Vitamin D regulates COVID-19 associated severity by suppressing the NLRP3 inflammasome pathway.

BACKGROUND: The role of vitamin D3 (VitD3) in modulating innate and adaptive immunity has been reported in different disease contexts. Since the start of the coronavirus disease-2019 (COVID-19) pandemic, the role of VitD3 has been highlighted in many correlational and observational studies. However, the exact mechanisms of action are not well identified. One of the mechanisms via which VitD3 modulates innate immunity is by regulating the NLRP3-inflammasome pathway, being a main underlying cause of SARS-CoV-2-induced hyperinflammation. AIMS AND MAIN METHODS: Blood specimens of severe COVID-19 patients with or without VitD3 treatment were collected during their stay in the intensive care unit and patients were followed up for 29 days. qPCR, western blot, and ELISA were done to investigate the mechanism of action of VitD3 on the NLRP3 inflammasome activation. KEY FINDINGS: We here report the ability of VitD3 to downregulate the NLRP3-inflammsome pathway in severe COVID-19 patients. Lower inflammasome pathway activation was observed with significantly lower gene and protein expression of NLRP3, cleaved caspase-1, ASC and IL-1ß among severe COVID-19 patients treated with VitD3. The reduction of the inflammasome pathway was associated with a reduction in disease severity markers and enhancement of type I IFN pathway. SIGNIFICANCE: Our data reveals an important anti-inflammatory effect of VitD3 during SARS-CoV-2 infection. Further investigations are warranted to better characterize the ability of VitD3 to control disease pathogenesis and prevent progression to severe states. This will allow for a more efficient use of a low cost and accessible treatment like VitD3.

Airway tree caliber heterogeneity and airflow obstruction among older adults.

Smaller mean airway tree caliber is associated with airflow obstruction and chronic obstructive pulmonary disease (COPD). We investigated whether airway tree caliber heterogeneity was associated with airflow obstruction and COPD. Two community-based cohorts (MESA Lung, CanCOLD) and a longitudinal case-control study of COPD (SPIROMICS) performed spirometry and computed tomography measurements of airway lumen diameters at standard anatomical locations (trachea-to-subsegments) and total lung volume. Percent-predicted airway lumen diameters were calculated using sex-specific reference equations accounting for age, height, and lung volume. The association of airway tree caliber heterogeneity, quantified as the standard deviation (SD) of percent-predicted airway lumen diameters, with baseline forced expired volume in 1-second (FEV1), FEV1/forced vital capacity (FEV1/FVC) and COPD, as well as longitudinal spirometry, were assessed using regression models adjusted for age, sex, height, race-ethnicity, and mean airway tree caliber. Among 2,505 MESA Lung participants (means ± SD age: 69 ± 9 yr; 53% female, mean airway tree caliber: 99 ± 10% predicted, airway tree caliber heterogeneity: 14 ± 5%; median follow-up: 6.1 yr), participants in the highest quartile of airway tree caliber heterogeneity exhibited lower FEV1 (adjusted mean difference: -125 mL, 95%CI: -171,-79), lower FEV1/FVC (adjusted mean difference: -0.01, 95%CI: -0.02,-0.01), and higher odds of COPD (adjusted odds ratio: 1.42, 95%CI: 1.01-2.02) when compared with the lowest quartile, whereas longitudinal changes in FEV1 and FEV1/FVC did not differ significantly. Observations in CanCOLD and SPIROMICS were consistent. Among older adults, airway tree caliber heterogeneity was associated with airflow obstruction and COPD at baseline but was not associated with longitudinal changes in spirometry.NEW & NOTEWORTHY In this study, by leveraging two community-based samples and a case-control study of heavy smokers, we show that among older adults, airway tree caliber heterogeneity quantified by CT is associated with airflow obstruction and COPD independent of age, sex, height, race-ethnicity, and dysanapsis. These observations suggest that airway tree caliber heterogeneity is a structural trait associated with low baseline lung function and normal decline trajectory that is relevant to COPD.

