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Transient Blockade of Endothelin-1 Mitigates Amiodarone-Induced Pulmonary Fibrosis

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Abstract

Introduction

A number of studies indicate that endothelin-1 (ET-1) may act as an inflammatory cell “gatekeeper," by regulating the influx of neutrophils following pulmonary injury. To further examine the role of ET-1 in modulating lung inflammation, hamsters were treated with an endothelin receptor antagonist (ERA), HJP272, either 1 h prior to intratracheal instillation of amiodarone (AM) or 24 h afterwards.

Methods

In both cases, the extent of lung injury and repair was determined by (1) histopathological changes; (2) neutrophil content in bronchoalveolar lavage fluid (BALF); (3) lung collagen content; (4) tumor necrosis factor receptor 1 expression by BALF macrophages; (5) BALF levels of (a) transforming growth factor beta-1, (b) stromal cell-derived factor 1 (commonly referred to as CXCL12), and (c) platelet-derived growth factor BB; (6) alveolar septal cell apoptosis.

Results

For each parameter, pretreatment with HJP272 resulted in a significant reduction compared to AM alone, whereas post-treatment was either ineffective or produced only a marginally significant change, suggesting that the course of lung inflammation and repair is programmed at a very early stage.

Conclusions

This finding may explain why ERAs are not an effective treatment for human pulmonary fibrosis. Nevertheless, they may be useful as an adjunct to therapeutic regimens involving drugs that have fibrogenic potential.

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Authors and Affiliations

  1. College of Pharmacy and Health Sciences, St John’s University, Queens, NY, 11439, USA

    Xingjian Liu, Nikhil Khadtare, Hardek Patel, Ralph Stephani & Jerome Cantor

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  1. Xingjian Liu
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  2. Nikhil Khadtare
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  3. Hardek Patel
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  4. Ralph Stephani
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  5. Jerome Cantor
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Correspondence to Jerome Cantor.

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Liu, X., Khadtare, N., Patel, H. et al. Transient Blockade of Endothelin-1 Mitigates Amiodarone-Induced Pulmonary Fibrosis. Lung 196, 321–327 (2018). https://doi.org/10.1007/s00408-018-0103-0

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  • DOI: https://doi.org/10.1007/s00408-018-0103-0

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