Pharmacological inhibition of toll-like receptor 4 suppresses ischemia-reperfusion injury-induced inflammation and improves lung allograft function after transplantation

Ischemia reperfusion injury (IRI) is a significant risk factor for primary graft dysfunction following lung transplantation. Toll-like receptor 4 (TLR4) signaling plays an important role not only in IRI but also in the development of acute and chronic allograft rejection. We investigated the therapeutic effect of Viral Inhibitory Peptide for TLR4 (VIPER), a pharmacological TLR4-inhibitory peptide, in a clinically relevant murine lung transplantation model. VIPER-treated lungs demonstrated improved function, with reduced mean airway pressure and increased compliance and inspiratory volume. The wet-to-dry weight ratio was significantly reduced, indicating decreased pulmonary edema. Inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1), interferon-gamma (IFN-γ), and interleukin-6 (IL-6) were significantly decreased, with a trend toward lower levels of the fibrogenetic cytokine transforming growth factor-beta (TGF-β). Histological evaluation revealed reduced acute lung injury scores and fewer inducible nitric oxide synthase (iNOS)-positive inflammatory cells. These findings demonstrate that pharmacological inhibition of TLR4 with VIPER effectively attenuates IRI-associated inflammation and improves early graft function. Such pharmacological TLR4-targeting strategies might represent a therapeutic approach in lung transplantation.