Pneumonia and acute inflammatory diseases of the lungs affect over 450 million people worldwide each year and result in over 4 million deaths. Pathologic hallmarks include neutrophil accumulation in the airspaces, injury to alveolar epithelial and endothelial cells, and resultant loss of epithelial-capillary integrity with impaired gas exchange. Accordingly, restoration of lung function requires repair of injured alveoli, replacement of injured epithelial and endothelial cells, and re-establishment of capillary barrier function. Macrophages are recognized as critical orchestrators of tissue repair, however the mechanisms that drive their programming are poorly understood. During health the airspaces are occupied by a stable population of resident alveolar macrophages (RAM) that arise during embryogenesis and self-renew throughout life. RAMs remain during inflammation but are joined by recruited macrophages (RecM?) that arise from circulating monocytes. These RecM? remain in the lung while lung structure and function are restored, and then undergo apoptosis leaving RAMs to once again populate the healthy airspaces. The contributions provided by RAM and RecM? to alveolar repair are largely unknown and represent an important barrier to advancement in the field. In order to address this unmet need, our group performed time-resolved RNA sequencing on RAMs and RecM? isolated from LPS treated mice during acute and resolving inflammation. Our data showed marked differences in the transcriptomal profiles of RAMs and RecM? at all time points studied, with over 50% of genes differentially expressed. Pathway analysis and functional studies demonstrated that RecM? produce high levels of epithelial and endothelial proliferative factors and suggested that RecM? are key orchestrators of tissue repair. Studies using CCR2 -/- mice, which have defects in monocyte migration and impaired accumulation of RecM?, further supported this concept; LPS treated CCR2-/- and wild type mice had equivalent degrees of lung injury, but CCR2-/- mice had reduced epithelial and endothelial proliferation and prolonged capillary barrier dysfunction. Transcriptomal and metabolic analyses suggested that HIF-1? transcription and stabilization were increased in RecM? and that HIF-1? induced metabolically reprograming the RecM? toward glycolysis. These data led us to hypothesize that RecM? are essential orchestrators of epithelial and endothelial cell proliferation following acute lung injury and that the relevant programming of RecM? is driven by HIF-1? and glycolytic energy metabolism. This will be tested in three Specific Aims. 1) Test the hypothesis that recruited macrophages are programed to stimulate proliferation of alveolar epithelial and endothelial cells following acute lung injury. 2) Test the hypothesis that glycolytic metabolism in recruited macrophages promotes their production of epithelial and endothelial proliferative factors and stimulates tissue repair. 3) Test the hypothesis that HIF-1? is responsible for metabolic reprogramming of recruited macrophages with enhanced anaerobic glycolysis and reduced oxidative phosphorylation.
Pneumonia and other acute inflammatory diseases of the lungs result in damage to the alveolar epithelium and endothelium. Alveolar macrophages are critical orchestrators of alveolar repair, however the mechanisms that underpin their function remain largely unknown. This proposal tests the hypothesis that a subset of alveolar macrophages, referred to as recruited macrophages, are critical drivers of alveolar repair and that their function is driven by HIF-1? and a change in cellular metabolism. Achieving the aims of this proposal will enhance our understanding of lung repair and pave the way for new strategies to hasten recovery from lung injury.
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