This proposal is focused on the challenge of understanding and thus improving treatment for idiopathic pulmonary fibrosis, a devastating interstitial lung disease without effective treatments. Deregulation of lipid signaling and metabolism has long been studied in pulmonary fibrosis, pointing to changes in sphingolipid and ceramide pathways that may impact pathology. In recent years, increased attention has been paid to a possible role for senescent cells in the lung as a critical factor driving pulmonary fibrosis. Senescent cells express inflammatory factors, including signaling lipids, which may drive the fibrotic process. Current questions include why senescent cells accumulate in these patients and how their pro-inflammatory activity might be mitigated. An inference is that preventing formation of senescent cells, blocking their lipid signaling and/or promoting their clearance from the lung might prevent pulmonary fibrosis or block disease progression. Importantly, there may be a direct link between sphingolipid pathways and cellular senescence. Ceramides have been shown to induce senescence in otherwise proliferating cells. Our studies have implicated lipid peroxidation and its aldehyde end-products such as 4-hydroxynonenal as key mediators of accelerated senescence. Transcriptomic, proteomic and lipidomic analysis of proliferative and senescent lung cells will be used to identify key senescence factors and networks that may point to the specific lipid metabolic pathways that drive senescence and inflammatory signaling. We will then examine lipids and modulators for the ability to promote or prevent senescence. Finally, we will examine whether manipulation of lipid metabolic pathways can be used to potentiate clearance of senescent cells and thereby limit pulmonary fibrosis. With success in these studies, we anticipate identification of candidate therapeutics with potential to move to clinical trials.
This proposal is focused on a major lung disease of older Americans, idopathic pulmonary fibrosis. In IPF, the lungs become stiff and patients experience increasing shortness of breath, often leading to lung failure and death within two to three years. We will explore whether simple drugs related to oils and fats that might be provided as part of the diet can maintain normal function in the lung and slow the progression of pulmonary fibrosis.
