# Loss of Endothelial S1PR1 Drives Post-Influenza Pulmonary Fibrosis

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $729,408

## Abstract

Project Summary
Respiratory viral infections such as influenza and coronaviruses are frequent causes of acute respiratory distress
syndrome (ARDS), a disabling condition with a mortality up to 46%. While supportive interventions have reduced
the overall mortality of ARDS, severe cases requiring prolonged mechanical ventilation remain common, and
many cases are complicated by the development of fibrosis in the lung. Post-viral pulmonary fibrosis can lead to
chronic disability due to respiratory dysfunction, exercise intolerance and disabling symptoms such as shortness
of breath and cough. Endothelial injury and dysfunction contribute to the severity of ARDS, persistence of lung
injury, and dysregulated tissue repair. Currently there are no therapies to prevent the development of post-viral
pulmonary fibrosis, and in fact supportive mechanical ventilation may further perpetuate pathological endothelial
injury and worsen fibrotic outcomes.
The sphingosine-1-phosphate (S1P)-S1P receptor 1 (S1PR1) signaling axis on endothelial cells (EC) is a key
modulator of endothelial function, including a regulatory role in vascular permeability. However, the role of
S1PR1 during the fibroproliferative phase of pulmonary viral infection induced ARDS has not been well explored.
Specifically, cross talk between EC and lung fibroblasts, key effector cells in the development of pulmonary
fibrosis because of their production of extracellular matrix and their ability to contract and distort tissue
architecture, has not been defined. Reversing endothelial dysfunction and restoring pulmonary vascular integrity
via augmentation of EC S1PR1 after viral infection could have great therapeutic value by preventing the
development of post-viral pulmonary fibrosis.
Our preliminary results demonstrate that persistent loss of endothelial S1PR1 is deleterious during influenza A
virus (IAV) infection, resulting in increased vascular permeability and increased pulmonary fibrosis. We
hypothesize that IAV infection induced lung injury induces loss of EC S1PR1, leading to altered EC-fibroblast
cross talk which drives fibrosis. Furthermore, we propose that augmenting EC S1PR1 expression in the context
of IAV infection will lead to the development of a novel anti-fibrotic strategy. We will use endothelial specific gain-
of-function and loss-of-function mice in an IAV infection model to determine how IAV infection drives sustained
reduction of EC S1PR1 (Aim 1), how EC S1PR1 affects transcriptomic signatures and cross talk with fibroblasts
after IAV infection (Aim 2), and how augmentation of EC S1PR1 can be used in a therapeutic manner to prevent
post-IAV pulmonary fibrosis (Aim 3). A better understanding of the molecular mechanisms and sequelae of EC
dysfunction after IAV and the effects on subsequent fibroproliferation will lead to novel therapeutics to prevent
this debilitating complication of pulmonary viral infections.

## Key facts

- **NIH application ID:** 10867501
- **Project number:** 5R01HL168138-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Rachel S Knipe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $729,408
- **Award type:** 5
- **Project period:** 2023-06-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867501

## Citation

> US National Institutes of Health, RePORTER application 10867501, Loss of Endothelial S1PR1 Drives Post-Influenza Pulmonary Fibrosis (5R01HL168138-02). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10867501. Licensed CC0.

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