrations of nitric oxide (NO) are found, likely a result of increased activity of the inducible nitric oxide synthase (NOS2), giving rise to products that contribute to fibrosis development. It is known that pharmacological inhibition or knockdown of NOS2 reduces pulmonary fibrosis, suggesting a role for NOS inhibitors in the treatment of fibrosis. Recent reports identified a critical enzyme, dimethylarginine dimethylaminohydrolase (DDAH), which is exceedingly active in patients suffering from IPF and in mice treated with bleomycin. An up-regulation of DDAH was observed in primary alveolar epithelial type II (ATII) cells from mice and patients with pulmonary fibrosis, where it co-localizes with NOS2. DDAH is a key enzyme that breaks down an endogenous inhibitor of NOS, asymmetric dimethylarginine (ADMA), by metabolizing it to l-citrulline and dimethylamine. DDAH was shown to modulate key fibrotic signalling cascades, and inhibition of this enzyme attenuated many features of the disease in in vivo experiments, suggesting a possible new therapeutic strategy for the treatment of patients suffering from IPF.
肺纤维化是一种破坏性的、进行性的实质肺疾病，预后极差。特发性肺纤维化 (IPF) 患者的肺功能受损，同时伴有生理病理特征，如细胞外基质过度生成、肺泡上皮细胞功能障碍和纤维增生紊乱，这些特征是由于对肺泡损伤的失调反应。在 IPF 的病理生理条件下，发现异常高浓度的一氧化氮 (NO)，可能是诱导型一氧化氮合酶 (NOS2) 活性增加的结果，导致促进纤维化发展的产物。已知 NOS2 的药理学抑制或敲低可减少肺纤维化，这表明 NOS 抑制剂在纤维化治疗中的作用。最近的报道确定了一种关键酶，即二甲基精氨酸二甲氨基水解酶 (DDAH)，它在 IPF 患者和接受博莱霉素治疗的小鼠中极为活跃。在来自肺纤维化小鼠和患者的原代肺泡上皮 II 型 (ATII) 细胞中观察到 DDAH 的上调，它与 NOS2 共定位。DDAH 是一种关键酶，通过将内源性 NOS 抑制剂不对称二甲基精氨酸 (ADMA) 代谢为 l-瓜氨酸和二甲胺来分解它。DDAH 被证明可调节关键的纤维化信号级联反应，并且该酶的抑制在体内实验中减轻了疾病的许多特征，这表明针对 IPF 患者的一种新的潜在治疗策略。
