As an intracellular enzyme, iNAMPT regulates NAD biosynthesis (Revollo et al., 2007), however, when secreted into the circulation, eNAMPT ligates Toll–like receptor 4 (TLR4) (Camp et al., 2015) to function as a DAMP protein (tissue damage-associated molecular pattern) and master regulator of evolutionarily-conserved NFkB-driven inflammatory cascades that are involved in ARDS/VILI pathobiology (Camp et al., 2015; Quijada et al., 2021; Bermudez et al., 2022). Here, TLR4 is linked to acute respiratory distress syndrome.