Angiotensin receptor blockade attenuates cigarette smoke-induced lung injury and rescues lung architecture in mice
Angiotensin receptor blockade attenuates cigarette smoke-induced lung injury and rescues lung architecture in mice
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DOI：
10.1172/jci46215
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发表时间：
2012-01-01
影响因子：
15.9
通讯作者：
Neptune, Enid
中科院分区：
文献类型：
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作者：
Podowski, Megan;Calvi, Carla;Neptune, Enid
慢性阻塞性肺疾病（COPD）是一种流行的吸烟相关疾病，目前还没有改变疾病的治疗方法。由于TGF-β信号转导失调与COPD患者和慢性暴露于香烟烟雾（CS）诱导的肺损伤动物模型中的肺病理学相关，我们推测抑制TGF-β信号转导可预防CS诱导的肺损伤。我们首先证实了TGF-β信号在长期暴露于CS的小鼠的肺中以及在COPD患者样本中被诱导。重要的是，吸烟相关性肺病患者的关键病理特征，例如，肺泡损伤伴明显肺气肿和气道上皮增生伴纤维化，伴随CS暴露小鼠中由增强的TGF-β信号引起的CS诱导的肺泡细胞凋亡。全身给予TGF-β特异性中和抗体使TGF-β信号传导和肺泡细胞死亡正常化，从而改善CS暴露小鼠的肺结构和肺力学。氯沙坦是一种广泛用于临床的血管紧张素受体1型阻滞剂，已知可拮抗TGF-β信号传导，其使用也可改善氧化应激、炎症、金属蛋白酶活化和弹性蛋白重塑。这些数据支持了我们的假设，即通过血管紧张素受体阻断剂抑制TGF-β信号传导可以减轻已建立的小鼠模型中CS诱导的肺损伤。更重要的是，我们的发现为COPD患者开发其他TGF-β靶向治疗提供了临床前平台。
Chronic obstructive pulmonary disease (COPD) is a prevalent smoking-related disease for which no disease-altering therapies currently exist. As dysregulated TGF-beta signaling associates with lung pathology in patients with COPD and in animal models of lung injury induced by chronic exposure to cigarette smoke (CS), we postulated that inhibiting TGF-beta signaling would protect against CS-induced lung injury. We first confirmed that TGF-beta signaling was induced in the lungs of mice chronically exposed to CS as well as in COPD patient samples. Importantly, key pathological features of smoking-associated lung disease in patients, e.g., alveolar injury with overt emphysema and airway epithelial hyperplasia with fibrosis, accompanied CS-induced alveolar cell apoptosis caused by enhanced TGF-beta signaling in CS-exposed mice. Systemic administration of a TGF-beta-specific neutralizing antibody normalized TGF-beta signaling and alveolar cell death, conferring improved lung architecture and lung mechanics in CS-exposed mice. Use of losartan, an angiotensin receptor type 1 blocker used widely in the clinic and known to antagonize TGF-beta signaling, also improved oxidative stress, inflammation, metalloprotease activation and elastin remodeling. These data support our hypothesis that inhibition of TGF-beta signaling through angiotensin receptor blockade can attenuate CS-induced lung injury in an established murine model. More importantly, our findings provide a preclinical platform for the development of other TGF-beta-targeted therapies for patients with COPD.