Bone morphogenetic protein (BMP)–Smad1/5/8 signaling plays a crucial regulatory role in lung development and adult lung homeostasis. However, it remains elusive whether BMP–Smad1/5/8 signaling is involved in the pathogenesis of emphysema. In this study, we downregulated BMP–Smad1/5/8 signaling by overexpressing its antagonist Noggin in adult mouse alveolar type II epithelial cells (AT2s), resulting in an emphysematous phenotype mimicking the typical pathological features of human emphysema, including distal airspace enlargement, pulmonary inflammation, extracellular matrix remodeling, and impaired lung function. Dysregulation of BMP–Smad1/5/8 signaling in AT2s leads to inflammatory destruction dominated by macrophage infiltration, associated with reduced secretion of surfactant proteins and inhibition of AT2 proliferation and differentiation. Reactivation of BMP–Smad1/5/8 signaling by genetics or chemotherapy significantly attenuated the morphology and pathophysiology of emphysema and improved the lung function in Noggin-overexpressing lungs. We also found that BMP–Smad1/5/8 signaling was downregulated in cigarette smoke-induced emphysema, and that enhancing its activity in AT2s prevented or even reversed emphysema in the mouse model. Our data suggest that BMP–Smad1/5/8 signaling, located at the top of the signaling cascade that regulates lung homeostasis, represents a key molecular regulator of alveolar stem cell secretory and regenerative function, and could serve as a potential target for future prevention and treatment of pulmonary emphysema. © 2023 The Pathological Society of Great Britain and Ireland.

中文翻译：

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下调的 BMP-Smad1/5/8 信号通过肺泡 II 型上皮细胞功能障碍导致肺气肿

骨形态发生蛋白 (BMP)-Smad1/5/8 信号在肺发育和成人肺稳态中发挥着至关重要的调节作用。然而，BMP-Smad1/5/8 信号传导是否参与肺气肿的发病机制仍不清楚。在这项研究中，我们通过在成年小鼠肺泡II型上皮细胞（AT2s）中过表达其拮抗剂Noggin来下调BMP-Smad1/5 /8信号传导，从而产生模仿人类肺气肿典型病理特征的肺气肿表型，包括远端空腔扩大，肺部炎症、细胞外基质重塑和肺功能受损。AT2 中 BMP-Smad1/5/8 信号传导失调会导致以巨噬细胞浸润为主的炎症破坏，与表面活性剂蛋白分泌减少以及 AT2 增殖和分化抑制相关。通过遗传学或化疗重新激活 BMP-Smad1/5/8 信号，显着减弱了肺气肿的形态和病理生理学，并改善了Noggin过度表达的肺的肺功能。我们还发现，在香烟烟雾诱发的肺气肿中，BMP-Smad1/5/8 信号传导被下调，而在小鼠模型中，增强 AT2 中的 BMP-Smad1/5/8 信号传导活性可以预防甚至逆转肺气肿。我们的数据表明，BMP-Smad1/5/8 信号位于调节肺稳态的信号级联的顶部，是肺泡干细胞分泌和再生功能的关键分子调节因子，可作为未来预防的潜在靶点以及肺气肿的治疗。© 2023 大不列颠及爱尔兰病理学会。