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

作者：Nancy G. Casanova, Jose D. Herazo‐Maya, Carrie L. Kempf, Belinda Sun, Jin H. Song, Annie Hernandez, Jason Canizales Galaviz, Xiaoguang Sun, Sara M. Camp, Julie G. Ledford, Riley D. Hellinger, Marisela Rodriguez, Amy Zhao, Avraham Unterman, Iván O. Rosas, Steve Duncan, Victor J. Thannickal, Matthew K. Hufford, Mohamed Ahmed, Nahla Zaghloul, Akash Gupta, Christian Bime, Saad Sammani, Ben N. Stansfield, Jinjing Chen, Annadurai Anandhan, Matthew D. Disney, Aikseng Ooi, Shaira Limson Kee, Theodoros Karampitsakos, Panayiotis V. Benos, Naftali Kaminski, Donna D. Zhang, Joe G. N. Garcia · 发表于：American Journal of Respiratory Cell and Molecular Biology · 年份：2025 · DOI：10.1165/rcmb.2024-0342oc · 被引用次数：10 · 研究领域：Inhalation and Respiratory Drug Delivery、Respiratory viral infections research

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disorder without curative therapies, underscoring the critical unmet need for identification of novel therapeutic strategies. eNAMPT (extracellular nicotinamide phosphoribosyltransferase) is a damage-associated molecular pattern protein (DAMP) and TLR4 (Toll-like receptor 4) ligand that contributes to the severity of radiation-induced lung fibrosis and nonalcoholic steatohepatitis-associated hepatic fibrosis. This study investigates eNAMPT as a druggable target in human and preclinical IPF using the eNAMPT-neutralizing ALT-100 monoclonal antibody (mAb). Blood, peripheral blood mononuclear cells (PBMCs), and lung tissues from patients with IPF 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 increased in plasma, lung tissues, and PBMCs from subjects with IPF, 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 TGF-β pathway-related protein and gene expression, with each index significantly mitigated in mice receiving ALT-100 mAb. Single-cell RNA seque...