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?:abstract
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RATIONALE: The SARS-CoV-2/COVID-19 pandemic has highlighted the serious unmet need for effective therapies that reduce ARDS mortality We explored whether extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a ligand for Toll-like receptor 4 and a master regulator of innate immunity and inflammation, is a potential ARDS therapeutic target METHODS: Wild type C57BL/6J or endothelial cell (EC)-cNAMPT (-/-) knockout mice (targeted EC NAMPT deletion) were exposed to either a lipopolysaccharide (LPS)-induced (\'one-hit\') or a combined LPS/ventilator (\'two-hit\')-induced acute inflammatory lung injury model A NAMPT-specific mAb imaging probe ((99m)Tc-ProNamptor(TM)) was used to detect NAMPT expression in lung tissues Either an eNAMPT-neutralising goat polyclonal antibody (pAb) or a humanised monoclonal antibody (ALT-100 mAb) were utilised in vitro and in vivo RESULTS: Immunohistochemical, biochemical, and imaging studies validated time-dependent increases in NAMPT lung tissue expression in both preclinical ARDS models Intravenous delivery of either eNAMPT-neutralising pAb/mAb significantly attenuated inflammatory lung injury (H & E staining, BAL protein, BAL PMNs, plasma IL-6) in both preclinical models In vitro human lung EC studies demonstrated eNAMPT-neutralising antibodies (pAb, mAb) to strongly abrogate eNAMPT-induced TLR4 pathway activation and EC barrier disruption In vivo studies in wild type and EC-cNAMPT (-/-) mice confirmed a highly significant contribution of EC-derived NAMPT to the severity of inflammatory lung injury in both preclinical ARDS models CONCLUSIONS: These findings highlight both the role of EC-derived eNAMPT and the potential for biologic targeting of the eNAMPT/TLR4 inflammatory pathway In combination with predictive eNAMPT biomarker and NAMPT genotyping assays, this offers the opportunity to identify high-risk ARDS subjects for delivery of personalised medicine
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