Epidemiological and Clinical Characteristics Associated with COVID-19 Severity Among Hospitalized Patients in the United Arab Emirates: A Retrospective Multicentre Study.

OBJECTIVES: To investigate the clinical and epidemiological factors associated with severe COVID-19 cases in hospitalized patients across two emirates within the United Arab Emirates (UAE). METHODS: A retrospective observational analytical study analysed data from 738 medical records and conducted 573 in-depth interviews with patients hospitalized across multiple healthcare centers in the UAE, between 29 January 2020 and 14 October 2021. Regression analysis predicted risk factors for COVID-19 severity. RESULTS: Main risk factors identified were crowding (aOR 1.919; 95%CI 1.144, 3.221), obesity (aOR 2.383; 95%CI 1.332, 4.263), diabetes (aOR 11.14; 95%CI 2.653-46.797), severe dehydration (aOR 3.219; 95%CI 2.161, 4.795), cough or sore throat (aOR 1.607; 95%CI 1.032, 2.502), shortness of breath (aOR 1.921; 95%CI 1.294, 2.853), increased days from symptom onset to admission (aOR 1.055; 95%CI 1.006, 1.105), elevated ANC (aOR 1.263, 95%CI 1.121, 1.424), and AST/SGOT (aOR 1.055, 95% CI 1.016, 1.095). Protective factors included smoking (aOR 0.367; 95%CI 0.182, 0.740), first dose of COVID-19 vaccination (aOR 0.595; 95%CI 0.377, 0.93), higher oxygen saturation (aOR 0.853; 95%CI: 0.801, 0.907) and elevated ALC (aOR 0.540; 95%CI 0.323, 0.905). CONCLUSION: Identifying risk factors is crucial for high-risk individuals who may require closer monitoring to improve their outcomes. This can provide guidance for surveillance systems and early detection strategies to mitigate the impact of future outbreaks.

Assessment of Knowledge, Perceptions, and Attitudes During the Global Mpox Outbreak in June 2022: A Cross-Sectional Study From the United Arab Emirates.

Objectives: To examine knowledge, worry, anxiety, and vaccine acceptance for mpox among UAE adults. Methods: An online survey, advertised on academic and social media platform in June 2022 collected data from 959 participants (aged 18 and above) on mpox beliefs, risks, knowledge, worry, anxiety, COVID-19 infection, vaccination, and willingness to receive the mpox vaccine. Bivariate and logistic regression analysis identified associations and predictors between variables. Results: 56% had optimal knowledge of mpox transmission and symptoms. 54% were worried, and 27% experienced anxiety related to the outbreak. Knowledge scores were higher among women, healthcare workers, and those with reliable information sources. High perceived infection risk, changes in precautionary measures, and belief in difficult treatment predicted more worry and anxiety. Higher worry and two or more doses of the COVID-19 vaccine predicted higher likelihood of taking the mpox vaccine. Conclusion: The UAE population showed low knowledge and high worry and anxiety during the global mpox outbreak. Increasing public awareness through targeted educational campaigns is vital. Promoting better understanding of infectious diseases, addressing concerns, and encouraging vaccine uptake can prepare for future outbreaks.

Cell free ACE2 RNA: A potential biomarker of COVID-19 severity.

