Our laboratory previously discovered a central role for ceramide in the development of emphysema. We demonstrated that ceramide is a proximal hub of amplification for apoptosis, oxidative stress, and for its own synthesis, and is both necessary and sufficient to induce airspace enlargement and functional decreases of lung elastance, fundamental characteristics of emphysema. In this application we address the novel concept that cigarette smoke (CS) exposure disrupts sphingolipid homeostasis in the lung to generate distinct acute and chronic ceramide responses, responsible for the death of structural alveolar epithelial and endothelial cells, inhibition of clearance of apoptotic cells by alveolar macrophages, and impairment of cell repair that sustain an irreversible lung destruction in emphysema. We hypothesize that CS-induced ceramides trigger alveolar cell death, impair proper removal of apoptotic bodies, and disrupt cell repair due to sequential activation of acid sphingomyelinase followed by de novo ceramide synthesis. We will test this hypothesis by using transgenic in vivo approaches complemented with pharmacological inhibition of target enzymes and by assessing structural and functional endpoints that characterize cigarette smoke-induced emphysema. Sphingolipid measurements and their effect on alveolar apoptosis and clearance of apoptotic cells will be studied by tandem mass spectrometry and intravital/time-lapse two-photon microscopy, respectively.
The specific aims are: 1) To determine that the CS-activated acid sphingomyelinase triggers alveolar cell apoptosis and causes airspace enlargement in mice. 2) To establish that CS and paracellular ceramides activate the de novo pathway in alveolar macrophages causing inhibition of apoptotic body removal. 3) To elucidate if the paracrine activation of de novo ceramide synthesis causes alveolar cell apoptosis and decreased lung repair by CS. Our experimental questions and approach will address fundamental questions of emphysema pathogenesis and will provide the rationale and basis for developing a therapeutic strategy for patients with COPD.
We propose to renew our studies on the role of ceramides in emphysema with a new investigation to identify specific regulatory and amplifying sphingolipid pathways triggered by progressive cigarette smoke exposure. Ceramide molecular species are differentially regulated via either synthesis or metabolism through enzymatic pathways activated in distinct cellular subcompartments. Our work will address fundamental questions of emphysema pathogenesis by defining processes that occur in the early stages of CS exposure and mechanistically linking them to the development of chronic injury. Our results will provide the rationale and basis for developing a therapeutic strategy for patients with COPD, will define several sphingolipids as sensor molecules of CS-induced lung tissue damage, and will link alveolar epithelial and endothelial cell damage to paracellular releases of ceramides which may lead paracrine and systemic COPD manifestations.
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