{"doi":"10.31488/ejrm.141","title":"TLR4 Ligation by eNAMPT, a Novel DAMP, is Essential to Sulfur Mustard- Induced Inflammatory Lung Injury and Fibrosis","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.","journal":"European Journal of Respiratory Medicine","year":2024,"id":467773,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9676,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":392783,"name":"Jin H. Song","orcid":"0000-0002-0123-2909","position":1,"is_corresponding":false},{"id":688438,"name":"Saad Sammani","orcid":"0000-0002-7933-6388","position":2,"is_corresponding":false},{"id":688892,"name":"Tadeo Bermudez","orcid":null,"position":3,"is_corresponding":false},{"id":688896,"name":"Vivian Reyes Hernon","orcid":null,"position":4,"is_corresponding":false},{"id":889654,"name":"Lin Tang","orcid":"0000-0003-2597-6694","position":5,"is_corresponding":false},{"id":646741,"name":"Hua Cai","orcid":"0000-0001-8747-6156","position":6,"is_corresponding":false},{"id":389496,"name":"Sara M. Camp","orcid":null,"position":7,"is_corresponding":false},{"id":1129786,"name":"Carly Johnson","orcid":null,"position":8,"is_corresponding":false},{"id":1234378,"name":"Mohamed S. Basiouny","orcid":null,"position":9,"is_corresponding":false},{"id":1129789,"name":"Leslie A. Bloomquist","orcid":null,"position":10,"is_corresponding":false},{"id":1300044,"name":"Jacqueline S. Rioux","orcid":null,"position":11,"is_corresponding":false},{"id":612825,"name":"Carl W. White","orcid":"0000-0002-4975-6189","position":12,"is_corresponding":false},{"id":1129426,"name":"Livia A. Veress","orcid":"0000-0003-4981-9634","position":13,"is_corresponding":false},{"id":300875,"name":"Joe G. N. Garcia","orcid":"0000-0002-6934-0420","position":14,"is_corresponding":false},{"id":688890,"name":"Carrie L. Kempf","orcid":null,"position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-19T02:05:15.025255Z","pmid":"38390523","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}