Cholesterol crystal-mediated inflammation during lung fibrosis
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The lung is normally not considered a lipid metabolic organ. However, there is growing evidence that impaired regulation of lipid metabolism contributes to lung diseases. We recently found impaired cholesterol metabolism on an animal model of spontaneous lung fibrosis, where alveolar macrophages presented accumulation of crystals in their cytoplasm. We hypothesize that impaired cholesterol metabolism leads to formation of cholesterol crystals in alveolar macrophages, activating the complement system and the NLRP3-inflammasome, contributing to lung fibrosis. We also hypothesize that SP-C regulates cholesterol metabolism and cholesterol crystal formation. Therefore, immunometabolic reprogramming of alveolar macrophages will open a new therapeutic target for the treatment of lung fibrosis. Therefore, the objectives of the project are: 1) finding the lipid pathways altered in human fibrosis; 2) describe the molecular mechanism of cholesterol crystal formation in alveolar macrophages and the potential inflammasome activation and; 3) investigate the regulatory mechanism of SP-C on cholesterol metabolism in alveolar macrophages. Results from these objectives will help us to understand the molecular mechanisms involved in proper and aberrant cholesterol metabolism, identifying at the same time, targets for a potential treatment. These therapeutic strategies will aim to immunometabolically reprogram AMs to either metabolize efficiently cholesterol, including the use of statins, or promote the cholesterol efflux, by using LXR agonists, therefore preventing the inflammasome activation. In addition, contributing to the field, by correlating the impaired cholesterol metabolism to the development of lung fibrosis.
Correlation of human sample data, in vitro experiments and preliminary data will create enough evidence to elucidate the molecular mechanisms of cholesterol crystal formation in alveolar macrophages, its potential regulation through the SP-C:CD14:TLR4:CD36 axis and the potential immunoreprogramming of alveolar macrophages as therapeutic option.