Phenotype-Specific Therapeutic Effect of Rhodiola wallichiana var. cholaensis Combined with Dexamethasone on Experimental Murine Asthma and Its Comprehensive Pharmacological Mechanism.

Zhiqiang Pang,Cuizhu Wang,Fang Wang,Hongqiang Lin,Jinping Liu,Yuze Yuan,Nan Ran,Alan Chen-Yu Hsu,Guoqiang Wang

doi:10.3390/ijms20174216

Zhiqiang Pang, Cuizhu Wang + Show 7 more

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https://doi.org/10.3390/ijms20174216

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Abstract

The heterogeneity of asthma involves complex pathogenesis leading to confusion regarding the choice of therapeutic strategy. In the clinic, asthma is commonly classified as having either eosinophilic asthma (EA) or non-eosinophilic asthma (NEA) phenotypes. Microbiota colonizing in airways has been demonstrated to induce distinct phenotypes of asthma and the resistance to steroids. Rhodiola wallichiana var. cholaensis (RWC) has the potential to alleviate asthmatic inflammation according to recent studies, but its pharmacological mechanisms remain unclarified. In our study, murine asthmatic phenotypes were established and treated with RWC and/or dexamethasone (DEX). Combined treatment with RWC and DEX could improve spirometry and airway hyperresponsiveness (AHR) in asthmatic phenotypes, alleviate steroid resistance in NEA, and reduce the inflammatory infiltration of the both phenotypes. The combined treatment increased Th1, regulated the imbalance of Th2/Th1, and decreased the related cytokines in EA. As for NEA, the combined treatment reduced Th17 and promoted the accumulation of regulatory T cells (Tregs) in lung. A microbiome study based on 16S rDNA sequencing technique revealed the significantly changed structure of the lower airway microbiota after combined treatment in NEA, with 4 distinct genera and 2 species identified. OPLS-DA models of metabolomics analysis based on UPLC-Q/TOF-MS technique identified 34 differentiated metabolites and 8 perturbed metabolic pathways. A joint multiomics study predicted that the colonized microbiota in airways might be associated with susceptibility of asthma and steroid resistance, which involved systematic and pulmonary metabolic perturbation. In summary, the pharmacological network of RWC included the complicated interaction mechanisms of immune regulation, microbiota change, and metabolic perturbation.

Highlights

Asthma, as a heterogenous disease, displays different biological phenotypes which are tightly associated with prognosis [1,2]
According to the fitting degree of OPLS-DA models, we discovered that compared to healthy control (HC), non-eosinophilic asthma (NEA) seemed to be perturbed at a larger scale than eosinophilic asthma (EA)
The incubated cells were labeled with a mix of IL-14 antibody conjugated with APC, IL-17 antibody conjugated with PE, and IFN-γ antibody conjugated with FITC

Summary

Introduction

As a heterogenous disease, displays different biological phenotypes which are tightly associated with prognosis [1,2]. The phenotypes are often identified based on clinical characteristics or the inflammatory status of asthmatics [3]. Typical asthmatic phenotypes include eosinophilic asthma (EA) and non-eosinophilic asthma (NEA) mainly consisting of neutrophilic asthma [7,8]. Asthma is an airway-restricted disease involving significant mucus inflammation. Environmental allergens can stimulate airway epithelia and induce the recruitment of eosinophils and huge release of cytokines, including IL-4, IL-5, and IL-13, which are dominated by Th2 and downregulated by Th1 [11,12]. Despite the use of dexamethasone and various monoclonal antibody medicines that have been developed to control Th2-dominated asthmatic inflammation, the neutrophilic phenotype has barely been controlled in the clinic [15,16]

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