{Reference Type}: Journal Article
{Title}: TLR4 Ligation by eNAMPT, a Novel DAMP, is Essential to Sulfur Mustard- Induced Inflammatory Lung Injury and Fibrosis.
{Author}: Kempf CL;Song JH;Sammani S;Bermudez T;Reyes Hernon V;Tang L;Cai H;Camp SM;Johnson CA;Basiouny MS;Bloomquist LA;Rioux JS;White CW;Veress LA;Garcia JGN;
{Journal}: Eur J Respir Med
{Volume}: 6
{Issue}: 1
{Year}: 2024 Feb
暂无{Abstract}: <B>UNASSIGNED: </B>Human and preclinical studies of sulfur mustard (SM)-induced acute and chronic lung injuries highlight the role of unremitting inflammation. We assessed the utility of targeting the novel DAMP and TLR4 ligand, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), utilizing a humanized mAb (ALT-100) in rat models of SM exposure.<BR><B>UNASSIGNED: </B>Acute (SM 4.2 mg/kg, 24 hrs), subacute (SM 0.8 mg/kg, day 7), subacute (SM 2.1 mg/kg, day 14), and chronic (SM 1.2 mg/kg, day 29) SM models were utilized.<BR><B>UNASSIGNED: </B>Each SM model exhibited significant increases in eNAMPT expression (lung homogenates) and increased levels of phosphorylated NFkB and NOX4. Lung fibrosis (Trichrome staining) was observed in both sub-acute and chronic SM models in conjunction with elevated smooth muscle actin (SMA), TGFβ, and IL-1β expression. SM-exposed rats receiving ALT-100 (1 or 4 mg/kg, weekly) exhibited increased survival, highly significant reductions in histologic/biochemical evidence of lung inflammation and fibrosis (Trichrome staining, decreased pNFkB, SMA, TGFβ, NOX4), decreased airways strictures, and decreased plasma cytokine levels (eNAMPT, IL-6, IL-1β. TNFα).<BR><B>UNASSIGNED: </B>The highly druggable, eNAMPT/TLR4 signaling pathway is a key contributor to SM-induced ROS production, inflammatory lung injury and fibrosis. The ALT-100 mAb is a potential medical countermeasure to address the unmet need to reduce SM-associated lung pathobiology/mortality.