eNAMPT Is a Novel DAMP and Therapeutic Target in Human and Murine Pulmonary Fibrosis.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disorder without curative therapies, underscoring the critical unmet need for identification of novel therapeutics. Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a damage-associated molecular pattern protein (DAMP) and Toll-Like Receptor 4 (TLR4) ligand that contributes to the severity of radiation-induced lung fibrosis and NASH-associated hepatic fibrosis. This study investigates eNAMPT as a druggable target in human and preclinical IPF utilizing the eNAMPT-neutralizing ALT-100 monoclonal antibody (mAb). Blood, PBMCs, and lung tissues from IPF patients and from an experimental bleomycin-induced lung fibrosis model in C57Bl6 mice were analyzed. Biochemical and histologic measurements, as well as gene expression through bulk and single-cell RNA sequencing of human PBMCs and murine lung tissues were performed. Human studies revealed NAMPT expression to be significantly elevated in plasma, lung tissues, and in PBMCs from IPF subjects, correlating with disease severity and inversely associated with IPF survival. Bleomycin-exposed mice exhibited increased inflammatory indices associated with lung fibrosis development (including NAMPT levels), as well as physiologic lung stiffening, and TGFβ pathway-related protein and gene expression with each indice significantly mitigated in mice receiving ALT-100 mAb. scRNAseq studies demonstrated the ALT-100 mAb to reverse bleomycin-induced dramatic expansion of alveolar type 2 epithelium (AT2) and indiction of endothelial- and epithelial cell-to-mesenchymal/myofibroblast transitions (EndMT, EMT). These finding support the fundamental involvement of eNAMPT/TLR4 signaling pathway in lung fibrosis pathobiology with eNAMPT neutralization a viable therapeutic strategy to directly address the unmet need for novel IPF treatments.