Targeting pepsin provides superior protection to acid suppression in reflux‐associated airway inflammation and lung dysfunction
6 affiliations
- 1Department of Nursing Estácio University Center of Ceará Fortaleza Ceará Brazil
- 2Department of Clinical Medicine, Faculty of Medicine Federal University of Ceará Fortaleza Ceará Brazil
- 3Department of Physiology and Pharmacology, Faculty of Medicine Federal University of Ceará Fortaleza Ceará Brazil
- 4Laboratory of Inflammation and Translational Gastroenterology (LIGAT) Federal University of Delta do Parnaíba, Parnaíba Piauí Brazil
- 5Department of Morphology, Faculty of Medicine Federal University of Ceará Fortaleza Ceará Brazil
- 6Barts and the London School of Medicine and Dentistry Queen Mary University of London London UK
Abstract
Gastro‐oesophageal reflux disease is a prevalent condition associated with extra‐oesophageal manifestations, such as pulmonary inflammation. Pepsin, an essential gastric enzyme, has been implicated in pulmonary complications owing to its inflammatory effects. Although acid‐suppressive therapies, such as proton pump inhibitors, reduce gastric acidity, they do not prevent reflux episodes, microaspiration or the harmful effects of pepsin. This study evaluated the effects of pepsin inhibition by pepstatin on inflammation and pulmonary dysfunction in a murine model of reflux. Male Swiss mice were anaesthetized with ketamine and xylazine and subjected to a surgical procedure involving pyloric stenosis and complete stenosis of the gastric fundus to induce reflux. The mice were divided into four groups: sham, reflux, reflux + pepstatin and reflux + omeprazole. Treatments were administered daily for 28 days. The evaluated parameters included oesophageal and pulmonary wet weights, myeloperoxidase activity, cytokine levels [interleukin (IL)‐6, IL‐10 and keratinocyte chemoattractant], histopathological alveolitis scores, functional analyses of spirometry and tracheal contractility. The reflux group exhibited significant oesophageal and pulmonary oedema, increased myeloperoxidase activity, elevated levels of IL‐6 and keratinocyte chemoattractant, reduced IL‐10, severe alveolitis, impaired pulmonary function and tracheal hyper‐reactivity. Pepstatin treatment significantly reduced inflammatory and functional alterations in the reflux model. In contrast, omeprazole was less effective at controlling inflammation and improving pulmonary function. These findings suggest that pepsin inhibition might reduce pulmonary inflammation and help to preserve lung function in a murine reflux model. Targeting pepsin, rather than solely suppressing gastric acidity, shows promise in mitigating reflux‐related extra‐oesophageal complications.
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BibTeX
@article{sales2026targeting,
title = {{Targeting pepsin provides superior protection to acid suppression in reflux‐associated airway inflammation and lung dysfunction}},
author = {Thiago Meneses Araújo Leite Sales and Humberto Barbosa da Costa Filho and Kalinne Kelly Lima Gadelha and Kerolayne de Melo Nogueira and Álvaro Xavier Franco and Carlos Eduardo da Silva Monteiro and Maria Klayre Araújo de Sousa and Monalisa Cássias Souza and Isabele de Sá Silveira Melo and Lucas Antonio Duarte Nicolau and Marco Antonio de Freitas Clementino and Pedro Jorge Caldas Magalhães and Alexandre Havt and Pedro Marcos Gomes Soares and Daniel Sifrim and Marcellus Henrique Loiola Ponte de Souza},
journal = {Experimental Physiology},
year = {2026},
month = nov,
doi = {10.1113/ep093251},
url = {https://doi.org/10.1113/ep093251},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting pepsin provides superior protection to acid suppression in reflux‐associated airway inflammation and lung dysfunction
AU - Thiago Meneses Araújo Leite Sales
AU - Humberto Barbosa da Costa Filho
AU - Kalinne Kelly Lima Gadelha
AU - Kerolayne de Melo Nogueira
AU - Álvaro Xavier Franco
AU - Carlos Eduardo da Silva Monteiro
AU - Maria Klayre Araújo de Sousa
AU - Monalisa Cássias Souza
AU - Isabele de Sá Silveira Melo
AU - Lucas Antonio Duarte Nicolau
AU - Marco Antonio de Freitas Clementino
AU - Pedro Jorge Caldas Magalhães
AU - Alexandre Havt
AU - Pedro Marcos Gomes Soares
AU - Daniel Sifrim
AU - Marcellus Henrique Loiola Ponte de Souza
PY - 2026
DA - 2026/11/05
JO - Experimental Physiology
DO - 10.1113/ep093251
UR - https://doi.org/10.1113/ep093251
AB - Gastro‐oesophageal reflux disease is a prevalent condition associated with extra‐oesophageal manifestations, such as pulmonary inflammation. Pepsin, an essential gastric enzyme, has been implicated in pulmonary complications owing to its inflammatory effects. Although acid‐suppressive therapies, such as proton pump inhibitors, reduce gastric acidity, they do not prevent reflux episodes, microaspiration or the harmful effects of pepsin. This study evaluated the effects of pepsin inhibition by pepstatin on inflammation and pulmonary dysfunction in a murine model of reflux. Male Swiss mice were anaesthetized with ketamine and xylazine and subjected to a surgical procedure involving pyloric stenosis and complete stenosis of the gastric fundus to induce reflux. The mice were divided into four groups: sham, reflux, reflux + pepstatin and reflux + omeprazole. Treatments were administered daily for 28 days. The evaluated parameters included oesophageal and pulmonary wet weights, myeloperoxidase activity, cytokine levels [interleukin (IL)‐6, IL‐10 and keratinocyte chemoattractant], histopathological alveolitis scores, functional analyses of spirometry and tracheal contractility. The reflux group exhibited significant oesophageal and pulmonary oedema, increased myeloperoxidase activity, elevated levels of IL‐6 and keratinocyte chemoattractant, reduced IL‐10, severe alveolitis, impaired pulmonary function and tracheal hyper‐reactivity. Pepstatin treatment significantly reduced inflammatory and functional alterations in the reflux model. In contrast, omeprazole was less effective at controlling inflammation and improving pulmonary function. These findings suggest that pepsin inhibition might reduce pulmonary inflammation and help to preserve lung function in a murine reflux model. Targeting pepsin, rather than solely suppressing gastric acidity, shows promise in mitigating reflux‐related extra‐oesophageal complications.
SN - 0958-0670
SN - 1469-445X
ER -