Macrophage Responses to Epithelial Dysfunction Promote Lung Fibrosis in Aging
Technical Report,30 Sep 2015,29 Sep 2016
Northwestern University, Feinberg School of Medicine, Division of Pulmonary and Critical Care Chicago United States
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Purpose To test the hypothesis that the replacement of tissue-resident alveolar macrophages with monocyte-derived macrophages in response to repeated injury over the lifespan explains the delayed onset of lung fibrosis until the later decades of life. We will use our experimental findings in mice to guide an unbiased assessment of macrophage heterogeneity in normal human lungs and lungs from patients with pulmonary fibrosis. The overarching goal of these studies is to identify clinically applicable biomarkers that can guide therapy and factors released from tissue-resident macrophages or bone marrow-derived macrophages that prevent or promote fibrosis, respectively so they can be targeted for prevention or therapy. Aim 1 To determine whether replacement of tissue-resident alveolar macrophages by monocyte-derived alveolar macrophages during aging contributes to the enhanced susceptibility to lung fibrosis in aged mice. Mice are currently being aged. The work is continuing according to SOW, no major findings to report. However, we have generated improved, more economical and robust mouse model to distinguish tissue-resident and monocyte-derived alveolar macrophages. Aim 2 To determine whether tissue-resident alveolar macrophages or monocyte-derived alveolar macrophages differentially respond to epithelial injury in a murine model of accelerated pulmonary fibrosis. The work on this aim is in progress, in accordance with SOW, no major findings to report at the moment expected in the year 2 of award. Aim 3 To identify novel biomarkers expressed by human tissue-resident and monocyte-derived alveolar macrophages based on single cell molecular classification in patients with pulmonary fibrosis. We have recruited a planned number of patients into the study and performed transcriptional profiling by means of RNA-seq on single cell and bulk sorted populations or alveolar macrophages.
- Anatomy and Physiology
- Medicine and Medical Research