Targeting JNK1/2 and P38 Mitogen-Activated Protein Kinases With Pazopanib Mitigates Bleomycin-Induced Lung Fibrosis

Abstract

Idiopathic pulmonary fibrosis is considered the most common type of interstitial lung disease. The principal aim of our research was to investigate the potential role of pazopanib treatment in alleviating bleomycin-elicited pulmonary fibrosis and elucidate the underlying molecular mechanisms. Twenty-four male mice were allocated into four groups (n = 6): control animals (received saline intraperitoneally (i.p.)), bleomycin group received bleomycin (40 U/kg, i.p.) on 5 days, 0, 3, 7, 10, and 14, and bleomycin and pazopanib-treated group received bleomycin on the specified days and then received pazopanib (10 mg/kg, i.p.) once daily starting on Day 15 to Day 28, plus pazopanib-treated group, which received pazopanib only in the previously specified dose and duration. Our results demonstrated the promising role of pazopanib in mitigating pulmonary fibrosis, as reflected by the remarkable improvement in body weight loss and pulmonary histopathological features. This finding was primarily ascribed to the documented suppression of mitogen-activated protein kinase kinase kinase 2 (MEKK2) and MEKK3 mRNA expressions, which subsequently repressed p-c-Jun N-terminal kinase (p-JNK1/2) and p-P38 group of protein kinases (p-P38) protein expressions. Moreover, pazopanib administration to bleomycin-treated mice remarkably adjusted the bleomycin-mediated dysregulation of the levels of examined cytokines, including interleukin (IL)-1β, IL-13, IL-33, tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa-B (NF-κB) P65. Remarkably, pazopanib treatment reversed the bleomycin-induced elevation in transforming growth factor-beta-1 (TGF-β1) and α-smooth muscle actin (α-SMA) levels. Our research highlighted the beneficial role of pazopanib in attenuating bleomycin-elicited lung fibrosis through the suppression of MEKK2 and MEKK3 and the modulation of JNK and P38 cascades.