Xi Zheng, Xiaoying Chen, Xiaoxiao Hu, Lidan Chen, Nana Mi, Qianqian Zhong, Linfang Wang, Chensheng Lin, YiPing Chen, Fancai Lai, Xuefeng Hu, Yanding Zhang
The Journal of pathology 2024 MarBone 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. © 2023 The Pathological Society of Great Britain and Ireland.
Xi Zheng, Xiaoying Chen, Xiaoxiao Hu, Lidan Chen, Nana Mi, Qianqian Zhong, Linfang Wang, Chensheng Lin, YiPing Chen, Fancai Lai, Xuefeng Hu, Yanding Zhang. Downregulated BMP-Smad1/5/8 signaling causes emphysema via dysfunction of alveolar type II epithelial cells. The Journal of pathology. 2024 Mar;262(3):320-333
PMID: 38108121
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