eNAMPT Is a Novel Damage-associated Molecular Pattern Protein That Contributes to the Severity of Radiation-induced Lung Fibrosis

Alexander N. Garcia, Nancy G. Casanova, Carrie L. Kempf, Tadeo Bermudez, Daniel G. Valera, Jin H. Song, Xiaoguang Sun, Hua Cai, Liliana Moreno-Vinasco, Taylor Gregory, Radu C. Oita, Vivian Reyes Hernon, Sara M. Camp, Claude Rogers, Espoir M. Kyubwa, Naresh Menon, James Axtelle, Jay Rappaport, Christian Bime, Saad SammaniAnne E. Cress, Joe G.N. Garcia

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The paucity of therapeutic strategies to reduce the severity of radiation-induced lung fibrosis (RILF), a life-threatening complication of intended or accidental ionizing radiation exposure, is a serious unmet need. We evaluated the contribution of eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a damage-associated molecular pattern (DAMP) protein and TLR4 (Toll-like receptor 4) ligand, to the severity of whole-thorax lung irradiation (WTLI)-induced RILF. Wild-type (WT) and Nampt1/2 heterozygous C57BL6 mice and nonhuman primates (NHPs, Macaca mulatta) were exposed to a single WTLI dose (9.8 or 10.7 Gy for NHPs, 20 Gy for mice). WT mice received IgG1 (control) or an eNAMPTneutralizing polyclonal or monoclonal antibody (mAb) intraperitoneally 4 hours after WTLI and weekly thereafter. At 8-12 weeks after WTLI, NAMPT expression was assessed by immunohistochemistry, biochemistry, and plasma biomarker studies. RILF severity was determined by BAL protein/cells, hematoxylin and eosin, and trichrome blue staining and soluble collagen assays. RNA sequencing and bioinformatic analyses identified differentially expressed lung tissue genes/pathways. NAMPT lung tissue expression was increased in both WTLIexposed WT mice and NHPs. Nampt1/2 mice and eNAMPT polyclonal antibody/mAb-treated mice exhibited significantly attenuated WTLI-mediated lung fibrosis with reduced: 1) NAMPT and trichrome blue staining; 2) dysregulated lung tissue expression of smooth muscle actin, p-SMAD2/p-SMAD1/5/9, TGF-b, TSP1 (thrombospondin-1), NOX4, IL-1b, and NRF2; 3) plasma eNAMPT and IL-1b concentrations; and 4) soluble collagen. Multiple WTLI-induced dysregulated differentially expressed lung tissue genes/pathways with known tissue fibrosis involvement were each rectified in mice receiving eNAMPT mAbs.The eNAMPT/TLR4 inflammatory network is essentially involved in radiation pathobiology, with eNAMPT neutralization an effective therapeutic strategy to reduce RILF severity.

Original languageEnglish (US)
Pages (from-to)497-509
Number of pages13
JournalAmerican journal of respiratory cell and molecular biology
Volume66
Issue number5
DOIs
StatePublished - May 2022
Externally publishedYes

Keywords

  • DAMP
  • TLR4
  • eNAMPT
  • nicotinamide phosphoribosyltransferase
  • whole-lung thoracic irradiation

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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