# The role of Nampt in age-associated persistent lung fibrosis

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2021 · —

## Abstract

The pathophysiology of Idiopathic pulmonary fibrosis (IPF), a rapidly progressive and deadly fibrotic lung
disease remains poorly understood. Aging is a well-recognized risk factor for IPF, and IPF disproportionately
affects the aging veteran population. Given this shift in demographic, it is critical to understand the contribution
of aging to the cellular/molecular mechanism(s) leading to the pathogenesis of age-related diseases, such
as IPF. In resolving fibrosis, lung myofibroblasts (the key `scar tissue generating' cell) undergo apoptosis
to promote healing. In contrast, myofibroblasts from aged mice with non-resolving fibrosis acquire a
senescent and apoptosis-resistant phenotype, mediated in part by persistent expression of NADPH-
oxidase-4 (Nox4). Similarly, lung myofibroblasts from IPF patients exhibit senescence and apoptosis-
resistance, associated with elevated Nox4 expression. However, the mechanisms that drive persistence of
Nox4 and apoptosis-resistance of myofibroblasts in the context of aging/IPF remain unknown. We have
identified a critical role for Nampt, a known regulator of innate immune responses and apoptosis, in driving
the senescent and apoptosis-resistant myofibroblast phenotype in age-associated pathological lung fibrosis.
We demonstrate that Nampt is upregulated in vivo in 2 injury models of age-dependent fibrosis, and in fibrotic
regions of the IPF lung. Intracellular Nampt (iNampt) is persistently expressed in senescent and IPF
fibroblasts, which fail to undergo apoptosis, and these cells secrete significantly elevated levels of extracellular
Nampt (eNampt). We found that eNampt mediates profibrotic effects via TLR4, including myofibroblast
differentiation, oxidative signaling, senescence, and apoptosis-resistance. Our data suggest that defective
TGF-mediated downregulation of iNampt in senescent/IPF fibroblasts contributes to persistent iNampt
expression, subsequent elevated eNampt levels, which promotes profibrotic effects. Reductions in Nampt
expression facilitated myofibroblast apoptosis and led to protection from fibrosis in vivo. The mechanisms that
drive continued propagation of fibrogenic responses, beyond initial injury, are not well understood. We
propose a novel auto-regulatory mechanism (eNampt/iNampt), which temporally reinforces profibrotic
responses in age-dependent pathological fibrosis. These studies will prvide insight into novel age-relevant
mechanisms/cellular phenotypes in IPF pathogenesis. Further, we will evaluate the pre-clinical efficacy of
FK-866 (iNampt inhibitor currently in phase II clinical trials as an anti-cancer agent) in rigorous aging
animal models of fibrosis, enhancing the potential fo rapid clinical translation of novel therapeutics for
IPF.

## Key facts

- **NIH application ID:** 10046286
- **Project number:** 7I01BX003919-04
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** LOUISE HECKER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 7
- **Project period:** 2017-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10046286

## Citation

> US National Institutes of Health, RePORTER application 10046286, The role of Nampt in age-associated persistent lung fibrosis (7I01BX003919-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10046286. Licensed CC0.

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