Despite encouraging preclinical data,
therapies to reduce ARDS mortality remains a globally unmet need, including during the
COVID-19 pandemic. We previously identified extracellular
nicotinamide phosphoribosyltransferase (eNAMPT) as a novel damage-associated molecular pattern
protein (DAMP) via TLR4
ligation which regulates inflammatory cascade activation. eNAMPT is tightly linked to
human ARDS by
biomarker and genotyping studies in ARDS subjects. We now hypothesize that an eNAMPT-neutralizing mAb will significantly reduce the severity of ARDS lung inflammatory
lung injury in diverse preclinical rat and porcine models. Sprague Dawley rats received eNAMPT mAb intravenously following exposure to intratracheal
lipopolysaccharide (LPS) or to a traumatic blast (125 kPa) but prior to initiation of
ventilator-induced lung injury (VILI) (4 h). Yucatan minipigs received intravenous eNAMPT mAb 2 h after initiation of
septic shock and VILI (12 h). Each rat/porcine ARDS/VILI model was strongly associated with evidence of severe inflammatory
lung injury with NFkB pathway activation and marked dysregulation of the Akt/
mTORC2 signaling pathway. eNAMPT neutralization dramatically reduced inflammatory indices and the severity of
lung injury in each rat/porcine ARDS/VILI model (~ 50% reduction) including reduction in serum
lactate, and plasma levels of eNAMPT,
IL-6, TNFα and Ang-2. The eNAMPT mAb further rectified NFkB pathway activation and preserved the Akt/
mTORC2 signaling pathway. These results strongly support targeting the eNAMPT/TLR4 inflammatory pathway as a potential ARDS strategy to reduce inflammatory
lung injury and ARDS mortality.