Despite the downward trend of COVID-19 pandemic and increased immunity of the general population, COVID-19 is still an elusive disease with risks due to emerging variants. Fast and reliable diagnosis of COVID-19 disease would allow better therapeutic interventions for patients at risk to develop more severe outcomes. Cell-free RNAs (cfRNAs) have been proven to be an effective biomarker in cancer and infectious diseases. It has been reported that cfRNAs are amplified in the bloodstream of these patients and at earlier stages of the disease, reflecting tissue damage. Hence, we hypothesize that cfRNAs may serve as a potential indicator of COVID-19 disease severity. To our knowledge, this is the first report to display a significant link between COVID-19 severity and cfRNA of angiotensin converting enzyme-2 (ACE2), the receptor for SARS-CoV-2 virus. qRT-PCR analysis of liquid biopsies from COVID-19 patients (n = 82) displayed a significant increase in ACE2-cfRNA levels in patients with severe manifestations. This finding correlated with blood biomarkers (ANC, WBC, and Creatinine) that were also significantly increased in these patients. We previously showed that bronchial cells from obese subjects express higher ACE2 levels, hence, we further analysed the involvement of obesity as a main contributor to severe outcomes. We confirm a significant increase of ACE2-cfRNA in the plasma of obese/overweight (Ob/Ov) COVID-19 patients compared to lean subjects, with no observed significant change in blood biomarkers. These findings suggest that monitoring ACE2-cfRNAs, as a biomarker, during COVID-19 infection may allow for better disease management, specifically for severe-COVID-19 patients.

Nucleic acid sensor STING drives remodeling and its inhibition enhances steroid responsiveness in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is progressive and irreversible chronic lung inflammatory disease. Cigarette smoke, the main cause of COPD, is often associated with double-stranded DNA release which potentially activates DNA-sensing pathways, such as STING. This study, therefore, analyzed the role of STING pathway in inducing pulmonary inflammation, steroid resistance, and remodeling in COPD. METHODS: Primary cultured lung fibroblasts were isolated from healthy non-smoker, healthy smoker, and smoker COPD individuals. The expression of STING pathway, remodeling, and steroid resistance signatures were investigated in these fibroblasts upon LPS stimulation and treatment with dexamethasone and/or STING inhibitor, at both mRNA and protein levels using qRT-PCR, western blot, and ELISA. RESULTS: At baseline, STING was elevated in healthy smoker fibroblasts and to a higher extent in smoker COPD fibroblasts when compared to healthy non-smoker fibroblasts. Upon using dexamethasone as monotherapy, STING activity was significantly inhibited in healthy non-smoker fibroblasts but showed resistance in COPD fibroblasts. Treating both healthy and COPD fibroblasts with STING inhibitor in combination with dexamethasone additively inhibited STING pathway in both groups. Moreover, STING stimulation triggered a significant increase in remodeling markers and a reduction in HDAC2 expression. Interestingly, treating COPD fibroblasts with the combination of STING inhibitor and dexamethasone alleviated remodeling and reversed steroid hyporesponsiveness through an upregulation of HDAC2. CONCLUSION: These findings support that STING pathway plays an important role in COPD pathogenesis, via inducing pulmonary inflammation, steroid resistance, and remodeling. This raises the possibility of using STING inhibitor as a potential therapeutic adjuvant in combination with common steroid treatment.

Lung Epithelial Cells from Obese Patients Have Impaired Control of SARS-CoV-2 Infection.

Obesity is known to increase the complications of the COVID-19 coronavirus disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the exact mechanisms of SARS-CoV-2 infection in obese patients have not been clearly elucidated. This study aims to better understand the effect of obesity on the course of SARS-CoV-2 infection and identify candidate molecular pathways involved in the progression of the disease, using an in vitro live infection model and RNA sequencing. Results from this study revealed the enhancement of viral load and replication in bronchial epithelial cells (NHBE) from obese subjects at 24 h of infection (MOI = 0.5) as compared to non-obese subjects. Transcriptomic profiling via RNA-Seq highlighted the enrichment of lipid metabolism-related pathways along with LPIN2, an inflammasome regulator, as a unique differentially expressed gene (DEG) in infected bronchial epithelial cells from obese subjects. Such findings correlated with altered cytokine and angiotensin-converting enzyme-2 (ACE2) expression during infection of bronchial cells. These findings provide a novel insight on the molecular interplay between obesity and SARS-CoV-2 infection. In conclusion, this study demonstrates the increased SARS-CoV-2 infection of bronchial epithelial cells from obese subjects and highlights the impaired immunity which may explain the increased severity among obese COVID-19 patients.

The Role of ATP-Binding Cassette Subfamily A in Colorectal Cancer Progression and Resistance.

