Role of Amino Acid Metabolism in Pulmonary Fibrosis
Abstract
The proposed research project addresses Pulmonary Fibrosis, which is one of the FY21 PRMRP Topic Areas. Pulmonary fibrosis is the medical term used to describe scarring of lungs. Pulmonary fibrosis or lung scarring can be due to inflammatory conditions of the lung or due to exposure to environmental pollutants, drugs, or radiation. However, in many cases, the cause of pulmonary fibrosis cannot be identified and thus classified as idiopathic. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease affecting 150,000 patients in the U.S. Patients usually have a life expectancy of 3-5 years after the diagnosis of IPF is made. Recent reports showed that the number of Veterans diagnosed with IPF has doubled in the last 10 years. Currently approved therapies for IPF have limited efficacy and do not prevent disease progression, emphasizing the need for better understanding of how pulmonary fibrosis occurs. The lung scarring caused by pulmonary fibrosis occurs when cells called myofibroblasts become excessively activated and produce excess collagen protein. Progressive accumulation of collagen distorts the lung architecture and impairs lung function. The collagen proteins also lead to further activation of myofibroblasts, producing a feed-forward cycle. Therefore, targeting pathways required for collagen production has the potential to prevent disease progression and possibly lead to resolution. Compared to other proteins in humans, collagen has a unique structure in terms of its amino acids, the building blocks that make up proteins. Two amino acids, glycine and proline, make up more than 50% of amino acids in collagen protein. We have recently discovered that myofibroblasts do not take up glycine and proline from outside of the cell, but make their own glycine and proline from other nutrients to support collagen protein production. The enzymatic pathway that myofibroblasts use to produce glycine and proline is upregulated in lung tissue from patients with IPF as well as in mice with experimental lung fibrosis. We also found that mTORC1, which is a protein that regulates cell growth and metabolism, is required for upregulation of glycine and proline production in myofibroblasts. In preliminary studies, we found that in addition to glycine and proline, myofibroblasts have increased levels of the transporters and metabolic enzymes of two other amino acids, arginine and leucine. Similar to glycine and proline, cells can produce their own arginine, but leucine needs to be taken by diet and is therefore an essential amino acid. Myofibroblasts have increased the levels of arginine and leucine and removal of arginine or leucine from the nutrients in the media used to culture and feed cells decreased collagen protein production. Arginine and leucine can be incorporated into proteins, but they make up only a small fraction of collagen protein compared to glycine and proline. On the other hand, arginine and leucine can be metabolized or broken down inside the cells to precursors that can be used to produce proline and glycine, which can then be used to synthesize collagen. In addition, arginine and leucine are important regulators of mTORC1. While increased levels of arginine and leucine activate mTORC1, low levels inhibit it. Based on these preliminary findings, we hypothesized that arginine and leucine uptake by the cell and their metabolism regulate TGF-beta-induced collagen protein production by activating mTORC1 signaling and providing precursors for proline and glycine synthesis. To test our hypothesis, we will use lung tissues and fibroblasts that we have collected and stored from donors (to be used as control normal lungs and normal human lung fibroblasts) and from patients with IPF who had a lung transplant. We will also use an experimental model of pulmonary fibrosis in mice using instillation of bleomycin into lungs. The experiments that we propose will determine the role of exogenous (provided in diet or m
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210387
Entities
People
- Gokhan Mutlu
Organizations
- United States Army
- University of Chicago