Investigating Recruited Lung Macrophage Programming and Turnover in Self-Limited Versus Prolonged Lung Inflammation

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PROJECT SUMMARY The acute respiratory distress syndrome (ARDS) is characterized by severe lung inflammation and carries a mortality of 30-40%. Some patients recover quickly while others improve slowly and often develop lung fibrosis. The factors that drive these disparate outcomes are unclear. Pulmonary macrophages play key roles in the pathogenesis of ARDS by releasing inflammatory cytokines, recruiting neutrophils, and releasing cytotoxic and apoptotic factors which damage the lung epithelium. I hypothesize that inflammatory programming of pulmonary macrophages and continuous recruitment of monocytes with inflammatory programming into the lung drive prolonged inflammation and transient fibrosis in acute lung injury. Aim 1 of this proposal will use an existing single-cell RNA sequencing (scRNAseq) dataset generated by the Janssen laboratory to test the hypothesis that specific recruited monocyte-derived macrophage subsets from a mouse model of prolonged inflammation will exhibit transcription profiles consistent with perpetuating inflammation and fibrosis. This transcription profile would include expression of pro-inflammatory cytokines, chemokines, and cytotoxic factors. The transcriptional programming of recruited macrophages in a prolonged inflammation model will be compared to recruited macrophages from a model of self-limited inflammation. Aim 2 will use a compartment and lineage tracing mouse model I have optimized to test the hypothesis that prolonged lung inflammation is characterized by continuous recruitment of monocytes into the airspace and pulmonary interstitium that mature into pro-inflammatory macrophages, with little proliferation in situ whereas self-limited inflammation is characterized by an early, single wave of recruitment. Understanding the transcriptional profiles of recruited macrophage populations will provide insight into the pathophysiology of limited versus prolonged lung inflammation. Defining the kinetics of monocyte recruitment to the airspace and interstitium in limited versus prolonged inflammation will inform both the pathophysiology of slowly resolving lung inflammation and the timeline for interventions.