Colorectal cancer (CRC) is one of the most common malignancies worldwide; it is the fourth leading cause of cancer-related deaths. CRC arises due to mutations that can affect oncogenes, tumour suppressor genes and DNA repair genes. The lack of novel diagnostic and therapeutic targets and the development of chemoresistance are some of the major issues when dealing with CRC. The overexpression of ATP-binding cassette (ABC) transporters is considered one facilitating mechanism for chemoresistance. Furthermore, ABC transporters have additional roles in cancer development beyond multidrug resistance. In CRC, lipid dysregulation has a key role in tumour development and progression, as cancer cells rely on lipids for energy and rapid cell proliferation. ABC subfamily A (ABCA) contains the largest members of ABC proteins, mainly known for their role in lipid transport, mostly membrane lipids such as cholesterol and phospholipids. Although the exact mechanism of action of these members is not confirmed, their expression is usually correlated with tumour progression and therapy resistance, probably due to their role in lipid homeostasis. CRC shows alteration in the expression of ABCA transporters, which is usually linked to poor prognosis and overall survival. Therefore, as lipid transporters, their role in CRC is investigated, and their diagnostic and prognostic potential is evaluated. This minireview presents evidence from various studies suggesting that ABCA transporters might have an active role in CRC and can be utilized as potential diagnostic and therapeutic targets.

Airways tissue expression of type I interferons and their stimulated genes is higher in children than adults.

There is emerging evidence that age-dependent differences in susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) correlate with stronger innate immune response in the upper respiratory tract in children compared to adults. The efficient induction of interferon (IFN) alpha and beta (α and ß) signaling, and interferon-stimulated genes (ISGs) is fundamental to the host antiviral response. In-silico transcriptomic analyses was conducted to determine the expression levels of IFN α/ß pathway genes as well as 524 human ISGs in upper and lower airways of children and adults at baseline and post respiratory infections including coronavirus disease 2019 (COVID-19). To validate our in-silico analysis, we conducted qRT-PCR to measure ISGs levels in children and adult's nasal epithelial samples. At baseline, children had significantly higher levels of IFN α/ß and ISGs genes compared to adults. More distinction was also seen in bronchial compared to nasal basal levels. Children nasal epithelial cells exhibited superior antiviral IFN α/ß and associated ISGs response following ex-vivo poly (I:C) treatment model, and in clinical samples of SARS-CoV-2 infected patients. This was also confirmed in nasal epithelial samples using qRT-PCR validation. No gender-based difference in type I IFN levels across both age groups were observed. Understanding the biological basis for children resistance against severe COVID-19 is a challenge that has substantial clinical importance. More mechanistic studies are needed to carefully quantify how much of early IFN levels is needed to bypass the viral evasion mechanism and prevent its further replication and dissemination to lower airways and the rest of the body.

Saliva metabolomic profile of COVID-19 patients associates with disease severity.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is strongly linked to dysregulation of various molecular, cellular, and physiological processes that change abundance of different biomolecules including metabolites that may be ultimately used as biomarkers for disease progression and severity. It is important at early stage to readily distinguish those patients that are likely to progress to moderate and severe stages. OBJECTIVES: This study aimed to investigate the utility of saliva and plasma metabolomic profiles as a potential parameter for risk stratifying COVID-19 patients. METHOD: LC-MS/MS-based untargeted metabolomics were used to profile the changes in saliva and plasma metabolomic profiles of COVID-19 patients with different severities. RESULTS: Saliva and plasma metabolites were screened in 62 COVID-19 patients and 18 non-infected controls. The COVID-19 group included 16 severe, 15 moderate, 16 mild, and 15 asymptomatic cases. Thirty-six differential metabolites were detected in COVID-19 versus control comparisons. SARS-CoV-2 induced metabolic derangement differed with infection severity. The metabolic changes were identified in saliva and plasma, however, saliva showed higher intensity of metabolic changes. Levels of saliva metabolites such as sphingosine and kynurenine were significantly different between COVID-19 infected and non-infected individuals; while linoleic acid and Alpha-ketoisovaleric acid were specifically increased in severe compared to non-severe patients. As expected, the two prognostic biomarkers of C-reactive protein and D-dimer were negatively correlated with sphingosine and 5-Aminolevulinic acid, and positively correlated with L-Tryptophan and L-Kynurenine. CONCLUSION: Saliva disease-specific and severity-specific metabolite could be employed as potential COVID-19 diagnostic and prognostic biomarkers.

