# AMPK in the Development and resolution of Lung Fibrosis

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $761,371

## Abstract

PROJECT SUMMARY
Clearance of apoptotic cells (efferocytosis) is significantly reduced in lungs of patients with the fibrosing lung
disorder, idiopathic pulmonary fibrosis (IPF). Mechanism/s responsible for halted efferocytosis and the potential
benefit of restoring efferocytosis to fibrosis resolution has yet to be determined. The major goal of the proposed
studies is to establish how AMP-activated protein kinase (AMPK) affects macrophage population dynamics,
including influx of monocyte-derived transitional macrophages that promote fibrosis persistence versus
efferocytosis-competent populations involved in resolution of fibrosis. Macrophage dynamics and secretome will
be investigated in young-adult mice with resolving fibrosis, as well as the effect of AMPK-dependent stimulation
of efferocytosis and induced fibrosis resolution in aged mice. For specific role of AMPK in lung macrophages,
we will use AMPK deficient mice and adoptive transfer studies of macrophages in aged mice. The central
hypothesis is that: Senomorphic effects of AMPK promotes efferocytosis and resolution of age-associated
persistent lung fibrosis. Our Specific AIMs are designed to determine how AMPK activation affects macrophage
phenotypes for clearance of apoptotic cells during established lung fibrosis versus resolution (AIM 1). AIM2 will
establish the impact of AMPK activation in distinct areas of fibrotic vs. resolution niche, using spatial
transcriptomics, with focus on AMPK-dependent regulation of mitochondrial and lysosomal biogenesis to restore
efferocytotic competence in lung macrophages. AIM3 will delineate how AMPK activation reverses the non-
autonomous mechanism of efferocytosis suppression. Our findings will characterize efferocytosis-competent
macrophages in the fibrosis resolution niche, as well as the impact of AMPK on pro-fibrogenic population of MФs
(CX3CR1+SiglecF+). Furthermore, our findings is expected to motivate clinical studies of metformin or newer
classes of direct allosteric activators (e.g., MK-8722) of AMPK to test the gero-protective role of AMPK in chronic
fibrotic disorders such as IPF.

## Key facts

- **NIH application ID:** 10881556
- **Project number:** 2R01HL139617-05
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Victor J. Thannickal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $761,371
- **Award type:** 2
- **Project period:** 2019-01-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881556

## Citation

> US National Institutes of Health, RePORTER application 10881556, AMPK in the Development and resolution of Lung Fibrosis (2R01HL139617-05). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10881556. Licensed CC0.

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