Abstract
Airway remodeling consists of the structural changes of airway walls, which is often considered the result of longstanding airway inflammation, but it may be present to an equivalent degree in the airways of children with asthma, raising the need for early and specific therapeutic interventions. The arachidonic acid cytochrome P-450 (CYP) pathway has thus far received relatively little attention in its relation to asthma. In this study, we studied the inhibition of soluble epoxide hydrolase (sEH) on airway remodeling and hyperresponsiveness (AHR) in a chronic asthmatic model which long-term exposure to antigen over a period of 12 weeks. The expression of sEH and CYP2J2, the level of 14, 15-epoxyeicosatrienoic acids (EETs), airway remodeling, hyperresponsiveness and inflammation were analyzed to determine the inhibition of sEH. The intragastric administration of 3 or 10 mg/kg ZDHXB-101, which is a structural derivative of natural product honokiol and a novel soluble epoxide hydrolase (sEH) inhibitor, daily for 9 weeks significantly increased the level of 14, 15-EETs by inhibiting the expression of sEH and increasing the expression of CYP2J2 in lung tissues. ZDHXB-101 reduced the expression of remodeling-related markers such as interleukin (IL)-13, IL-17, MMP-9 N-cadherin, α-smooth muscle actin, S100A4, Twist, goblet cell metaplasia, and collagen deposition in the lung tissue or in bronchoalveolar lavage fluid. Moreover, ZDHXB-101 alleviated AHR, which is an indicator that is used to evaluate the airway remodeling function. The inhibitory effects of ZDHXB-101 were demonstrated to be related to its direct inhibition of the extracellular signal-regulated kinase (Erk1/2) phosphorylation, as well as inhibition of c-Jun N-terminal kinases (JNK) and the signal transducer and activator of transcription-3 (STAT3) signal transduction. These findings first revealed the anti-remodeling potential of ZDHXB-101 lead in chronic airway disease.
Highlights
Asthma is characterized by reversible airflow obstruction [1, 2]
We found that ZDHXB-101 inhibited airway remodeling and AHR by inhibiting soluble epoxide hydrolase (sEH), and activating the expression of Cytochrome P450 2 J2 (CYP2J2), and decreasing the phosphorylation of the Extracellular regulated (Erk1/2), Jun N-terminal kinases (JNK) and signal transducer and activator of transcription-3 (STAT3) signaling pathway proteins
ZDHXB-101 suppresses sEH expression and increases CYP2J2 expression and 14,15-Epoxyeicosatrienoic acid (EET) levels To verify the changes in the CYP450 pathway in the chronic asthma model, the expression of she and CYP2J2 and the levels of 14, 15-EETs were observed by immunohistochemical assay, Western blot and enzyme-linked immunosorbent assay (ELISA), respectively
Summary
Airway remodeling is one crucial part of the reversible airflow obstruction of asthma [3], including goblet cell metaplasia (GCM), epithelial-tomesenchymal transition (EMT), excessive subepithelial collagen deposition, airway smooth muscle hyperplasia, and increased vascularity [4, 5]. The effects of asthma therapy on airway remodeling are not been studied extensively due to the challenges of obtaining airway tissue in the context of clinical trials. Corticosteroids remain the cornerstone of asthma therapy because of their effects on inflammatory and structural cells, and their effects on remodeling have been better studied than those of other drugs [8, 9]. It is urgent to explore these mechanisms and find reliable drugs for the prevention and treatment of the airway remodeling processes underlying asthma pathology [8,9,10]
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