Targeting vascular transient receptor potential vanilloid 4 activity prevents lung transplant ischemia-reperfusion injury and rejection.

Ischemia-reperfusion injury (IRI) and acute cellular rejection (ACR) are common postoperative complications that lead to poor outcomes in lung transplant recipients. Transient receptor potential vanilloid 4 (TRPV4) is a plasma membrane Ca2+ channel that controls vascular tone and integrity. We examined whether TRPV4 influences IRI and alloimmune responses in a mouse model of orthotopic lung transplantation. Recipients receiving syngeneic lungs briefly treated with a TRPV4-specific inhibitor or engrafted with syngeneic lungs with an endothelial cell-specific TRPV4 gene ablation (TRPV4ΔEC) had better graft function, reduced endothelial cell adhesion molecule expression, and lower inflammatory cytokine expression and neutrophil recruitment. TRPV4ΔEC lungs transplanted into immunosuppressed, major histocompatibility complex-mismatched recipients had more intragraft CD25+ Foxp3+ CD4+ T cells and fewer IFN-γ+ CD8+ T cells and were more resistant to IRI-induced ACR than wildtype allografts. Finally, pharmacologic inhibition of TRPV4 reduced donor antigen-triggered production of IFN-γ and IL-17A by intragraft T cells and prevented ACR despite IRI. Our findings show that pulmonary endothelial cell TRPV4 activity couples ischemic tissue injury to T cell alloimmunity, highlighting the potential of therapies that enhance vascular integrity to promote transplant tolerance.