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Exposure to non-steroid anti-inflammatory drugs (NSAIDs) and suppressing hydrogen sulfide synthesis leads to altered structure and impaired function of the oesophagus and oesophagogastric junction

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Abstract

Introduction

The non-steroid anti-inflammatory drugs (NSAIDs) are among the drugs that can commonly cause injury in the esophagus, such as non-reflux oesophagitis, with important clinical consequences. This injury may be ‘silent’ and therefore often overlooked. Recently, we established that hydrogen sulfide (H2S) is a critical mediator of esophageal mucosal protection and repair. The aim of the study was to determine the effect of naproxen, the most commonly used NSAIDs, on the oesophagus and oesophagogastric junction and its relation with suppression or stimulation of endogenous H2S synthesis during naproxen-induced oesophageal injury.

Methods

Rats were treated with vehicle (control) or naproxen, with or without being subjected to water immersion restricted stress (Takagi et al. Chem Pharm Bul 12:465–472, 1964). Subgroups of rats were pre-treated with an inhibitor of H2S synthesis cystathionine γ-lyase (CSE) or cystathionine β-synthase (CBS), or with the Sodium sulphide (NaHS), which spontaneously generates H2S in solution. Damage of the oesophageal mucosa and oesophagogastric junction was estimated and scored using a histological damage index.

Results

Treatment with naproxen increased the thickness of the corneal and epithelial layers of the oesophagus, as well as producing disorganization of the muscle plate and irregular submucosal oedema. Both injury factors, stress and suppression of H2S synthesis resulted in the development of severe esophagitis and damage to the oesophagogastric junction. The damage was exacerbated by inhibitors of H2S biosynthesis, and attenuated by treatment with NaHS.

Conclusions

Inhibition of endogenous H2S synthesis provides a novel experimental model that can be useful in preclinical studies NSAID-related non-reflux oesophagitis. H2S contributes significantly to mucosal defence in the oesophagus.

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Abbreviations

CBS:

Cystathionine β-synthase

CHH:

O-carboxymethylhydroxylamine

CSE:

Cystathionine γ-lyase

EGJ:

Oesophagogastral junction

H2S:

Hydrogen sulfide

HE:

Hematoxylin and eosin

NaHS:

Sodium sulfide

NSAIDs:

Non-steroid anti-inflammatory drugs

PAG:

l-propargylglycine

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Acknowledgments

This article is based on our presentations (Bula et al. 2014) during the 8th International Symposium on Cell/Tissue Injury and Cytoprotection/Organoprotection, Budapest, September 24–26, 2014, a satellite meeting of the 17th World Congress of Basic and Clinical Pharmacology 2014. We also wish to acknowledge the important contributions of the Symposium Chair, Prof. Klara Gyires (Semmelweis University, Hungary) and her support to the Ukrainian participants.

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Authors and Affiliations

  1. Department of Physiology, Lviv National Medical University, 69 Pekarska str., 79010, Lviv, Ukraine

    Oksana Zayachkivska, Nazar Bula & Dzvinka Khyrivska

  2. Department of Pathology, Lviv National Medical University, 69 Pekarska str., 79010, Lviv, Ukraine

    Elena Gavrilyuk

  3. Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada

    John L. Wallace

  4. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada

    John L. Wallace

Authors
  1. Oksana Zayachkivska
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  2. Nazar Bula
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  3. Dzvinka Khyrivska
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  4. Elena Gavrilyuk
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  5. John L. Wallace
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Correspondence to Oksana Zayachkivska.

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Zayachkivska, O., Bula, N., Khyrivska, D. et al. Exposure to non-steroid anti-inflammatory drugs (NSAIDs) and suppressing hydrogen sulfide synthesis leads to altered structure and impaired function of the oesophagus and oesophagogastric junction. Inflammopharmacol 23, 91–99 (2015). https://doi.org/10.1007/s10787-015-0230-7

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