HJP272, a novel endothelin receptor antagonist, attenuates lipopolysaccharide-induced acute lung injury in hamsters.

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.

• Authors: Shikha Patel, Xingjian Liu, Ming Liu, Ralph Stephani, Hardik Patel, Jerome Cantor
• Journal: Lung (Lung) Vol. 192 Issue 5 Pg. 803-10 (Oct 2014) ISSN: 1432-1750 [Electronic] United States
• PMID: 25087133 (Publication Type: Journal Article)

Chemical References

• 3-(3-carboxybenzyl)-1-((6-ethylbenzo(d)(1,3)dioxol-5-yl)methyl)-6-hydroxy-4-oxo-1,4-dihydroquinoline-2-carboxylic acid
• Endothelin A Receptor Antagonists
• Endothelin-1
• Hydroxyquinolines
• Lipopolysaccharides
• Receptor, Endothelin A
• Receptors, Tumor Necrosis Factor, Type I

Topics

• Acute Lung Injury (chemically induced, immunology, metabolism, pathology, prevention & control)
• Animals
• Apoptosis (drug effects)
• Bronchoalveolar Lavage Fluid (cytology, immunology)
• Cytoprotection
• Disease Models, Animal
• Endothelin A Receptor Antagonists (pharmacology)
• Endothelin-1 (metabolism)
• Female
• Hydroxyquinolines (pharmacology)
• Lipopolysaccharides
• Lung (drug effects, immunology, metabolism, pathology)
• Macrophages (drug effects, immunology, metabolism)
• Mesocricetus
• Neutrophil Infiltration (drug effects)
• Neutrophils (drug effects, immunology, metabolism)
• Receptor, Endothelin A (drug effects, metabolism)
• Receptors, Tumor Necrosis Factor, Type I (metabolism)
• Signal Transduction (drug effects)
• Time Factors