Too much stretching is bad for the lungs

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Science Signaling  21 Jan 2020:
Vol. 13, Issue 615, eaba9167
DOI: 10.1126/scisignal.aba9167

Excessive mechanical strain on alveolar stem cells induces TGF-β signaling and progressive lung fibrosis.

Idiopathic pulmonary fibrosis, which starts at the periphery and progresses inward to the center of the lungs, culminates in respiratory failure. During lung homeostasis or after lung injury, alveolar stem cells, also called alveolar type 2 (AT2) cells, differentiate into AT1 cells, which are also called pneumocytes and which function in gas exchange between alveoli and capillaries. Wu et al. (see also Sainz de Aja and Kim) found that mice deficient in the Rho GTPase family member CDC42 in AT2 cells developed lung fibrosis in a pattern reminiscent of idiopathic pulmonary fibrosis (from the periphery to the center of the lungs). Stretching AT2 cells increased the abundance of GTP-bound CDC42, which was also increased in the lungs of control mice subjected to post-lung lobe resection injury. These mice showed increased differentiation of AT2 cells into AT1 cells and alveolar regeneration, effects not seen in mice deficient in Cdc42 in AT2 cells, which developed periphery-to-center lung fibrosis, enlarged alveoli, and ultimately respiratory function failure. Single-cell transcriptomic analysis showed that Cdc42-deficient mice had a subpopulation of AT2 cells with a gene expression pattern that differed from those of AT1 cells and the other subpopulation of AT2 cells. Fibrotic regions in Cdc42-deficient lungs showed increased tissue stiffness compared with nonfibrotic regions. Fibrosis development and alveolar size in the lungs and mortality were reduced in Cdc42-deficient mice when mechanical tension was alleviated. Stretched AT2 cells showed increased activity of the profibrotic transforming growth factor–β (TGF-β) signaling pathway. In artificially inflated lungs in wild-type mice, alveoli in the periphery were larger, were subjected to greater mechanical pressure, and had increased TGF-β signaling compared with those in the center of the lungs. Genetic ablation in AT2 cells of Tgfbr2, which encodes a TGF-β receptor, resulted in decreased lung fibrosis development and mortality in Cdc42-deficient mice. Thus, defects in the CDC42-dependent differentiation of AT2 cells into AT1 cells impairs alveolar regeneration and imposes mechanical stress on AT2 cells, activating TGF-β signaling that results in progressive lung fibrosis.

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