Macrophage Responses to Epithelial Dysfunction Promote Lung Fibrosis in Aging

Project: Research project

Project Details

Description

Repeated lung injury over the lifespan results in a gradual replacement of tissue-resident alveolar macrophages with bone marrow-derived alveolar macrophages. The resulting loss of protective signals from the tissue-resident macrophages and the relatively exuberant response of bone marrow-derived alveolar macrophages to subsequent injury accelerates the age-related decline in the function of the epithelial proteostasis network, thereby creating a vicious circle of accelerating proteostatic decline, reduced lung resilience and an enhanced susceptibility to fibrosis.
We have generated a set of novel tools to address this question. These include (1) flow cytometry techniques to fully characterize the numbers and activation state of all of the inflammatory cell populations in the lung (2) techniques to allow us to distinguish between tissue-resident and bone marrow-derived macrophages (bone marrow chimeric mice with lead shielding/busulfan myeloablation combined with diphtheria toxin-mediated depletion of tissue resident macrophages) (3) a set of procedures to isolate and adoptively transfer tissue-resident or bone marrow-derived alveolar macrophages into the lungs of mice and (4) a gene expression panel (Luminex QuantiGene 2.0 assay) allowing simultaneous detection of 52 genes, which covers the full spectrum of classical/alternative (M1/M2) macrophage activation, differentiation and function in the same sample using as few as 40,000 cells. We have used this panel to show that bone marrow-derived, express pro-fibrotic genes during bleomycin-induced fibrosis, while tissue-resident macrophages maintain non-fibrotic, non-inflammatory signature.
StatusFinished
Effective start/end date9/30/159/29/19

Funding

  • U.S. Army Medical Research and Materiel Command (W81XWH-15-1-0215)

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