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HJP272, A Novel Endothelin Receptor Antagonist, Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Hamsters

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Abstract

Introduction

Previous studies from this laboratory indicate that endothelin-1 (ET-1), a potent vasoconstrictor, may play an important role in lipopolysaccharide (LPS)-induced release of neutrophils from the pulmonary microvasculature. To further test this concept, Syrian hamsters were treated with a novel endothelin receptor A (ETA) antagonist (HJP272) prior to intratracheal instillation of LPS.

Methods

The effect of HJP272 on the LPS-induced inflammatory reaction was determined by measuring: (1) lung histopathological changes, (2) total neutrophils in bronchoalveolar lavage fluid (BALF), (3) expression of tumor necrosis factor receptor 1 (TNFR1) by BALF macrophages, and (4) alveolar septal cell apoptosis.

Results

Treatment with HJP272 significantly reduced each of these parameters during a 24-hr period following LPS instillation, supporting the concept that limiting the activity of ET-1 may reduce the extent of lung injury. This hypothesis was further tested by giving ET-1 prior to LPS instillation, which resulted in a marked enhancement of LPS-induced lung inflammation, as measured by BALF neutrophils and TNFR1-positive macrophages. Furthermore, the increase in neutrophils resulting from treatment with ET-1 was significantly reduced by HJP272, again demonstrating the ability of ETA receptor antagonists to limit the influx of these cells into the lung.

Conclusions

These findings suggest a potential therapeutic role for these agents in diseases where neutrophils are a significant cause of lung injury, such as bronchopneumonia, respiratory distress syndrome, and chronic obstructive pulmonary disease.

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Authors and Affiliations

  1. College of Pharmacy and Health Sciences, St John’s University, Queens, NY, USA

    Shikha Patel, Xingjian Liu, Ralph Stephani, Hardik Patel & Jerome Cantor

  2. Department of Pathology, Brookdale Hospital and Medical Center, Brooklyn, NY, USA

    Ming Liu

Authors
  1. Shikha Patel
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  2. Xingjian Liu
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  3. Ming Liu
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  4. Ralph Stephani
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  5. Hardik Patel
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  6. Jerome Cantor
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Correspondence to Jerome Cantor.

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Patel, S., Liu, X., Liu, M. et al. HJP272, A Novel Endothelin Receptor Antagonist, Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Hamsters. Lung 192, 803–810 (2014). https://doi.org/10.1007/s00408-014-9628-z

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  • DOI: https://doi.org/10.1007/s00408-014-9628-z

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