Carrie L Kempf, Jin H Song, Saad Sammani, Tadeo Bermudez, Vivian Reyes Hernon, Lin Tang, Hua Cai, Sara M Camp, Carly A Johnson, Mohamed S Basiouny, Leslie A Bloomquist, Jacqueline S Rioux, Carl W White, Livia A Veress, Joe G N Garcia
{"title":"TLR4 Ligation by eNAMPT, a Novel DAMP, is Essential to Sulfur Mustard- Induced Inflammatory Lung Injury and Fibrosis.","authors":"Carrie L Kempf, Jin H Song, Saad Sammani, Tadeo Bermudez, Vivian Reyes Hernon, Lin Tang, Hua Cai, Sara M Camp, Carly A Johnson, Mohamed S Basiouny, Leslie A Bloomquist, Jacqueline S Rioux, Carl W White, Livia A Veress, Joe G N Garcia","doi":"","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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).</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":72981,"journal":{"name":"European journal of respiratory medicine","volume":"6 1","pages":"389-397"},"PeriodicalIF":0.0000,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10883439/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European journal of respiratory medicine","FirstCategoryId":"1085","ListUrlMain":"","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/8 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
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.