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      The Effects of Nebulized Inhaled Triptolide on Airway Inflammation in a Mouse Model of Asthma

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      Canadian Respiratory Journal

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          Inhalation of nebulized TP has received little attention in the past. Here, we intend to investigate the effect of nebulized inhaled TP on airway inflammation in a mouse model of asthma. 29 SPF BALB/c mice were divided into four groups: blank control (Blk, n = 5), normal saline (NS, n = 8), dexamethasone (Dex, n = 8), and TP ( n = 8). During the process of sensitization, mice in the three intervention groups were treated with nebulized NS, an injection of Dex, and nebulized triptolide, respectively. Then bronchoalveolar lavage fluid (BALF), peripheral blood, and lung tissue were collected. Relevant cytokines, transcriptional factors, and CD4+Th17+ T cell proportions were assessed and compared. IL-6, IL-17, IL-23, and TGF- β1 demonstrated a significant difference between groups in the following order: Dex < TP < NS ( P ≤ 0.001), while IL-10 changed in the opposite direction ( P < 0.001). At the transcriptional level in lung tissue, the Ct value of IL-17 in the Dex group was significantly higher than in the NS and TP groups ( P < 0.001). Meanwhile, it was higher in the TP group than in the NS group ( P < 0.001). The Ct value of ROR γt demonstrated a significant difference among three groups in the following order: Dex > TP > NS ( P < 0.001). An opposite trend of FoxP3 Ct value was revealed in the order: NS > TP > Dex. The proportion of CD4+Th17+ cells was 9.53 ± 2.74% in the NS group, 4.23 ± 2.26% in the Dex group, and 6.76 ± 2.99% in the TP group, which shows significant differences between the NS and Dex ( P < 0.001) or NS and TP groups ( P < 0.05). Inhalation of nebulized triptolide can play a role in suppressing airway inflammation with inflammatory cytokines and transcriptional factors reduced and CD4+Th17+ T cells dampened, also in a manner less than injected dexamethasone.

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          XPB, a subunit of TFIIH, is a target of the natural product triptolide.

          Triptolide (1) is a structurally unique diterpene triepoxide isolated from a traditional Chinese medicinal plant with anti-inflammatory, immunosuppressive, contraceptive and antitumor activities. Its molecular mechanism of action, however, has remained largely elusive to date. We report that triptolide covalently binds to human XPB (also known as ERCC3), a subunit of the transcription factor TFIIH, and inhibits its DNA-dependent ATPase activity, which leads to the inhibition of RNA polymerase II-mediated transcription and likely nucleotide excision repair. The identification of XPB as the target of triptolide accounts for the majority of the known biological activities of triptolide. These findings also suggest that triptolide can serve as a new molecular probe for studying transcription and, potentially, as a new type of anticancer agent through inhibition of the ATPase activity of XPB.
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            Neutrophil cytoplasts induce TH17 differentiation and skew inflammation toward neutrophilia in severe asthma

            Severe asthma is a debilitating and treatment refractory disease. As many as half of these patients have complex neutrophil-predominant lung inflammation that is distinct from milder asthma with type 2 eosinophilic inflammation. New insights into severe asthma pathogenesis are needed. Concomitant exposure of mice to an aeroallergen and endotoxin during sensitization resulted in complex neutrophilic immune responses to allergen alone during later airway challenge. Unlike allergen alone, sensitization with allergen and endotoxin led to NETosis. In addition to neutrophil extracellular traps (NETs), enucleated neutrophil cytoplasts were evident in the lungs. Surprisingly, allergen-driven airway neutrophilia was decreased in peptidyl arginine deiminase 4–deficient mice with defective NETosis but not by deoxyribonuclease treatment, implicating the cytoplasts for the non–type 2 immune responses to allergen. Neutrophil cytoplasts were also present in mediastinal lymph nodes, and the cytoplasts activated lung dendritic cells in vitro to trigger antigen-specific interleukin-17 (IL-17) production from naïve CD4+ T cells. Bronchoalveolar lavage fluid from patients with severe asthma and high neutrophil counts had detectable NETs and cytoplasts that were positively correlated with IL-17 levels. Together, these translational findings have identified neutrophil cytoplast formation in asthmatic lung inflammation and linked the cytoplasts to T helper 17–mediated neutrophilic inflammation in severe asthma.
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              Severe Asthma Phenotypes - How Should They Guide Evaluation and Treatment?

              Although patients with "severe" asthma tend to be characterized by ongoing symptoms and airway inflammation despite treatment with high doses of inhaled and systemic corticosteroids, there is increasing recognition of marked phenotypic heterogeneity within affected patients. Although "precision medicine" approaches for patients with severe asthma are needed, there are many hurdles that must be overcome in daily practice. The National Heart, Lung and Blood Institute's Severe Asthma Research Program (SARP) has been at the forefront of phenotype discovery in severe asthma for the past decade. SARP, along with other international groups, has described clinical severe asthma phenotypes in both adults and children that can be evaluated in the clinical setting. Although these clinical phenotypes provide a good "starting point" for addressing disease heterogeneity in severe asthma in everyday practice, more efforts are needed to understand how these phenotypes relate to underlying disease mechanisms and pharmacological treatment responses. This review highlights the clinical asthma phenotypes identified to date, their associations with underlying endotypes and potential biomarkers, and remaining knowledge gaps that must be addressed before precision medicine can become a reality for patients with severe asthma.

                Author and article information

                Can Respir J
                Can Respir J
                Canadian Respiratory Journal
                21 August 2023
                : 2023
                : 2983092
                PCCM, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
                Author notes

                Academic Editor: Sami Deniz

                Author information
                Copyright © 2023 Yafang Miao et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 14 November 2022
                : 31 March 2023
                : 27 July 2023
                Funded by: Shanghai University of Medicine and Health Sciences
                Award ID: ZPBRK-18-08
                Award ID: HMSF-17-22-038
                Funded by: Shanghai Municipal Health and Family Planning Commission
                Award ID: 201740310
                Funded by: Shanghai Pudong New Area Health Commission
                Award ID: PWZxk2017–22
                Research Article


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