TLR4 Ligation by eNAMPT, a Novel DAMP, is Essential to Sulfur Mustard- Induced Inflammatory Lung Injury and Fibrosis.

Autor:	Kempf CL; Department of Medicine, University of Arizona Health Sciences, Tucson, AZ., Song JH; Department of Medicine, University of Arizona Health Sciences, Tucson, AZ., Sammani S; Department of Medicine, University of Arizona Health Sciences, Tucson, AZ., Bermudez T; Department of Medicine, University of Arizona Health Sciences, Tucson, AZ., Reyes Hernon V; Department of Medicine, University of Arizona Health Sciences, Tucson, AZ., Tang L; Department of Medicine, University of Arizona Health Sciences, Tucson, AZ., Cai H; Department of Anesthesiology, University of California Los Angeles, Los Angeles, CA., Camp SM; Department of Medicine, University of Arizona Health Sciences, Tucson, AZ., Johnson CA; Department of Pediatrics, Center for Advanced Drug Development, University of Colorado Anschutz Campus, Aurora, CO., Basiouny MS; Department of Pediatrics, Center for Advanced Drug Development, University of Colorado Anschutz Campus, Aurora, CO., Bloomquist LA; Department of Pediatrics, Center for Advanced Drug Development, University of Colorado Anschutz Campus, Aurora, CO., Rioux JS; Department of Pediatrics, Center for Advanced Drug Development, University of Colorado Anschutz Campus, Aurora, CO., White CW; Department of Pediatrics, Center for Advanced Drug Development, University of Colorado Anschutz Campus, Aurora, CO., Veress LA; Department of Pediatrics, Center for Advanced Drug Development, University of Colorado Anschutz Campus, Aurora, CO., Garcia JGN; Department of Medicine, University of Arizona Health Sciences, Tucson, AZ.
Jazyk:	angličtina
Zdroj:	European journal of respiratory medicine [Eur J Respir Med] 2024 Feb; Vol. 6 (1), pp. 389-397. Date of Electronic Publication: 2024 Jan 08.
Abstrakt:	Objective: 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. Methods: 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. Results: 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). Conclusion: 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. Competing Interests: COI Disclosures: Joe GN Garcia MD is CEO and Founder of Aqualung Therapeutics Corporation. All other authors report no conflict of interest.
Databáze:	MEDLINE
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