Transient receptor potential vanilloid 4 channel inhibition attenuates lung ischemia-reperfusion injury in a porcine lung transplant model

Raymond J Strobel; Huy Q Ta; Andrew M Young; Alex M Wisniewski; Anthony V Norman; Evan P Rotar; Mark H Stoler; Irving L Kron; Swapnil K Sonkusare; Mark E Roeser; Victor E Laubach

doi:10.1016/j.jtcvs.2024.03.001

Transient receptor potential vanilloid 4 channel inhibition attenuates lung ischemia-reperfusion injury in a porcine lung transplant model

J Thorac Cardiovasc Surg. 2024 Apr 1:S0022-5223(24)00192-2. doi: 10.1016/j.jtcvs.2024.03.001. Online ahead of print.

Affiliations

¹ Department of Surgery, University of Virginia School of Medicine, Charlottesville, Va.
² Department of Pathology, University of Virginia School of Medicine, Charlottesville, Va.
³ Robert M. Berne Cardiovascular Research Center and the Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, Va.
⁴ Department of Surgery, University of Virginia School of Medicine, Charlottesville, Va. Electronic address: laubach@virginia.edu.

PMID: 38678474
DOI: 10.1016/j.jtcvs.2024.03.001

Abstract

Objective: Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel important in many physiological and pathophysiological processes, including pulmonary disease. Using a murine model, we previously demonstrated that TRPV4 mediates lung ischemia-reperfusion injury, the major cause of primary graft dysfunction after transplant. The current study tests the hypothesis that treatment with a TRPV4 inhibitor will attenuate lung ischemia-reperfusion injury in a clinically relevant porcine lung transplant model.

Methods: A porcine left-lung transplant model was used. Animals were randomized to 2 treatment groups (n = 5/group): vehicle or GSK2193874 (selective TRPV4 inhibitor). Donor lungs underwent 30 minutes of warm ischemia and 24 hours of cold preservation before left lung allotransplantation and 4 hours of reperfusion. Vehicle or GSK2193874 (1 mg/kg) was administered to the recipient as a systemic infusion after recipient lung explant. Lung function, injury, and inflammatory biomarkers were compared.

Results: After transplant, left lung oxygenation was significantly improved in the TRPV4 inhibitor group after 3 and 4 hours of reperfusion. Lung histology scores and edema were significantly improved, and neutrophil infiltration was significantly reduced in the TRPV4 inhibitor group. TRPV4 inhibitor-treated recipients had significantly reduced expression of interleukin-8, high mobility group box 1, P-selectin, and tight junction proteins (occludin, claudin-5, and zonula occludens-1) in bronchoalveolar lavage fluid as well as reduced angiopoietin-2 in plasma, all indicative of preservation of endothelial barrier function.

Conclusions: Treatment of lung transplant recipients with TRPV4 inhibitor significantly improves lung function and attenuates ischemia-reperfusion injury. Thus, selective TRPV4 inhibition may be a promising therapeutic strategy to prevent primary graft dysfunction after transplant.

Keywords: TRPV4 channel; endothelial barrier; inflammation; ischemia-reperfusion injury; lung transplantation; primary graft dysfunction.