# Critical Role of NAMPT and Toll-Like Receptor 4 in Inflammation and Mechanical Ventilator-Induced Lung Injury (VILI)

> **NIH NIH P01** · UNIVERSITY OF ARIZONA · 2021 · $459,929

## Abstract

PROJECT #2 SUMMARY: 
Insights into ARDS and VILI pathobiology have been incremental and effective targeted pharmacotherapies 
have not yet been realized. Project #2 addresses the novel role of NAMPT, the gene encoding nicotinamide 
phosphoribosyltransferase, in the pathobiology of ARDS and ventilator–induced lung injury (VILI). We identified 
NAMPT by genomic–intensive approaches utilizing cellular and preclinical models of excessive mechanical 
stress and VILI. We demonstrated that excessive mechanical stress induces robust NAMPT expression and 
secretion (extracellular NAMPT or eNAMPT) serves as a novel ARDS biomarker. We have shown that NAMPT 
exhibits 5' promoter single nucleotide polymorphisms (SNPs) that significantly alter NAMPT promoter activity 
and confer significantly increased ARDS susceptibility and ARDS severity (reduced ventilator-free days, 
increased ARDS mortality). We determined that eNAMPT is an essential participant in VILI pathobiology directly 
producing a neutrophilic alveolitis and lung injury whereas reductions in eNAMPT availability (neutralizing 
antibodies, siRNAs, NAMPT+/- mice) dramatically attenuates the severity of lung injury in preclinical VILI /ARDS 
models. Finally, we demonstrated that NAMPT expression is spatially-localized with robust expression and 
secretion by lung endothelial cells (ECs) with eNAMPT a novel ligand for the Toll–like receptor 4 (TLR4) inducing 
NFκB transcriptional activities and inflammatory lung injury. Although eNAMPT is clearly an attractive 
ARDS/VILI target, critical gaps remain in the understanding of NAMPT-mediated lung pathobiology, issues 
which need to be addressed for robust translation to an ICU therapy. Project #2 will address these key gaps 
focusing on mechanical stress-challenged lung EC (a major source of secreted eNAMPT), on eNAMPT 
contribution to increases in vascular permeability (a major therapeutic target in ARDS), and on the critical influence 
of eNAMPT binding to lung EC TLR4 in VILI development. Project #2 Specific Aims (SAs) are designed to 
address these gaps with SA #1 elucidating mechanical stress-mediated genetic and epigenetic regulation of 
NAMPT expression (transcription factors, CpG demethylation, 3'UTR miRNA binding, NAMPT SNPs). Based 
on exciting preliminary data, SA #2 will define regulation of eNAMPT secretion by caspase-mediated cleavage 
and ABC transporters. With Core B (Molecular Biology & Genetics Core) and Core D (Protein Chemistry Core), 
SA #3 will define structure/function mechanisms involved in NAMPT binding of TLR4 and the influence of TLR4 
and NAMPT coding SNPs on ligand–receptor interactions. Finally, utilizing preclinical VILI/ARDS models, 
including a novel conditional EC–specific and lung epithelium-specific NAMPT KO mice (Core C: Pre-clinical 
Animal Model Core), SA #4 will translate SA #1- #3 data into actionable information to attenuate VILI/ARDS and 
define the impact of reduced NAMPT expression and secretion (STAT5/HIF2α inhi...

## Key facts

- **NIH application ID:** 10094248
- **Project number:** 5P01HL134610-04
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Joe G. N. Garcia
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $459,929
- **Award type:** 5
- **Project period:** 2018-02-05 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10094248

## Citation

> US National Institutes of Health, RePORTER application 10094248, Critical Role of NAMPT and Toll-Like Receptor 4 in Inflammation and Mechanical Ventilator-Induced Lung Injury (VILI) (5P01HL134610-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10094248. Licensed CC0.

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