PROJECT SUMMARY
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.