Gasdermin D silencing alleviates airway inflammation and remodeling in an ovalbumin-induced asthmatic mouse model.

Emerging evidence demonstrates that pyroptosis has been implicated in the pathogenesis of asthma. Gasdermin D (GSDMD) is the pyroptosis executioner. The mechanism of GSDMD in asthma remains unclear. The aim of this study was to elucidate the potential role of GSDMD in asthmatic airway inflammation and remodeling. Immunofluorescence staining was conducted on airway epithelial tissues obtained from both asthma patients and healthy controls (HCs) to evaluate the expression level of N-GSDMD. ELISA was used to measure concentrations of cytokines (IL-1ß, IL-18, IL-17A, and IL-10) in serum samples collected from asthma patients and healthy individuals. We demonstrated that N-GSDMD, IL-18, and IL-1ß were significantly increased in samples with mild asthma compared with those from the controls. Then, wild type and Gsdmd-knockout (Gsdmd-/-) mice were used to establish asthma model. We performed histopathological staining, ELISA, and flow cytometry to explore the function of GSDMD in allergic airway inflammation and tissue remodeling in vivo. We observed that the expression of N-GSDMD, IL-18, and IL-1ß was enhanced in OVA-induced asthma mouse model. Gsdmd knockout resulted in attenuated IL-18, and IL-1ß production in both bronchoalveolar lavage fluid (BALF) and lung tissue in asthmatic mice. In addition, Gsdmd-/- mice exhibit a significant reduction in airway inflammation and remodeling, which might be associated with reduced Th17 inflammatory response and M2 polarization of macrophages. Further, we found that GSDMD knockout may improve asthmatic airway inflammation and remodeling through regulating macrophage adhesion, migration, and macrophage M2 polarization by targeting Notch signaling pathway. These findings demonstrate that GSDMD deficiency profoundly alleviates allergic inflammation and tissue remodeling. Therefore, GSDMD may serve as a potential therapeutic target against asthma.

Identification of key genes and pathways in chronic rhinosinusitis with nasal polyps and asthma comorbidity using bioinformatics approaches.

Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma comorbidity (ACRSwNP) present severe symptoms and are more likely to relapse. However, the pathogenesis of ACRSwNP is not fully understood. The aim of this study was to explore the underlying pathogenesis of ACRSwNP using bioinformatics approaches. ACRSwNP-related differentially expressed genes (DEGs) were identified by the analysis of the GSE23552 dataset. The clusterProfiler R package was used to carry out functional and pathway enrichment analysis. A protein-protein interaction (PPI) network was built using the STRING database to explore key genes in the pathogenesis of ACRSwNP. The bioinformatics analysis results were verified through qRT-PCR. The Connectivity Map (CMap) database was used to predict potential drugs for the treatment of ACRSwNP. A total of 36 DEGs were identified, which were mainly enriched in terms of regulation of immune response and detection sensory perception of taste. Thirteen hub genes including AZGP1, AQP9, GAPT, PIP, and PRR4 were identified as potential hub genes in ACRSwNP from the PPI network. Analysis of the GSE41861 dataset showed that upregulation of CST1 in nasal mucosa was associated with asthma. qRT-PCR detection confirmed the bioinformatics analysis results. Tacrolimus and spaglumic acid were identified as potential drugs for the treatment of ACRSwNP from the CMap database. The findings of this study provide insights into the pathogenesis of ACRSwNP and may provide a basis for the discovery of effective therapeutic modalities for ACRSwNP.

Improvement of Subjective Olfactory Dysfunction in Chronic Rhinosinusitis With Nasal Polyps After Endoscopic Sinus Surgery.

