The Garcia-Arcos Lab investigates the critical and often underappreciated role of lipid metabolism in lung health and disease. The lung is rarely thought of as a lipid metabolic organ, yet alveoli are home to some of the most metabolically active cells in the body, alveolar type 2 cells (AT2C), which synthesize and secrete pulmonary surfactant, a lipid-protein complex essential for lung function. Our research sits at the unique intersection of pulmonary physiology and lipid biology, exploring how disturbances in lipid metabolic pathways within lung cells contribute to major respiratory diseases, including chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, and smoke-induced lung injury.

A central focus of our work is understanding how lipid metabolism in AT2C governs surfactant production, secretion, and recycling, and how disruptions in these processes lead to disease. We have shown that surfactant lipids are dramatically and persistently decreased in COPD patients, with specific lipid species correlating strongly with pulmonary function. More recently, we identified the low-density lipoprotein receptor-related protein 1 (LRP1) as a critical regulator of surfactant lipid metabolism in AT2C. Genetic variants in LRP1 are associated with COPD in humans, and our work using AT2C-specific LRP1 knockout mice demonstrated that loss of LRP1 impairs surfactant phospholipid availability, upregulates detoxification and inflammatory pathways, decreases lung compliance, and exacerbates fibrotic remodeling after smoke exposure, altogether providing a mechanistic link between lipid metabolism and COPD pathogenesis.

Beyond surfactant biology, the lab explores broader questions of metabolic reprogramming in the lung. We have shown that hyperglycemia-like glucose concentrations trigger metabolic shifts in bronchial epithelial cells, rerouting glucose toward the pentose phosphate pathway and glycogen storage and inducing the secretion of profibrotic mediators that activate neighboring fibroblasts, which provides insight into the metabolic crosstalk underlying diabetes-associated pulmonary fibrosis. By characterizing lipids and metabolic pathways that have not previously been studied in the pulmonary context, we aim to uncover new players and potential therapeutic targets in lung pathology.

We use a multidisciplinary approach that spans biochemistry, molecular biology, cell biology, -omics approaches, and integrative physiology. Our toolkit includes advanced lipid profiling of bronchoalveolar lavage fluid and isolated cells, air-liquid interface cell culture models of human lung epithelial cells for in vitro studies, tamoxifen-inducible cell-specific knockout models for dissecting gene function, continuous oxygen consumption monitoring in vitro, kinetic and enzymatic activity assays, proteomics and RNA sequencing and pathway enrichment analysis for unbiased transcriptomic discovery, confocal microscopy to analyze cellular protein localization and subcellular colocalization,  radiolabel tracing studies to define lipid trafficking, whole body plethysmography and forced oscillatory pulmonary function testing using the FlexiVent system, and interventions to model COPD, pulmonary fibrosis and acute lung injury. This combination allows us to move from molecular and cellular mechanisms to whole-organ physiology, bridging the gap between bench findings and clinical relevance.

Ultimately, our goal is to advance the understanding of how lipid metabolism shapes lung function and disease, and to translate these findings into novel therapeutic strategies. By integrating cutting-edge approaches and modern genetic tools with classical physiology and biochemistry, we strive to build a comprehensive picture of the lung as a dynamic lipid metabolic organ, where dysfunction in surfactant homeostasis, cholesterol trafficking and lipid metabolism critically contributes to some of the most common and debilitating respiratory diseases.