ZDHXB-101 (3′,5-Diallyl-2, 4′-dihydroxy-[1,1′-biphen-yl]-3,5′-dicarbaldehyde) protects against airway remodeling and hyperresponsiveness via inhibiting both the activation of the mitogen-activated protein kinase and the signal transducer and activator of transcription-3 signaling pathways

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

Novel aerosol treatment of airway hyper-reactivity and inflammation in a murine model of asthma with a soluble epoxide hydrolase inhibitor

“…Airway inflammation, airway contraction/dilation [ 15 ], and remodeling [ 17 , 48 , 49 ] processes are strongly impacted by EpFAs and diols in the CYP450 pathway. EpFAs have been shown to inhibit the expression of inflammatory cytokines (e.g., vascular cell adhesion molecule 1), secretion and adherence of tumor necrosis factor-alpha from monocytes, and nuclear translocation of the nuclear factor kappa-light-chain-enhancer of activated B cells [ 12 ], which are closely associated with inflammatory responses, AHR, or airway remodeling via various pathways in asthma [ 50 ].…”

“…Jiang et al . [ 17 ] recently described the biological anti-remodeling effects of 14,15-EET in a chronic asthma model. In contrast, dihydroxyeicosatrienoic acids (DiHETrEs) have been shown to be influential in monocyte chemoattractant protein-1-induced monocyte chemotaxis, an essential occurrence in inflammation processes [ 53 ].…”

“…Other mechanisms not explored in the present study but reported for other sEHIs included downregulation of c-Jun N-terminal kinases (critical regulators involved in the processes of pro-inflammation, tissue remodeling, and apoptosis) and other cytokines [ 16 ]; reduced expression of remodeling-related markers in BALF and lung tissues; and decreased and collagen deposition in lungs [ 17 ]. Though, in previous studies, airway remodeling was frequently related and not always second to airway inflammation [ 59 ], results from the present study suggested sEHIs may effectively alleviate both airway remodeling and inflammation.…”

“…, histamine) by human lung mast cells activated in hyper-reactive airways [ 15 ]. One example is 14,15-EET, which produced beneficial biological outcomes, including suppressing airway remodeling in a chronic asthma model [ 16 , 17 ]. It should be noted that linoleic acid (LA), the most abundant PUFA in the Western diet [ 18 ], is converted into epoxyoctadecenoic acids (EpOMEs) through the CYP450 pathway and metabolized by sEH into dihydroxyoctadecenoic acids (DiHOMEs).…”

Targeting Airway Smooth Muscle Hypertrophy in Asthma: An Approach Whose Time Has Come

“…Importantly, AR and ASM cell hypertrophy were reduced. 104 Muscarinic receptors are potential targets for reducing ASM hypertrophy in asthma, as they regulate mediators of ASM migration and AR. 72,105 It is well-known that muscarinic receptor antagonists (anti-cholinergic agents), particularly of the M3 receptor subtype, have bronchodilating properties.…”