Objective: Olfactory impairment is a common complaint in patients with chronic rhinosinusitis with nasal polyps (CRSwNP), but the influence of endoscopic sinus surgery (ESS) on olfaction and the factors predicting olfactory impairment are not fully understood. This study aimed to assess the effect of ESS on improving olfactory dysfunction in patients with CRSwNP and to identify factors that predict prognosis. Methods: A total of 56 patients with CRSwNP reported their self-evaluated olfactory dysfunction score preoperatively and 1 month, 3 months, and 12 months after ESS. Preoperative clinical characteristics, computed tomography (CT) scan, and sinonasal endoscopy examination results were collected before surgery. Additionally, factors that predicted olfactory loss and affected the improvement of olfaction after ESS were evaluated. Results: Olfactory improvement can be observed 1 month after ESS. A total of 73.2% (41/56) subjects experienced sustained recovery of subjective olfaction with the self-evaluated olfactory dysfunction score improving from 2.04 to 0.64 (P < 0.001) after 12 months. The Lund-Mackay scores (r = 0.593, P < 0.001) and Lund-Kennedy scores (r = 0.265, P < 0.05) correlated with the preoperative olfactory dysfunction score. Multivariate logistic regression analysis revealed that longer duration of olfactory dysfunction, blood eosinophilia, lower Lund-Mackay scores, and peripheral distribution of CT opacification were risk factors that adversely affected the recovery of olfactory function (P < 0.05). Conclusion: ESS improved self-evaluated olfactory function in patients with CRSwNP. Lund-Mackay scores and Lund-Kennedy scores were correlated with olfactory function prior to surgery, while a longer course of the disease, higher blood eosinophilia, lower Lund-Mackay scores, and peripheral distribution of CT opacification were risk factors for poor olfactory prognosis.

TIPE2 Inhibits Migration and Promotes Apoptosis as a Tumor Suppressor in Hypopharyngeal Carcinoma.

BACKGROUND: Hypopharyngeal squamous cell carcinoma (HSCC) is a common malignant cancer characterized by high metastasis and infiltration. The development of new approaches for the early diagnosis and identification of new therapeutic targets is essential. TIPE2 is well known as a tumor suppressor and related to a favorable prognosis of HSCC. However, its underlying mechanism remains unclear. METHODS AND MATERIALS: TIPE2 expression was determined by immunohistochemistry and RT-qPCR. A TIPE2 overexpression stable cell line was generated by lentivirus infection. TIPE2 and other related protein levels were detected by western blotting. The cell cycle and apoptosis were performed by flow cytometric analysis. Cell proliferation was measured with a Cell Counting Kit-8 (CCK-8) assay, and the activity of caspase-3 and caspase-7 was assessed by Caspase-Glo® 3/7 Assay. All data were analyzed with SPSS 25 and GraphPad Prism 8.0. RESULTS: TIPE2 expression was significantly down-regulated in HSCC. Low TIPE2 expression may be associated with poor prognosis in HSCC. TIPE2 overexpression markedly inhibited tumor cell migration. Moreover, TIPE2 decreased cell proliferation but promoted apoptosis. TIPE2 suppressed tumor growth by activating Epithelial-Mesenchymal Transition (EMT) and the extrinsic apoptosis pathway. CONCLUSION: TIPE2 inhibited tumor progression by suppressing cell migration but promoting apoptosis. TIPE2 can be a new therapeutic target in HSCC.

The different functions of short and long thymic stromal lymphopoietin isoforms in autophagy-mediated asthmatic airway inflammation and remodeling.

Asthma is a chronic respiratory disease characterized by airway inflammation and remodeling as well as hyper-responsiveness. Thymic stromal lymphopoietin (TSLP), which is a crucial inflammatory cytokine in immune homeostasis, consists of two isoforms, the long isoform lfTSLP and short isoform sfTSLP. The lfTSLP promotes inflammation and plays a pivotal role in asthma pathogenesis, while sfTSLP had been reported to have anti-asthma effects. Experiments have shown that lfTSLP could induce autophagy in hepatocytes. It is unknown whether lfTSLP or sfTSLP could influence autophagy and affect the progression of asthma. Using house dust mite (HDM)-stimulated airway smooth muscle cells as an in vitro model and HDM-induced asthma mice as in vivo model, we found that lfTSLP could induce autophagy and remodeling, while sfTSLP has the reverse effect. Strikingly, sfTSLP treatment in vivo reversed HDM-mediated activation of inflammation and airway remodeling, partly determined by autophagy change. These findings may help us understand the function of TSLP isoforms in the pathogenesis of asthma, and they support the use of drugs targeting sfTSLP and TSLP for asthma treatment.