Endothelial Signaling Pathway Linked to Pulmonary Fibrosis
In This Article
- A Massachusetts General Hospital study has found a link between sphingosine-1-phosphate receptor 1 (S1PR1) in the endothelium and the development of pulmonary fibrosis
- Researchers used a pre-clinical model to target the endothelium by deleting S1PR1
- The study found more severe pulmonary fibrosis occurred when endothelial S1PR1 deletion caused increased vascular permeability in the lungs
- These findings will inform future research on the endothelium as an avenue to develop pulmonary fibrosis treatments
Research at Massachusetts General Hospital has found that the loss of sphingosine-1-phosphate receptor 1 (S1PR1) in the endothelium contributes to the development of pulmonary fibrosis.
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The study, published in the American Journal of Respiratory Cell and Molecular Biology, was led by Rachel Knipe, MD, physician-researcher in the Division of Pulmonary and Critical Care Medicine at Mass General. Her research focuses on the mechanisms driving the development of pulmonary fibrosis.
"Prior studies have suggested a linkage between sphingosine-1-phosphate (S1P) and fibrosis, but this is the first study where we have used the transgenic mouse with an endothelial specific defect to show worse outcomes in an experimental model of lung injury and fibrosis," Dr. Knipe says.
Research Motivated by Need for Better Pulmonary Fibrosis Treatments
Idiopathic pulmonary fibrosis (IPF) is a progressive disease that leads to respiratory failure. Currently, there are two drugs approved for use in IPF, but they only slow the rate of lung function in people with the disease. With her studies, Dr. Knipe aims to lay the groundwork to develop new treatments that can halt or reverse IPF progression.
Lipid mediators such as S1P regulate multiple homeostatic processes in the lungs. Dr. Knipe's study demonstrates that the endothelial cell-specific deletion of S1PR1 in mice results in increased lung vascular permeability and, ultimately, more severe pulmonary fibrosis.
Preclinical Models to Understand the Pathogenesis of Pulmonary Fibrosis
In collaboration with Dr. Timothy Hla's lab at Boston Children's Hospital, Dr. Knipe's team used a Cre recombinase system and tamoxifen treatment to delete S1PR1 in mouse endothelial cells. Cre recombinase is an enzyme utilized to induce DNA sequence-specific recombination in mammalian cells.
The team then injected the mouse tracheas with bleomycin to induce fibrosis. After several weeks, they observed the differences in fibrosis that developed in mouse lungs before and after bleomycin treatment with several measurements:
- Studying lung permeability utilizing Evans blue dye
- Examining inflammatory cells in the bronchoalveolar lavage (BAL) fluid
- Measuring D-dimer levels to indicate coagulation in the lungs
"We found that the mice got worse fibrosis when we deleted S1PR1 and injected them with bleomycin; we exaggerated the fibrosis after injury by making the endothelium dysfunctional," Dr. Knipe says.
Previous studies on the endothelium used pharmacologic modulators, which can affect immune trafficking and other processes, possibly convoluting the pathogenesis of pulmonary fibrosis.
"In this study, we can't attribute the worsening of the fibrosis to anything other than our endothelial modulation. It furthers our understanding of the pathogenesis of fibrosis and gives insight on the best way to target the endothelium to mitigate the development or progression of pulmonary fibrosis," she says.
The researchers also found that the mice with S1PR1 deletion that were not injected with bleomycin did not spontaneously develop fibrosis.
"This adds to our understanding that there can be endothelial-specific defects that can affect the fibrotic outcome after injury," says Dr. Knipe. "Endothelium dysfunction is not enough to induce fibrosis, but it may make an individual more likely to develop fibrosis after an injury."
Developing Pulmonary Fibrosis Treatments Targeting the Endothelium
Dr. Knipe notes that this is relatively new work, as researchers have historically overlooked the endothelium when studying pulmonary fibrosis. She is hopeful this study is a stepping stone to future research on the endothelium as an avenue to develop therapeutic targets for pulmonary fibrosis.
"Though this particular study doesn't directly impact patient care, I think there will be studies down the road that will," she says. "In our next studies using mouse models, we're going to overexpress S1PR1 in the endothelium and show that we can prevent fibrosis by enhancing endothelial function."
The COVID-19 pandemic and resulting increase in patients developing acute respiratory distress syndrome (ARDS) have revealed a new potential application of this work beyond IPF. "More patients are developing pulmonary fibrosis following a COVID-19 infection," Dr. Knipe says. "Some of the fibrotic processes that happen in IPF may also happen in patients that go on to develop ARDS."
She further notes that the research and clinical environments at Mass General convey a significant advantage to all these investigations of the pathogenesis of pulmonary fibrosis and the role of the endothelium.
"I've gotten help from many collaborative colleagues. We have a robust group of pulmonary fibrosis and immunology researchers that have contributed to this work. Mass General also has great core facilities that make this research possible."
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