Endothelial Transient Receptor Potential Vanilloid 4 Channels Mediate Lung Ischemia-Reperfusion Injury

BACKGROUND Lung ischemia-reperfusion injury (IRI), involving severe inflammation and edema, is a major cause of primary graft dysfunction after transplant. Activation of transient receptor potential vanilloid 4 (TRPV4) channels modulates vascular permeability. Thus, this study tests the hypothesis that endothelial TRPV4 channels mediate lung IRI. METHODS A left lung hilar-ligation model was used to induce lung IR in C57BL/6 wild-type (WT), Trpv4(-/-,) tamoxifeninducible endothelial Trpv4 knockout (Trpv4(EC)(-/-)), and tamoxifen-treated control (Trpv4(fl/fl)) (n >= 6 mice/group). WT mice were also treated with GSK2193874 (WT+GSK219), a TRPV4-specific inhibitor (1 mg/kg). Partial pressure of arterial oxygen, edema (wet-to-dry weight ratio), compliance, neutrophil infiltration, and cytokine concentrations in bronchoalveolar lavage fluid were assessed. Pulmonary microvascular endothelial cells were characterized in vitro after exposure to hypoxia-reoxygenation. RESULTS Compared with WT, partial pressure of arterial oxygen after IR was significantly improved in Trpv4(-/-) mice (133.1 +/- 43.9 vs 427.8 +/- 83.1 mm Hg, P < .001) and WT+GSK219 mice (133.1 +/- 43.9 vs 447.0 +/- 67.6 mm Hg, P < .001). Pulmonary edema and neutrophil infiltration were also significantly reduced after IR in Trpv4(-/-) and WT+GSK219 mice vs WT. Trpv4(EC)(-/-) mice after IR demonstrated significantly improved oxygenation vs control (109.2 +/- 21.6 vs 405.3 +/- 41.4 mm Hg, P < .001) as well as significantly improved compliance and significantly less edema, neutrophil infiltration, and proinflammatory cytokine production (tumor necrosis factor-a, chemokine [C-X-C motif] ligand 1, interleukin 17, interferon -y). Hypoxia-reoxygenation-induced permeability and chemokine (C-X-C motif) ligand 1 expression by pulmonary microvascular endothelial cells were significantly attenuated by TRPV4 inhibitors. CONCLUSIONS Endothelial TRPV4 plays a key role in vascular permeability and lung inflammation after IR. TRPV4 channels may be a promising therapeutic target to mitigate lung IRI and decrease the incidence of primary graft dysfunction after transplant. (c) 2022 by The Society of Thoracic Surgeons

Automated summary

This study demonstrates that endothelial TRPV4 channels play a key role in vascular permeability and lung inflammation after ischemia-reperfusion injury (IRI). TRPV4 channels may be a promising therapeutic target to mitigate lung IRI and decrease the incidence of primary graft dysfunction after transplant.