Exposure to high levels of ozone contributes to insensitivity to glucocorticoids in asthma treatment, but the underlying mechanisms are not known. We built two asthma models: a “T2-high” asthma model was established by ovalbumin (OVA) sensitization/challenge and OVA sensitization/challenge combined with ozone exposure (OVA + ozone) was used to induce airway inflammation with increased numbers of neutrophils to simulate “T2-low” asthma. The expression of T-helper (Th)1/2/17-related cytokines was measured by cytokine antibody arrays. Bronchial provocation tests were carried out to evaluate the lung resistance of mice. Hematoxylin and eosin staining, periodic acid-Schiff staining, and immunohistochemical (IHC) analyses of alpha-smooth muscle actin were undertaken to observe morphology changes in lungs. The expression of glucocorticoid receptors (GRs) and phosphorylated-GR (p-GR) was measured by western blotting. Nr3c1 mRNA was quantified by RT-qPCR. Protein expression of proinflammatory cytokines, signal transducer and activator of transcription 3 (STAT3), suppressor of cytokine signaling 3 (SOCS3), and CXCL1 was measured through ELISAs, western blotting, or IHC analyses. Resected lung tissue from seven asthma patients and 10 healthy controls undergoing thoracotomy for pulmonary nodules was evaluated by IHC analyses and ELISAs. In both asthma models, mucus hypersecretion, as well as inflammation, hyperresponsiveness, and remodeling of the airways, was present compared with the control group, whereas the OVA + ozone group showed severe neutrophil infiltration. The expression of Th17-related cytokines (interleukin (IL)-6, IL-17A, IL-21), GR protein, and CXCL1 increased in the OVA + ozone group, whereas the expression of p-GR decreased. Dexamethasone (Dex) could not totally reverse the expression of p-GR and histone deacetylase-2 in the OVA + ozone group. STAT3 expression increased in the OVA + ozone group and could not be completely reversed by Dex, and nor could IL-6 expression. A positive correlation between IL-6 or IL-17A and STAT3 and negative correlation between SOCS3 and STAT3 were shown, suggesting that the IL-6/STAT3 pathway may be involved in OVA + ozone–induced corticosteroid-resistant airway inflammation. In clinical samples, IL-17A expression in lung tissue was positively correlated with percent STAT3-positive area and negatively correlated with SOCS3 expression. The IL-6/STAT3 pathway may contribute to corticosteroid insensitivity in OVA + ozone–induced neutrophilic airway inflammation through regulation of Th17 cells and could provide new targets for individual treatment of corticosteroid resistance in asthma.
Background: Since the outbreak of coronavirus disease 2019 , the pattern of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA shedding has not been well characterized.Methods: In our study, 652 patients in Wuhan Designated Hospital were recruited, and their clinical and laboratory findings were extracted and analyzed. Results:The median duration of SARS-CoV-2 RNA detection was 23 days [interquartile range (IQR), 18 days] from symptom onset. Compared to patients with early viral RNA clearance (<23 days after illness onset), we found that patients with late viral RNA clearance (≥23 days) had a higher proportion of clinical features, as follows: symptoms, including fever, dry cough, and sputum production; comorbidities, including hypertension, chronic kidney disease, uremia, chronic liver disease, anemia, hyperlipidemia, and bilateral lung involvement; complications, such as liver injury; delayed admission to hospital; laboratory parameters at baseline, including higher eosinophils, uric acid, cholesterol, triglycerides, and lower hemoglobin; and less treatment with arbidol, chloroquine, or any antivirals. After generalized linear regression, prolonged SARS-CoV-2 RNA shedding was independently associated with younger age; delayed admission to hospital; symptoms including fever, shivering, and sputum production; comorbidities including hypertension, diabetes, cardiovascular disease, anemia, hyperlipidemia, uremia, and lung involvement; and higher alanine aminotransferase (ALT), uric acid, and cholesterol levels at baseline. Conclusions:In conclusion, the factors mentioned above are associated with the negative conversion of SARS-CoV-2 RNA. A deeper insight into virological dynamics will be helpful for establishing patient discharge and quarantine release criteria.
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