Undaria pinnatifida extract attenuates combined allergic rhinitis and asthma syndrome by the modulation of epithelial cell dysfunction and oxidative stress

Abstract

Undaria pinnatifida (U. pinnatifida) has long been a part of the human diet and medicine. Although U. pinnatifida has been reported to have immunomodulatory, anti-inflammatory, anti-diabetic and antibacterial activities, its specific effect on patients with combined allergic rhinitis and asthma syndrome (CARAS) has not been clarified. In this study, the anti-allergic and anti-inflammatory effects of U. pinnatifida extract (UPE) are investigated in a mouse model of ovalbumin (OVA)-induced CARAS. The oral administration of UPE inhibits allergic responses by reducing OVA-specific immunoglobulin levels. As a result, the symptoms of early reactions are also improved. UPE inhibits the accumulation of inflammatory cells and attenuates the expression of Th2 cytokines in both nasal and bronchoalveolar lavage fluid. Furthermore, UPE treatment inhibits the NF-κB/MAPK signaling pathway in lung homogenates. Additionally, UPE prevents shedding of the nasal mucosal epithelium, protects the integrity of the epithelium, enhances the expression of E-cadherin at the junction of epithelial cells, and inhibits the degradation of ZO-1 and occludin in the airway epithelium. In addition, UPE ameliorates dysfunction of the nasal epithelial barrier by enhancing antioxidant properties and downregulating the expression of the inflammatory factor IL-33. These results suggest that UPE may treat CARAS by modulating epithelial cell dysfunction and oxidative stress.

1. Introduction

Combined allergic rhinitis and asthma syndrome (CARAS) is a new form of uniform airway inflammation composed of upper respiratory tract inflammation, "allergic rhinitis", and lower respiratory tract inflammation, asthma" [1]. The majority of patients typically have both allergic asthma and rhinitis. According to epidemiological data, up to 40% of people with asthma also have allergic rhinitis, and up to 80% of people with asthma have nasal symptoms [2]. This finding indicates a close relationship between the two symptoms. Therefore, the term CARAS has been used to characterize these two diseases as one disease because their origin, etiology, pathophysiology and shared treatment are closely related [1,3].

Both allergic rhinitis and asthma involve a type 2 immune response (Th2 spectrum) and are inflammatory diseases characterized by the infiltration of eosinophils, T cells, and mast cells; the release of multiple mediators, chemokines, and cytokines; and the synthesis of systemic IgE [4]. The main transcription factor, nuclear factor-kappa B (NF-κB), is responsible for triggering the inflammatory response in CARAS [5]. In addition, mitogen-activated protein kinases (MAPKs) regulate Th2 cytokine expression and influence the differentiation of inflammatory cells, including eosinophils and Th2 cells [6].

Previous reports have shown that reactive oxygen species (ROS) is also involved in the pathogenesis of asthma, mediating changes in protein and lipid oxidation that lead to pathological changes in respiratory epithelial cells, increased vascular permeability, barrier dysfunction, smooth muscle contraction, mucus overproduction, or airway hyper-responsiveness [7]. The barrier function of the airway epithelium depends on tight and adherent junctions formed by intercellular interactions of proteins such as zonula occludens-1 (ZO-1), epithelial cadherin, and occludin [8]. The function of these proteins is to protect the underlying tissue from harmful and allergenic stimuli [9]. Damage to tight junctions is an important cause of epithelial barrier breakdown during lung or nasal inflammation [10]. Interleukin 33 (IL-33) is defined as an endogenous "danger" signal or "alarm" released by epithelial cells after cell and tissue damage during trauma or inflammation to alert the immune system. The nuclear cytokine IL-33 is derived from tissues and belongs to the IL-1 family, which is abundantly expressed in epithelial cells and fibroblast-like cells [11]. IL-33 and suppression of tumorigenicity 2 (ST2)/IL1RL1 (IL-33 receptor) play a role in allergen-induced eosinophil inflammation, mucus epithelial chemotaxis, and airway hyperresponsiveness and