Modulation of the IL-23/IL-17 axis by fenofibrate ameliorates the ovalbumin/lipopolysaccharide-induced airway inflammation and bronchial asthma in rats

Abstract

The overlapping between asthmatic subtypes, including both CD4+ T helper (TH)2 and TH17 cells, is found in the natural course of allergic asthma, especially in exacerbations and severe and insensitive forms to steroids, which are in need of new molecular therapies. In the TH2-subset mediated asthma, fenofibrate displays therapeutic promises, besides evidenced therapeutic effects on TH17-mediated colitis and myocarditis. Therefore, the effects of fenofibrate versus dexamethasone on IL-23/IL-17 axis in ovalbumin (OVA)/lipopolysaccharide (LPS)-induced airway inflammation and bronchial asthma in rats were explored. The OVA/LPS sensitization and challenge were performed for 28 days in male Wistar rats. After sensitization, fenofibrate (100 mg/kg/day) or dexamethasone (2.5 mg/kg/day) was orally administered from the day 15 to 28. Either fenofibrate or dexamethasone attenuated the severity of OVA/LPS-induced airway inflammation and bronchial asthma through significant ameliorations in the total serum immunoglobulin (Ig)E assay; the total and differential leukocytic counts in the bronchoalveolar lavage (BAL) fluid; the lung inflammatory cytokines such as interleukin (IL)-4, IL-13, IL-17, and IL-23, transforming growth factor (TGF)-β, and tumor necrosis factor(TNF)-α levels; and the lung IL-17 and IL-23 expressions. In addition to the reduction in the inflammatory and fibrotic histopathological scores, fenofibrate significantly ameliorated the BAL neutrophilic count and the lung IL-17 and IL-23 expressions in comparison to dexamethasone. The suppression of IL-23/IL-17 axis could be considered a molecular therapeutic target for fenofibrate in OVA/LPS-induced airway inflammation and bronchial asthma. Combined therapeutic regimens of fenofibrate and steroids should be furtherly investigated in severe and resistant asthma.

Peroxisome Proliferator-Activated Receptors as a Therapeutic Target in Asthma

“…The combined use of fenofibrate and dexamethasone leads to the suppression of the production of IL-23 and IL-1 in rats with asthma. This is evidence of the effectiveness of the combined therapeutic regimens in asthma [12]. The opportunity of using fenofibrate both in therapy and the prevention of bronchial remodeling in asthma has been shown [147].…”

“…Close attention currently focuses on synthetic PPAR agonists (fibrates and thiazolidinediones). The effectiveness of their action in asthma is extensively studied and, according to some authors, is much higher in combination with corticosteroids [10][11][12][13]. At the same time, negative reactions to the application of synthetic PPAR agonists and their effect on different PPAR isoforms should be taken into account.…”

Fenofibrate Reduces the Asthma-Related Fibroblast-To-Myofibroblast Transition by TGF-Β/Smad2/3 Signaling Attenuation and Connexin 43-Dependent Phenotype Destabilization

“…Fenofibrate is a Food and Drug Administration (FDA)-approved agent, routinely used in hyperlipidemia treatment [ 18 ]. Studies performed with human, rat, and mouse models of lung disorders, including asthma and idiopathic pulmonary fibrosis [ 19 , 20 , 21 , 22 ], suggest that fenofibrate can be useful in the elaboration of pharmacotherapeutic approaches targeting fibrotic changes in the subepithelial layer of asthmatic bronchi. However, the effect of fenofibrate on bronchial wall remodeling and FMT efficiency in asthma is yet to be studied.…”

Inhibition of Airway Contraction and Inflammation by Pomalidomide in a Male Wistar Rat Model of Ovalbumin-induced Asthma

“…4 Its common features including augmentation of mast cells, lymphocytes and eosinophils, and mediators such as interleukin-3 (IL-3), IL-4, IL-5, and IL-13. 5 Eosinophil is an important factor and the number of eosinophils is higher in allergic pulmonary disease. 6,7 Some asthmatic patients have diverse forms of inflammation, consisting neutrophilic bronchitis or, less frequently, other inflammatory cells.…”