Cellular NAD + , fibroblast senescence and pulmonary fibrosis

Aging is a risk factor in fibrotic interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF). Cellular senescence is observed in IPF and animal models of lung fibrosis along with telomere dysfunction, although the potential differential pathogenic significance of their cell type specific localization is unknown. Removal of senescent cells ameliorates fibrosis in animal models and are considered as potential therapeutic approaches. However the pathogenic role of aging and/or cellular senescence in the development of lung fibrosis are not fully understood. Declining cellular nicotinamide adenine dinucleotide (NAD + ) levels as seen in aging, may impair the activity of senescence suppressor Sirt1, an NAD + ‐dependent deacetylase, hence boosting the levels of NAD+ have been proposed to delay or inhibit aging related illnesses and improved longevity. To elucidate the role of NAD + in cellular senescence in pathogenesis of pulmonary fibrosis, we investigated the impact of increasing or reducing NAD + levels on bleomycin (BLM)‐induced mouse pulmonary fibrosis by supplementation with nicotinamide mononucleotide (NMN) by i.p injection, or nicotinamide phosphoribosyltransferase (Nampt) deficiency, respectively. The latter was induced by treating transgenic mice bearing the floxed Nampt and Col1a2‐CreERT transgenes with tamoxifen, resulting in mesenchymal cell specific Nampt deletion. The results showed that pre‐treatment of NMN injection before BLM injury significantly reduced lung myofibroblast differentiation as manifested by decreased Acta2 mRNA, which was accompanied by decreased numbers of senescent type II alveolar epithelial cells (SPC + /p16 + ), and BM‐derived monocytic myeloid cells. In contrast, deletion of Nampt in mesenchymal cells with consequent reduction of NAD + levels caused increased myofibroblast differentiation, and more severe lung fibrosis measured by lung hydroxyproline and histology after BLM injury when compared to the response in wild type animals. In contrast to wild type cells, Nampt ‐ deficient lung fibroblasts exhibited elevated expression of p16, and senescence‐associated secretory phenotype (SASP) cytokines, including TNFα, IL‐1β, and IL‐6. Notably enhanced recruitment of BM‐derived myeloid cells into BLM‐injured lung was also observed. These findings suggest that NAD + may play a significant role in prevention of cellular senescence and protection from pulmonary injury/fibrosis. Support or Funding Information This study is supported by NIH grants HL112880 and HL 138417.