Vasoactive intestinal peptide (VIP) is a neuropeptide that exerts anti-inflammatory functions. We have reported that VIP mediated by lentivirus attenuates acute lung injury (ALI) in lipopolysaccharide (LPS)-induced murine model. However, the exact role of VIP in uncontrolled inflammation during ALI is largely unknown. Accumulating evidence indicates that the NLRP3 inflammasome has a critical role during ALI. In this study, we investigated the effects of VIP on the activation of NLRP3 inflammasome during the development of ALI in mice. Seven days after the intratracheal injection of VIP-lentivirus, a murine ALI model was induced by intratracheal injection of LPS. VIP-lentivirus significantly reduced the expression of NLRP3 inflammasome components in lung tissue, including NLRP3, pro-caspase-1, pro-IL-1β, and pro-IL-18. VIP-lentivirus also inhibited the formation of caspase-1 p10 and the maturation of IL-1β and IL-18. In vitro, exogenous VIP pre-treatment inhibited the priming of NLRP3 inflammasome in murine primary peritoneal macrophages, indicated by down-regulation of expression of NLRP3 inflammasome components. VIP pre-treatment effectively prevented the LPS-induced degradation of I-κB and the synthesis of the downstream of NF-κB, including TNF-α and IL-17A. Furthermore, VIP pre-treatment pronouncedly suppressed the autoproteolysis of caspase-1 and the secretion of IL-1β and IL-18 induced by LPS plus ATP in macrophages. In addition, VIP inhibited the generation of reactive oxygen species in macrophages by decreasing NOX1 and NOX2 expression. These findings illustrate one mechanism that VIP attenuates ALI induced by LPS through inhibiting the activation of the NLRP3 inflammasome and encourage further studies assessing the therapeutic potential of VIP to ALI.

Objective. Allergic asthma is a chronic inflammatory disease, which seriously affects the life quality of patients, especially children. Alanylglutamine is a nutritional supplement with potential protective and anti-inflammatory effects, but its function in allergic asthma remains elusive. In this study, we focused on the investigations of the roles and functional mechanism of Alanylglutamine in asthma. Methods. Ovalbumin (OVA) induction was utilized to establish a mouse asthma model. 16S rDNA sequencing was performed to compare the diversity of intestinal microorganisms under different treatments. Gas chromatography was utilized to screen the intestinal microbe-short-chain fatty acids in the stool. The lung tissue was extracted to determine signaling pathways, including AMPK, NF-κB, mTOR, STAT3, IKKβ, TGF-β, and IL-1β through Western blot or RT-qPCR. Results. It was observed that Alanylglutamine reduced the cytokine in OVA-induced allergic asthma mice. HE staining showed obvious pneumonia symptoms in the asthma group, while Alanylglutamine alleviated the inflammatory infiltration. Alanylglutamine reversed gut microbiota compositions in OVA-induced allergic asthma mice and enhanced the butyric acid level. The protective role of Alanylglutamine may be associated with the gut microbiota-butyric acid-GPR43 pathway in asthma mice. In contrast to the OVA group, Alanylglutamine activated the protein expression of P-AMPK/AMPK and inhibited the protein expression of P-mTOR/mTOR, P-P65/P65, P-STAT3/STAT3, P-IKKβ/IKKβ, TGF-β, and IL-1β, with similar effects from butyric acid. Conclusion. The results indicated that Alanylglutamine might be beneficial for asthma, and its effect was achieved through the regulation on microbiota and the derived metabolites. The therapeutic effects might be associated with AMPK, NF-κB, mTOR, and STAT3 signaling pathways. These findings will help identify effective therapeutic direction to alleviate allergic inflammation of the lungs and airways.