Vitamin D enhances type I IFN signaling in COVID-19 patients.

The ability of Vitamin D (VitD) to modulate antiviral responses through induction of antimicrobial peptide is well established. However, the effect of VitD on host responses to SARS-CoV-2 is not well investigated. We here report the ability of VitD to enhance host IFN-alpha/beta (a/ß) signaling both in vitro and among severe COVID-19 patients treated with VitD. Blood and saliva specimens were obtained from severe COVID-19 patients treated (43 patients), or not (37 patients), with vitD, during their stay in intensive care unit. Patients were followed up to 29 days following admission, and patient survival outcomes were collected. Higher activity levels of RIG-1/MDA-5 and JAK-STAT signaling pathways were observed with significantly higher gene and protein levels of antiviral interferon stimulating genes (ISGs) such as MX-1 and ISG-15; both in vitro, following treatment of PBMCs with vitD, and in whole blood and saliva specimens of VitD treated patients. Moreover, VitD treated patients had lower risk of all-cause mortality by day 29 compared to untreated patients (adjusted hazard ratio, 0.37, 95% confidence interval of 0.14-0.94; P = 0.038). The herein uncovered regulatory role of VitD on type I IFNs suggests the importance of insuring a normal level of VitD for the prevention and probably treatment of SARS-CoV-2 infection. Additional mechanistic studies, however, are needed to fully elucidate the antiviral effects of VitD particularly in the setting of COVID-19 infection.

The Role of Systems Biology in Deciphering Asthma Heterogeneity.

Asthma is one of the most common and lifelong and chronic inflammatory diseases characterized by inflammation, bronchial hyperresponsiveness, and airway obstruction episodes. It is a heterogeneous disease of varying and overlapping phenotypes with many confounding factors playing a role in disease susceptibility and management. Such multifactorial disorders will benefit from using systems biology as a strategy to elucidate molecular insights from complex, quantitative, massive clinical, and biological data that will help to understand the underlying disease mechanism, early detection, and treatment planning. Systems biology is an approach that uses the comprehensive understanding of living systems through bioinformatics, mathematical, and computational techniques to model diverse high-throughput molecular, cellular, and the physiologic profiling of healthy and diseased populations to define biological processes. The use of systems biology has helped understand and enrich our knowledge of asthma heterogeneity and molecular basis; however, such methods have their limitations. The translational benefits of these studies are few, and it is recommended to reanalyze the different studies and omics in conjugation with one another which may help understand the reasons for this variation and help overcome the limitations of understanding the heterogeneity in asthma pathology. In this review, we aim to show the different factors that play a role in asthma heterogeneity and how systems biology may aid in understanding and deciphering the molecular basis of asthma.

Intranasal administration of abatacept enhances IL-35+ and IL-10+ producing Bregs in lung tissues of ovalbumin-sensitized asthmatic mice model.

BACKGROUNDS: Treating asthmatic rheumatoid arthritis patients with abatacept has been shown to associate with better control of asthma symptoms. However, the mechanism behind that is not investigated. METHODS: Ovalbumin (OVA)- sensitized BALB/c female mice were treated intranasally (IN) or intraperitoneally (IP) with abatacept 4 hrs before the OVA challenge. The effects of abatacept IN or IP on the lungs and blood levels of Tregs and Bregs and their production of immunosuppressive cytokines, were determined using FACS analysis and ELISA assay. RESULTS: Treating OVA- sensitized asthmatic mice model with abatacept, IN or IP, reduced lung inflammation. IN treatment with abatacept increased the frequency of IL-35 and IL-10 producing Bregs in the lung tissues to a higher level compared to IP treatment. Moreover, the frequency of lungs LAG3+ Tregs was significantly increased following treatment. This was also associated with a reduction in lung tissue and serum IL-17 levels of treated mice. CONCLUSIONS: These results suggest that abatacept by enhancing IL-35+IL-10+ Bregs and LAG3+ Tregs might reverse IL-17 induced lung inflammation during asthma.

