Brent Carter, M.D.
University of Iowa, University of Alabama at Birmingham
NIEHS Grant R01ES015981, R01ES014871
Research, funded in part by NIEHS, has identified a molecular pathway that can be targeted to stop pulmonary fibrosis, a progressive and fatal disease that causes damage and scaring to lung tissue. Understanding the molecular mechanisms involved in pulmonary fibrosis could help lead to treatments that prevent or halt the disease.
Although scientists don’t fully understand the mechanisms involved in pulmonary fibrosis, they do know that reactive oxygen species — chemically reactive molecules that contain oxygen — play a critical role and that pulmonary macrophages help regulate how the body responds to lung injury. Previous studies have found that the mitochondrial production of hydrogen peroxide by pulmonary macrophages is directly linked to pulmonary fibrosis and that the small GTP-binding protein, Rac1, directly mediates this hydrogen peroxide production. Since the protein modification process of geranylgeranylation is required to activate Rac1, the researchers hypothesized that interrupting this protein modification might halt the production of oxidative stress and fibrosis.
Results from cell and mouse experiments showed that targeting the isoprenoid pathway by using digeranyl bisphosphonate to impair geranylgeranylation lessened Rac1 mitochondrial import, mitochondrial oxidative stress, and the progression of the fibrotic response to lung injury.
Citation: Osborn-Heaford HL, Murthy S, Gu L, Larson-Casey JL, Ryan AJ, Shi L, Glogauer M, Neighbors JD, Hohl R, AB Carter. 2015. Targeting the isoprenoid pathway to abrogate progression of pulmonary fibrosis. Free Radic Biol Med 86:47-56.