Valsartan prevents gefitinib-induced lung inflammation, oxidative stress, and alteration of plasma metabolites in rats

Gefitinib (GEF) is an inhibitor of the epidermal growth factor receptor, linked to higher risk of severe/fatal interstitial lung disease (ILD). This study was performed to determine the protective roles of an angiotensin-II type-1 receptor (AT1R) "valsartan (VAL)" in prevention of lung inflammation, oxidative stress and metabolites alteration induced by GEF. Four groups of male Wistar albino rats were received vehicle, VAL (30 mg/kg), GEF (30 mg/kg), or both for four weeks. Blood samples and lungs were harvested for plasma metabolites and histological analysis, respectively, and evaluation of inflammation and oxida-tive stress. GEF monotherapy showed a dense inflammation in lungs, and significantly increased tumor necrosis factor -a (P = 0.0349), interleukin-6 (P < 0.0001), chemokine ligand-3 (P = 0.0420), and interleukin-1b (P = 0.0377). GEF increased oxidative stress markers including glutathione, malondialde-hyde, and catalase levels. Also, several plasma metabolites including butanoic acid, N- methylphenylethanolamine, oxalic acid, L-alanine, phosphoric acid, L-theorinine, pyroglutamic acid, and 2-bromosebacic acid were changed by GEF. The combination of VAL plus GEF reduced the inflamma-tion and oxidative stress mediated by GEF monotherapy. In addition, the combination treatment returned plasma metabolites to the normal levels compared to GEF monotherapy. These findings revealed that VAL has a possible pulmonary protective role against pulmonary toxicity of GEF, which may lead to novel approaches for management of GEF-induced ILD.(c) 2022 The Author(s). 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/).