Original article Suppression of cytokine storm and associated inflammatory mediators by salicylaldehyde derivative of pregabalin: An innovative perspective for alleviating airway inflammation and lung remodeling Muhammad Shoaib Zafar a , Khadija Shahid b , Glenda C. Gobe c,d , Riffat Yasmin e , Nadia Naseem f , Muhammad Shahzad a,⇑ a Department of Pharmacology, University of Health Sciences, Lahore 54600, Pakistan b Riphah International University, Islamabad 46000, Pakistan c Faculty of Medicine, University of Queensland, Brisbane 4006, Queensland, Australia d Kidney Disease Research Collaborative, Princess Alexandra Hospital and University of Queensland, Translational Research Institute, Brisbane 4102, Queensland, Australia e Riphah International University, Faisalabad 38000, Pakistan f Department of Morbid Anatomy and Histopathology, University of Health Sciences, Lahore 54600, Pakistan article info Article history: Received 3 October 2021 Revised 9 January 2022 Accepted 26 January 2022 Available online 2 February 2022 Keywords: Pregabalin Salicylaldehyde Airway inflammation Lung remodelling Inflammatory mediators abstract Objectives: Pregsal is a novel salicylaldehyde derivative of pregabalin, a structural analogue of gamma- aminobutyric acid approved for treating epilepsy, neuropathic pain and diabetic peripheral neuropathy but not trialled to date for airway inflammatory diseases. The current study evaluated a preclinical model of airway inflammation and lung remodelling induced by ovalbumin (OVA) for the potential benefits of pregsal. Methods: Wistar rats (N = 10 per group) were divided into four groups sensitized intraperitoneally (i.p.) and then challenged intranasally with OVA, with or without i.p. pregsal (100 mg/kg) or methylpred- nisolone (MP) (15 mg/kg). Airway inflammation was assessed through inflammatory cell infiltration in the lungs, delayed-type hypersensitivity (DTH), and nitric oxide (NO) level using bronchoalveolar lavage fluid (BALF) and lung tissues. The mRNA expression levels of a panel of inflammatory mediators (cytoki- nes, chemokine and growth factors) in the lungs were measured by the reverse transcription-polymerase chain reaction (RT-PCR). Systemic inflammation was assessed using splenocyte proliferation and total and differential leucocyte count in blood and BALF. Lung remodelling was assessed by wet/dry lung weight ratio, epithelial thickness and goblet cell hyperplasia, hydroxyproline and osteopontin (OPN) levels, arginase activity in lungs, and ornithine decarboxylase (ODC) activity in lung mitochondria. Results: Pregsal significantly alleviated the total and differential leucocyte count in blood and BALF, NO production in BALF and recruitment of inflammatory cells in the lungs. It suppressed the T-cell response and attenuated the OVA-induced lung epithelial thickness, goblet cell hyperplasia, wet/dry lung weight ratio, hydroxyproline and OPN levels, arginase and ODC activity. Levels of inflammatory mediators were also downregulated in the lungs by pregsal. Conclusions: The key findings of this study indicate that pregsal significantly reduces the development of airway inflammation and lung remodelling by suppression of cytokine storm and associated inflamma- tory mediators. Ó 2022 Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction Acute and chronic airway inflammation occurs when the immune system responds to an infection or allergy. Such a situa- tion seems currently in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), where an over-activated innate immunity is a potential pathological mechanism (Liu et al., 2020). SARS-CoV-2 mediates damage in the lungs through exten- https://doi.org/10.1016/j.jksus.2022.101877 1018-3647/Ó 2022 Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). ⇑ Corresponding author Tel #: 0092-334-6061838. E-mail addresses: shahzad912@hotmail.com, shahzad912@uhs.edu.pk (M. Shah- zad). Peer review under responsibility of King Saud University. Production and hosting by Elsevier Journal of King Saud University – Science 34 (2022) 101877 Contents lists available at ScienceDirect Journal of King Saud University – Science journal homepage: www.sciencedirect.com