Stretch‐induced activation of Hippo signaling in lung microvascular endothelial cells: A novel mechanism of overventilation‐induced pulmonary fibrosis

Introduction Mechanical ventilation is a mainstay of current therapy for patients with acute respiratory distress syndrome (ARDS). Yet despite its benefits, mechanical ventilation can also cause ventilator‐induced lung injury (VILI) that may ultimately progress to pulmonary fibrosis. In this study, we aimed to elucidate cellular mechanisms by which mechanical ventilation triggers pulmonary fibrosis. Specifically, we focused on the mechanosensitive transcriptional co‐factor TAZ, a key player in the Hippo‐signaling pathway involved in mechanosensation, cell proliferation, and profibrotic responses. As such, TAZ translocates to the nucleus of fibrotic lungs but not in healthy tissue. Interestingly, TAZ distribution upon cyclic stretch has not been extensively characterized and the underlying mechanisms are not well defined. Objectives To examine the effect of mechanical stretch on the nuclear translocation of TAZ in endothelial cells, and to identify underlying regulatory mechanisms. Methods To mimic the effects of mechanical overventilation, human pulmonary microvascular endothelial cells (HPMECs) were subjected to stretch regimens at either 5%, mimicking low tidal volume ventilation, or 18% mimicking high tidal volume ventilation at 0.25 Hz for 1,3,6, 12h on a Flexcell 5000 Tension System and compared to static control (0%). Results Mechanical stretch induced expression and release of the profibrotic cytokine TGF‐β1 from HPMECs and concomitantly caused translocation of TAZ from the cytosol to the nucleus in a dose‐ and time‐dependent manner. Specifically, the nuclear to cytoplasmic ratio (N/C) of TAZ increased after 3h of stretch at 18% compared to the static control whereas stretching these cells at 5% increased TAZ nuclear localization after 6h. Stretch‐induced TAZ translocation was not prevented by pharmacological inhibition of JNK or Src kinases, known regulators of the Hippo kinase LATS2; yet TAZ translocation was blocked by inhibition of Aurora kinases with SNS 314 mesylate (10UM). Consistently, inhibition of Aurora kinases decreased LATS2 phosphorylation at Ser83, a known modulation site of LATS2 activity. Conclusion These data suggest that mechanical stretch activates TAZ and triggers release of pro‐fibrotic cytokines, at least partly, in an Aurora kinase and LATS2‐dependent mechanism. Interventions targeted at the Hippo‐signaling pathway as well as its upstream regulation may provide potential strategies to counteract the detrimental effects of mechanical ventilation. Support or Funding Information This work was supported by the Canadian Institutes of Health Research . This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

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