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New Target Identified for Treatment of Pulmonary Fibrosis

Key findings

  • Growing evidence links idiopathic pulmonary fibrosis to endothelial cell dysfunction in the lungs, which leads to an increase in permeability of the tissue vasculature
  • One of the principal pathways that regulate endothelial permeability is the interaction of a lipid metabolite, sphingosine-1-phosphate (S1P), with one of its cell surface receptors, S1PR1
  • In this study, deletion of endothelial cell S1pr1 in transgenic mice led to an increase in vascular permeability even in the absence of lung injury
  • Following lung injury, the knockout mice showed further increases in vascular permeability and increased fibrosis
  • Agonism of the S1P/S1PR1 interaction on endothelial cells may be a novel and effective strategy for the treatment of pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is believed to result from dysregulated wound repair after lung injury. One of the principal healing responses to any wound is endothelial cell dysfunction, which leads to increased permeability of tissue vasculature.

There's growing evidence that increased vascular permeability in the lungs correlates with IPF, and researchers at Massachusetts General Hospital recently provided evidence of a causal relationship. In the American Journal of Respiratory Cell and Molecular BiologyRachel S. Knipe, MD, a physician–researcher in the Division of Pulmonary and Critical Care MedicineBenjamin D. Medoff, MD, chief of the division, and colleagues explain how their findings could lead to better therapies.


One of the principal pathways that regulate endothelial permeability is the interaction of a lipid metabolite, sphingosine-1-phosphate (S1P), with one of its cell surface receptors, S1PR1. The researchers created transgenic mice that lacked the S1pr1 gene specifically in endothelial cells. They then used bleomycin to induce lung injury in these knockout mice as well as in wild-type controls.

Key Results

  • The knockout mice showed increased vascular permeability even at baseline, and it was exacerbated after lung injury
  • Compared with controls, the knockout mice showed greater increases in vascular permeability after lung injury and a greater fibrotic response to the injury
  • The knockout mice also exhibited increased immune cell infiltration and increased intra-alveolar coagulation
  • A different set of mice, which were bred to overexpress circulating S1P, were not protected against bleomycin-induced lung injury, suggesting that simply boosting blood levels of S1P would be ineffective

Potential New Approach to Drug Development

The two drugs currently approved for the treatment of IPF, nintedanib and pirfenidone, slow the rate of lung function decline but don't stop its progression or reverse established fibrosis. Considering the poor prognosis of the disease, there's a great need for additional therapies.

Agonism of S1PR1 expression or function on endothelial cells may represent a novel, effective strategy to treat IPF and other fibrosing diseases, including fibrosis after acute respiratory distress syndrome.

An additionally interesting finding was that in the knockout mice, increased permeability alone did not lead to lung fibrosis. The combination of increased permeability and lung injury was required for an exaggerated fibrotic response. Future work may show that in patients, a defect in vascular integrity is a risk factor for fibrosis in the context of a low-level injury, such as from inhaled toxins or a viral infection.

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Research at Massachusetts General Hospital identifies a link between endothelial S1PR1 and the development of pulmonary fibrosis.


Jehan W. Alladina, MD, and Benjamin D. Medoff, MD, of the Division of Pulmonary and Critical Care Medicine, and colleagues advise that high plasma concentrations of soluble suppression of tumorigenicity-2 may signify persistent lung injury in COVID-19 respiratory failure and the need for continued ventilatory support.