Interleukin-17, a salivary biomarker for COVID-19 severity.

OBJECTIVES: T-helper 17 cell-mediated response and their effector IL-17 cytokine induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a major cause of COVID-19 disease severity and death. Therefore, the study aimed to determine if IL-17 level in saliva mirrors its circulatory level and hence can be used as a non-invasive biomarker for disease severity. METHODS: Interleukin-17 (IL-17) level was evaluated by ELISA in saliva and blood of 201 adult COVID-19 patients with different levels of severity. The IL-17 saliva level was also associated with COVID-19 disease severity, and need for mechanical ventilation and/or death within 29 days after admission of severe COVID-19 patients. RESULTS: We found that IL-17 level in saliva of COVID-19 patients reflected its circulatory level. High IL-17 level in saliva was associated with COVID-19 severity (P<0.001), need for mechanical ventilation (P = 0.002), and/or death by 29 days (P = 0.002), after adjusting for patients' demographics, comorbidity, and COVID-19 serum severity markers such as D-Dimer, C-reactive protein, and ferritin. CONCLUSION: We propose that saliva IL-17 level could be used as a biomarker to identify patients at risk of developing severe COVID-19.

Recent advances in vitamin D implications in chronic respiratory diseases.

Chronic airway inflammatory and infectious respiratory diseases are the most common medical respiratory conditions, associated with significant morbidity and mortality. Vitamin D (1,25(OH)2D3) deficiency has been shown to be highly prevalent in patients with chronic airway inflammatory and infectious diseases, correlated with increased disease severity. It has been established that vitamin D modulates ongoing abnormal immune responses in chronic respiratory diseases and is shown to restrict bacterial and viral colonization into the lungs. On the contrary, other studies revealed controversy findings regarding vitamin D efficacy in respiratory diseases. This review aims to update the current evidence regarding the role of vitamin D in airway inflammation and in various respiratory diseases. A comprehensive search of the last five years of literature was conducted using MEDLINE and non-MEDLINE PubMed databases, Ovid MEDLINE, SCOPUS-Elsevier, and data from in vitro and in vivo experiments, including clinical studies. This review highlights the importance of understanding the full range of implications that vitamin D may have on lung inflammation, infection, and disease severity in the context of chronic respiratory diseases.

Upregulation of interleukin-19 in saliva of patients with COVID-19.

Cytokines are major players in orchestrating inflammation, disease pathogenesis and severity during COVID-19 disease. However, the role of IL-19 in COVID-19 pathogenesis remains elusive. Herein, through the analysis of transcriptomic datasets of SARS-CoV-2 infected lung cells, nasopharyngeal swabs, and lung autopsies of COVID-19 patients, we report that expression levels of IL-19 and its receptor, IL-20R2, were upregulated following SARS-CoV-2 infection. Of 202 adult COVID-19 patients, IL-19 protein level was significantly higher in blood and saliva of asymptomatic patients compared to healthy controls when adjusted for patients' demographics (P < 0.001). Interestingly, high saliva IL-19 level was also associated with COVID-19 severity (P < 0.0001), need for mechanical ventilation (P = 0.002), and/or death (P = 0.010) within 29 days of admission, after adjusting for patients' demographics, diabetes mellitus comorbidity, and COVID-19 serum markers of severity such as D-dimer, C-reactive protein, and ferritin. Moreover, patients who received interferon beta during their hospital stay had lower plasma IL-19 concentrations (24 pg mL-1) than those who received tocilizumab (39.2 pg mL-1) or corticosteroids (42.5 pg mL-1). Our findings indicate that high saliva IL-19 level was associated with COVID-19 infectivity and disease severity.

