Advanced age is an important risk factor for developing pulmonary fibrosis but the underlying mechanisms leading to this association are not understood. In this application, we describe a fundamental mechanism by which aging promotes the development of pulmonary fibrosis by impairing metabolic responses in the alveolar epithelium of the lung. In young mice, we show that bleomycin activates a metabolic program in which alveolar epithelial type II cells (AEC2) rapidly reduce utilization of acetyl-CoA in the cytoplasm and simultaneously divert the machinery for acetyl-CoA production to the nucleus in order to enhance core histone acetylation and augment DNA repair. We found that central to these metabolic changes is the activation of AMPK, which is critical for both reducing cytoplasmic utilization of acetyl CoA and mobilizing the acetyl-CoA producing enzyme ATP-citrate lyase (ACL) to the nucleus. Importantly, we show that this adaptive interplay between the cytoplasm and nucleus is impaired in the lungs of older mice due, in large part, to reduced AMPK activity. Further, we demonstrate that by enhancing AMPK activation or increasing the availability of metabolic intermediates we can augment core histone acetylation, increase DNA repair and attenuate fibrotic responses in uninjured whole lung tissues of older mice and in cultured AECs exposed to bleomycin. Taken together, these findings led us to propose the following central hypothesis: We hypothesize that age-related decreases in AMPK activation contribute to the enhanced susceptibility of the lung to bleomycin and that strategies aimed at restoring AMPK activation or enhancing the availability of metabolic intermediates in the nucleus will enhance core histone acetylation, increase DNA repair and attenuate fibrotic responses in the lung. To test these hypotheses we propose the following:
In Specific Aim 1, we will establish the importance of AMPK activation in the regulating cellular metabolism and controlling core histone acetylation/DNA repair in the alveolar epithelium and we will determine whether activating this pathway reduces fibrotic responses in lungs of young and old mice;
In Specific Aim 2, we will establish the critical role of ACL mobilization to the nucleus after bleomycin for core histone acetylation and DNA repair and we will determine whether ATP-citrate lyase levels are reduced in IPF lung tissue compared to age-matched controls; and lastly, in Specific Aim 3, we will establish the therapeutic utility of bypassing deficient AMPK activity by determining whether supplying different metabolic substrates restores core histone acetylation, augments DNA repair and attenuates fibrotic responses in lungs of young and old mice. In summary, this proposal will establish the mechanisms by which aging enhances susceptibility to lung fibrosis after bleomycin insult. Further, we anticipate that findings from these studies will lay the foundation for future investigations testing whether novel pharmacological approaches targeting metabolic pathways detailed in this application can attenuate the onset and/or severity of fibrotic responses in lung, and in other extrapulmonary tissues.
. This grant tests the hypothesis that age-related changes in the metabolic response to bleomycin promote fibrotic responses in the alveolar epithelium of the lung. The major objective of this research is to elucidate the mechanisms by which aging enhances susceptibility to lung fibrosis and to determine whether targeting metabolic pathways described in this application can enhance core histone acetylation, augment DNA repair and ameliorate fibrotic responses in the lung. These studies should foster the development of novel therapeutic strategies for patients with pulmonary fibrosis, a condition for which current therapies are of modest clinical benefit.
| Romero, Freddy; Hong, Xu; Shah, Dilip et al. (2018) Lipid Synthesis Is Required to Resolve Endoplasmic Reticulum Stress and Limit Fibrotic Responses in the Lung. Am J Respir Cell Mol Biol 59:225-236 |
| Kato, Kosuke; Zemskova, Marina A; Hanss, Alec D et al. (2017) Muc1 deficiency exacerbates pulmonary fibrosis in a mouse model of silicosis. Biochem Biophys Res Commun 493:1230-1235 |
| Romero, Freddy; Summer, Ross (2017) Protein Folding and the Challenges of Maintaining Endoplasmic Reticulum Proteostasis in Idiopathic Pulmonary Fibrosis. Ann Am Thorac Soc 14:S410-S413 |
| Fertala, Jolanta; Romero, Freddy; Summer, Ross et al. (2017) Target-Specific Delivery of an Antibody That Blocks the Formation of Collagen Deposits in Skin and Lung. Monoclon Antib Immunodiagn Immunother 36:199-207 |
