Cholesterol crystal-mediated inflammation in alveolar macrophages: an emerging role inidiopathic lung fibrosis?

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Idiopathic Pulmonary Fibrosis (IPF) is a chronic lung disease characterized by progressive scarring of the lung, eventually causing respiratory failure and death. It currently affects 80,000-111,000 people in Europe and has no cure yet. Alveolar macrophages (AMs) are important immune cells involved in the defense against microorganisms. Moreover, they are partially responsible of lung lipid recycling, even though the specific mechanism is still not known. Thus, altered activity of AMs may lead to lipid accumulation. Among lipids, cholesterol seems to play a key role, since animal models of IPF show accumulation of cholesterol in macrophages. Moreover, accumulation of structures similar to cholesterol crystals (CCs), have been observed in mouse lungs from different lung disease models. We hypothesize that altered cholesterol metabolism leads to formation of CCs in AMs, contributing to lung fibrosis. The main goal of present study is to detect altered lipid metabolic mechanisms in AMs and to clarify the mechanisms leading to CC formation/accumulation in AMs and their involvement in lung fibrosis. To this purpose, the project specifically aims to: characterize the molecular mechanism of CC formation in AMs and potential activation of inflammatory processes in AM-like cell cultures; validate the results in an animal model of lung fibrosis; detect altered lung lipid metabolic mechanisms involved in human IPF lung samples. The research will focus on an interdisciplinary approach including experiments in cells and in human samples by means of cutting-edge technologies, such as electron microscopy to detect changes in AM morphology and the ability of AMs to produce and/or uptake CCs, and mass spectrometry to elucidate altered lipid levels in IPF patients. Given the urgency of an effective therapy for IPF, the growing interest of the medical community on the role of lipid metabolism in the development of lung fibrosis, and the innovative approach proposed here, the project could provide new insights into the development of therapeutic targets and diagnostic tools. The applicant has expertise in lipid analyses of lung samples that will help in identifying altered mechanism. The proposed project will help her to develop further her laboratory competences, along with her professional growth through the collaboration with colleagues from different backgrounds, thus enabling the applicant to independently lead her own research projects in the field of lung physiology in the future.