Redente, E. F. | Search bioRxiv

bioRxiv2022

Alveolar macrophage lipid burden correlates with clinical improvement in patients with Pulmonary Alveolar Proteinosis

Pulmonary alveolar proteinosis (PAP) is a life-threatening rare lung syndrome characterized by the accumulation of surfactant and lipid-loaded macrophages within the alveoli for which there is no cure and no approved therapies. The clinical diagnosis of PAP, often made by invasive lung biopsies and/or cytology of bronchoalveolar lavage fluid does not identify the underlying cause of disease. In addition, no biomarkers exist to inform prognosis or therapeutic options in PAP. We now report on the use of comprehensive mass spectrometry to profile and define the lipid signature of alveolar macrophages obtained from PAP patients. In addition, we quantify how these macrophage-associated lipids change during clinical treatment. Our studies demonstrate that clinical improvement in treated PAP patients is associated with a decrease in total lipid content, indicating that levels of these macrophage-associated lipids correlate with the severity of the disease.

physiology↗

bioRxiv2020

Loss of Fas-signaling in pro-fibrotic fibroblasts impairs homeostatic fibrosis resolution and promotes persistent pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic disease of the distal lung alveoli that culminates in respiratory failure and reduced lifespan. Unlike normal lung repair in response to injury, IPF is associated with the accumulation and persistence of fibroblasts and myofibroblasts and continued production of collagen and other extracellular matrix (ECM) components. Prior in vitro studies have led to the hypothesis that the development of resistance to Fas-induced apoptosis by lung fibroblasts and myofibroblasts contibributes to their accumulation in the distal lung tissues of IPF patients. Here, we test this hypothesis in vivo in the resolving model of bleomycin-induced pulmonary fibrosis in mice. Using genetic loss-of-function approaches to inhibit Fas signaling in fibroblasts, novel flow cytometry strategies to quantify lung fibroblast subsets and transcriptional profiling of lung fibroblasts by bulk and single cell RNA-sequencing, we show that Fas is necessary for lung fibroblast apoptosis during homeostatic resolution of bleomycin-induced pulmonary fibrosis in vivo. Furthermore, we show that loss of Fas signaling leads to the persistence and continued pro-fibrotic functions of lung fibroblasts. Our studies provide novel insights into the mechanisms that contribute to fibroblast survival, persistence and continued ECM deposition in the context of IPF and how failure to undergo Fas-induced apoptosis prevents fibrosis resolution.

cell biology↗