Continuous positive airway pressure therapy suppresses inflammatory cytokines and improves glucocorticoid responsiveness in patients with obstructive sleep apnea and asthma: A case-control study.

CONTEXT: Asthma and obstructive sleep apnea (OSA) are prevalent respiratory disorders that frequently coexist. Continuous positive airway pressure (CPAP) therapy is the standard treatment for OSA. However, its effects on systemic inflammation and glucocorticoid responsiveness in OSA patients with asthma are largely unknown. AIMS: To examine the potential role of CPAP therapy in reducing systemic inflammation and improving glucocorticoid responsiveness in asthmatic patients with OSA. SETTINGS AND DESIGN: A case-control study was conducted at the respiratory and sleep clinics involving patients with OSA and patients with asthma and OSA. METHODS: The levels of inflammatory asthma biomarkers (interleukin [IL]-4, IL-17A, IL-8, IL-2, and interferon-γ [IFN-γ]), and glucocorticoid receptors (GR)-α and GR-ß, were determined to compare systemic inflammation and glucocorticoid responsiveness between pre- and post-1-month CPAP treatment in both groups. STATISTICAL ANALYSIS: The Wilcoxon signed-rank test was used to compare inflammatory biomarkers before and after CPAP therapy. P < 0.05 considered statistically significant. The analysis was performed using SPSS. RESULTS: Recruited patients (n = 47), 51% (n = 24) had OSA and 49% (n = 23), had OSA with asthma. Interestingly, the blood levels of IL-17 and IL-8 were significantly decreased post-CPAP therapy in OSA patients, whereas IL-4, IL-17, and IFN-γ were significantly reduced post-CPAP treatment in OSA patients with asthma. Remarkably, CPAP therapy improved glucocorticoid responsiveness in asthmatic patients with OSA, but not in the OSA group and an increase in the GR-α/GR-ß ratio was noted post-CPAP therapy. CONCLUSIONS: Continuous positive airway pressure therapy improved responsiveness to glucocorticoid treatment and demonstrated a suppressive effect on proinflammatory cytokines in asthmatics with OSA.

MiR-365-3p is a negative regulator in IL-17-mediated asthmatic inflammation.

Background: Interleukin-17, the major proinflammatory cytokine secreted by Th17 cells, makes essential contribution to pathogenesis of severe asthma, while the detailed mechanisms, especially the involvement of microRNAs which are also important participants in asthma progression, remains largely unclear. Methods: In this study, we established a house dust mite (HDM) extract-induced murine asthmatic models and the miRNA expression in the lung tissues of mice were profiled by miRNA microarray assay. The effect of miR-365-3p on IL-17-mediated inflammation was examined by qRT-PCR and immunoblotting analysis. The involvement of ARRB2 as target gene of miR-365-3p was verified by overexpression or RNA interference. Results: HDM extract-induced asthmatic inflammation was proved to be IL17-mediated and miR-365-3p was screened out to be the only miRNA exclusively responsive to IL-17. miR-365-3p, whose expression was significantly downregulated upon IL-17 stimulation, was demonstrated to exert remarkable anti-inflammatory effect to decrease IL-17-provoked inflammatory cytokines (KC/IL-8 and IL-6) in both airway epithelial cells and macrophages of murine and human origins, verifying its universal antagonizing activity against IL-17-initiated inflammation across the two species. ARRB2 was characterized as the key target of miR-365-3p to negate IL-17-induced inflammatory cytokines. Conclusion: Taken together, our data supported the notion that miR-365-3p, which was diminished by IL-17 in murine and human asthmatic pathogenesis, functioned as an essential negative mediator in IL-17-stimuated inflammatory response by targeting ARRB2, which would shed new light to the understanding and therapeutics thereof of asthmatic inflammation.