Asthma is a mysterious disease with heterogeneity in etiology, pathogenesis, and clinical phenotypes. Although ongoing studies have provided a better understanding of asthma, its natural history, progression, pathogenesis, diversified phenotypes, and even the exact epigenetic linkage between childhood asthma and adult‐onset/old age asthma remain elusive in many aspects. Asthma heritability has been established through genetic studies, but genetics is not the only influencing factor in asthma. The increasing incidence and some unsolved queries suggest that there may be other elements related to asthma heredity. Epigenetic mechanisms link genetic and environmental factors with developmental trajectories in asthma. This review provides an overview of asthma epigenetics and its components, including several epigenetic studies on asthma, and discusses the epigenetic linkage between childhood asthma and adult‐onset/old age asthma. Studies involving asthma epigenetics present valuable novel approaches to solve issues related to asthma. Asthma epigenetic research guides us towards gene therapy and personalized T cell therapy, directs the discovery of new therapeutic agents, predicts long‐term outcomes in severe cases, and is also involved in the cellular transformation of childhood asthma to adult‐onset/old age asthma.

Sex hormone has become a “hot topic” to evaluate the hormonal therapeutic potential in severe asthma. Th17 cell is one of the main influencing factors involved in the pathogenesis of severe asthma, hence also called as kernel of severe asthma, and Th17 subtype of non‐T2 asthma is less responsive (resistance) to inhaled corticosteroid (ICS), so severe in nature. Methyl‐CpG binding domain protein 2 (MBD2) is overexpressed and regulates the Th17 differentiation, showing the possibility of therapeutic target in treating Th17 mediated severe asthma. Sex hormone fluctuates at the different physiobiological conditions of the human body and affects the asthma pathobiology showing its role in asthma prevalence, severity, remission, and therapy. This review briefly overviews the sex hormones, their influence in asthma at the different physiobiological conditions of human body, and MBD2 severe asthma connection with the possible therapeutic potential of sex steroids in MBD2 mediated Th17 predominant severe asthma. Male sex hormone tends to show a beneficial effect and possibly downregulates the expression of Th17 cells via regulating MBD2 through a mechanism distinct from corticosteroid treatment and guides us towards discovery of new therapeutic agent, reduces the asthma‐related complications, and promotes long‐term survival by lowering the risk of therapy‐resistant issues of old age severe asthma.

Background and Purpose. Allergic asthma, a respiratory disease with high morbidity and mortality, is reported to be related to the airway allergic inflammation and autophagy‐induced oxidative stress. Although the therapeutic effects of fermentate prebiotic (YFP) on allergic asthma have been widely claimed, the underlying mechanism is still unclear. This study is aimed at investigating the possible mechanism for the antiasthma property of YFP in a mouse model. Methods. Ovalbumin was used to induce allergic asthma following administration of YFP for one week in mice, to collect the lung tissues, bronchoalveolar lavage fluid (BLFA), and feces. The pathological state, tight‐junction proteins, inflammatory and oxidative stress‐associated biomarkers, and TLRs/NF‐κB signaling pathway of the lung tissues were evaluated by HE staining, immunofluorescence, ELISA, and WB, separately. RT‐PCR was used to test oxidative stress‐associated genes. Leukocyte counts of BLFA and intestinal microbiota were also analyzed using a hemocytometer and 16S rDNA‐sequencing, separately. Result. YFP ameliorated the lung injury of the mouse asthma model by inhibiting peribronchial and perivascular infiltrations of eosinophils and increasing tight‐junction protein expression. YFP inhibited the decrease in the number of BALF leukocytes and expression of inflammatory‐related genes and reversed OVA‐induced TLRs/NF‐κB signaling pathway activation. YFP ameliorated the level of oxidative stress in the lung of the mouse asthma model by inhibiting MDA and promoting the protein level of GSH‐PX, SOD, CAT, and oxidative‐related genes. ATG5, Beclin1, and LC3BII/I were significantly upregulated in asthma mice, which were greatly suppressed by the introduction of YFP, indicating that YFP ameliorated the autophagy in the lung of the mouse asthma model. Lastly, the distribution of bacterial species was slightly changed by YFP in asthma mice, with a significant difference in the relative abundance of 6 major bacterial species between the asthma and YFP groups. Conclusion. Our research showed that YFP might exert antiasthmatic effects by inhibiting airway allergic inflammation and oxidative stress level through suppressing autophagy.