Acute lung injury occurs in over 200,000 subjects in the U.S. each year and over 40% of affected individuals succumb to this disease. Elderly patients represent a disproportionate number of afflicted individuals with acute lung injury, but the factors responsible for this increased susceptibility remain unclear. We now have evidence suggesting that aging renders the lung susceptible to disrepair through the establishment of a 'pro-fibrotic'state that is unleashed only after exposure to an injurious agent. When comparing mice at 2 months and 24 months of age, we found that, at baseline, the lungs of senescent mice show increased expression of the pro-fibrotic growth factor transforming growth factor beta, its receptor TGF-?RI, and its main intracellular transducer, Smad3;the fibronectin splicing variant EDA, a matrix glycoprotein linked to lung fibrogenesis;and the proteases MMP2 and MMP9. We also found that fibroblasts harvested from the lungs of senescent mice show decreased expression of Thy-1;Thy-1 negative fibroblasts promote fibrogenic responses. Importantly, when exposed to bleomycin, elderly animals show greater fibrosis as demonstrated histologically and by quantification of hydroxyproline. In view of the importance of the above findings, we turned our attention to the factors promoting these events. That search led us to investigate the role of oxidant stress. It has been shown that elderly animals (and humans) manifest oxidation of their plasma cysteine/cystine redox potential. We demonstrated that this type of oxidant stress promotes lung fibroblast proliferation, myofibroblast transdifferentiation, and expression of TGF-? and fibronectin in vitro. Based on the above, we hypothesize that aging, through oxidation of the cysteine/cystine redox potential, results in a 'pro- fibrotic'state that renders the host susceptible to disrepair and the development of acute lung injury after an insult. The hypothesis will be investigated by examining how oxidation of the extracellullar cysteine/cystine redox potential promotes a pro-fibrotic state in senescent murine lungs, by determining the impact of nutritional interventions as preventive strategies, and by testing for evidence of this pro-fibrotic state in the bronchoalveolar lavage fluid of young versus elderly humans who are otherwise healthy.
The incidence and mortality from acute lung injury are more common in elderly patients. Many reports suggest that senescent lungs are proned to disrepair after injury, but the mechanisms responsible for this remain incompletely understood. We believe that a special kind of oxidant stress (oxidation of the cysteine/cystine redox potential) induce a 'pro-fibrotic'state in senescent lungs thereby increasing susceptibility to acute lung injury. This project seeks to explore this possibility with the hope of identifying dietary interventions that could serve as preventive therapy.
