Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal respiratory disorder affecting ~150,000 patients in US each year. IPF is a disease of aging, with two-thirds of IPF patients over 60 years old at the time of presentation and average age of 66 years at the time of diagnosis. Effective therapeutic interventions are limited. Our proposed studies seek a solution to effectively stop and reverse established fibrosis. This proposal consists of highly mechanistic and translational studies that are result of a collaboration between Dr. Zmijewski and Dr. Thannickal. Both PIs and the collaborators bring complementary expertise in cellular metabolism, myofibroblast biology, aging, and lung injury and repair. We found that AMP-activated protein kinase (AMPK), a key sensor and metabolic regulator, is a viable target in lung fibrosis. In particular, AMPK activity is reduced in IPF lungs and the fibrotic regions following lung injury in mice. Moreover, AMPK inactivation is also associated with age-associated susceptibility to non-resolving fibrosis. This loss of AMPK activity is associated with mitochondrial dysfunction and deficient autophagy/mitophagy, events that are linked to myofibroblast resistance to apoptosis and impaired ECM turnover. We hypothesize that, in the repair response to lung injury, AMPK activation is essential for preservation of mitochondrial homeostasis, autophagy- dependent ECM turnover and myofibroblast sensitivity to apoptosis which promotes resolution of lung fibrosis. Our hypothesis will be tested using three specific AIMs.
AIM 1 is focused on AMPK-dependent activation of mitochondrial biogenesis and autophagy/mitophagy to reverse myofibroblast activation and resistance to apoptosis, both in ex vivo cellular systems and in a murine model of lung fibrosis in vivo.
AIM 2 will reveal mechanisms responsible for lack of AMPK activation in myofibroblasts, from IPF subjects and from fibrotic lungs of mice.
AIM 3 will test the efficacy of AMPK activators on age-associated susceptibility to lung fibrosis. Proof-of-concept studies with pharmacological AMPK activators will include an FDA-approved drug (metformin) and a more specific AMPK activator (AICAR). In addition, genetic approaches will include global AMPK knockouts and fibroblast-specific conditional deletion of AMPK in mice; transgenic models will also incorporate mice deficient for activators of biogenesis and autophagy/mitophagy. If confirmed, our studies will reveal new relationships between lung fibrosis and AMPK dysfunction that affects myofibroblast bioenergetic reprogramming, apoptosis susceptibility, and persistent lung fibrosis. Advancements in the field include signaling mechanisms responsible for AMPK inactivation in IPF and aging. Translational impact be realized by the re- purposing of metformin to treat lung fibrosis. Based on the safety profile of this drug, if the results confirm anti- fibrotic actions of metformin, clinical trials could be proposed to test its efficacy in IPF.

Public Health Relevance

Idiopathic pulmonary fibrosis is a progressive and ultimately fatal respiratory disorder. Because AMP-activated protein kinase (also called AMPK) plays a central role in regulating key metabolic-bioenergetic pathways, we will determine if AMPK activation promote transition from fibrogenesis to fibrosis resolution phase. The proposed studies will provide fundamental information not only concerning the pathological events associated with non- resolving fibrosis, but also suggest novel therapeutic interventions to prevent and potentially stimulate resolution of aging-mediated lung fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL139617-01A1
Application #
9662389
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Craig, Matt
Project Start
2019-01-15
Project End
2022-12-31
Budget Start
2019-01-15
Budget End
2019-12-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294