Epithelium-derived IL17A Promotes Cigarette Smoke-induced Inflammation and Mucus Hyperproduction.

The airway epithelium is a central modulator of innate and adaptive immunity in the lung. IL17A expression was found to be increased in the airway epithelium; however, the role of epithelium-derived IL17A in chronic obstructive pulmonary disease (COPD) remains unclear. In this study, we aimed to determine whether epithelium-derived IL17A regulates inflammation and mucus hyperproduction in COPD by using a cultured human bronchial epithelial (HBE) cell line in vitro and an airway epithelium IL17A-specific knockout mouse in vivo. Increased IL17A expression was observed in the mouse airway epithelium upon cigarette smoke (CS) exposure or in a mouse model of COPD that was induced by using CS and Eln (elastin). CS extract (CSE) also triggered IL17A expression in HBE cells. Blocking IL17A or IL17RA (IL17 receptor A) effectively attenuated CSE-induced MUC5AC and the inflammatory cytokines IL6, TNF-α, and IL1ß in HBE cells, suggesting that IL17A mediates CSE-induced inflammation and mucin production in an autocrine manner. CSE activated p-JUN (phospho-JUN) and p-JNK (phospho-c-Jun N-terminal kinase), which were also reduced by IL17RA siRNA, and JUN siRNA attenuated CSE-induced IL6 and MUC5AC. In vivo, selective knockout of IL17A in the airway epithelium markedly reduced the neutrophilic infiltration in BAL fluid, peribronchial inflammation, proinflammatory mediators (CXCL1 [CXC ligand 1] and CXCL2), and mucus production in a COPD mouse model. We showed a novel function of airway epithelium-derived IL17A, which can act locally in an autocrine manner to amplify inflammation and increase mucus production in COPD pathogenesis.

Induction of ferroptosis-like cell death of eosinophils exerts synergistic effects with glucocorticoids in allergic airway inflammation.

INTRODUCTION: Eosinophils are critical in allergic disorders, and promoting eosinophil death effectively attenuates allergic airway inflammation. Ferroptosis is a recently described novel form of cell death; however, little is known about ferroptosis in eosinophils and related diseases. This study aimed to investigate the effects of ferroptosis-inducing agents (FINs) on eosinophil death and allergic airway inflammation, and to explore their potential synergistic effect with glucocorticoids (GCs). METHODS: Eosinophils isolated from the peripheral blood of humans or mice were incubated with FINs, and eosinophil ferroptosis was assessed. The in vivo effects of FINs alone or in combination with dexamethasone (DXMS) were examined in a mouse model of allergic airway inflammation. Bronchoalveolar lavage fluid and lung tissue were collected to examine airway inflammation. RESULTS: Treatment with FINs time and dose dependency induced cell death in human and mouse eosinophils. Interestingly, FINs induced non-canonical ferroptosis in eosinophils, which generated morphological characteristics unique to ferroptosis and was iron dependent but was independent of lipid peroxidation. The antioxidants glutathione and N-acetylcysteine significantly attenuated FIN-induced cell death. Treatment with FINs triggered eosinophil death in vivo and eventually relieved eosinophilic airway inflammation in mice. Furthermore, FINs exerted a synergistic effect with DXMS to induce eosinophil death in vitro and to alleviate allergic airway inflammation in vivo. CONCLUSIONS: FINs induced ferroptosis-like cell death of eosinophils, suggesting their use as a promising therapeutic strategy for eosinophilic airway inflammation, especially due to the advantage of their synergy with GCs in the treatment of allergic disorders.

HDAC2 attenuates airway inflammation by suppressing IL-17A production in HDM-challenged mice.

Histone deacetylase (HDAC)2 is expressed in airway epithelium and plays a pivotal role in inflammatory cells. However, the role of HDAC2 in allergic airway inflammation remains poorly understood. In the present study, we determined the role of HDAC2 in airway inflammation using in vivo models of house dust mite (HDM)-induced allergic inflammation and in vitro cultures of human bronchial epithelial (HBE) cells exposed to HDM, IL-17A, or both. We observed that HDM-challenged Hdac2+/- mice exhibited substantially enhanced infiltration of inflammatory cells. Higher levels of T helper 2 cytokines and IL-17A expression were found in lung tissues of HDM-challenged Hdac2+/- mice. Interestingly, IL-17A deletion or anti-IL-17A treatment reversed the enhanced airway inflammation induced by HDAC2 impairment. In vitro, HDM and IL-17A synergistically decreased HDAC2 expression in HBE cells. HDAC2 gene silencing further enhanced HDM- and/or IL-17A-induced inflammatory cytokines in HBE cells. HDAC2 overexpresion or blocking IL-17A gene expression restored the enhanced inflammatory cytokines. Collectively, these results support a protective role of HDAC2 in HDM-induced airway inflammation by suppressing IL-17A production and might suggest that activation of HDAC2 and/or inhibition of IL-17A production could prevent the development of allergic airway inflammation.

Endothelial cell-specific anticoagulation reduces inflammation in a mouse model of acute lung injury.

Tissue factor (TF)-dependent coagulation contributes to lung inflammation and the pathogenesis of acute lung injury (ALI). In this study, we explored the roles of targeted endothelial anticoagulation in ALI using two strains of transgenic mice expressing either a membrane-tethered human tissue factor pathway inhibitor (hTFPI) or hirudin fusion protein on CD31+ cells, including vascular endothelial cells (ECs). ALI was induced by intratracheal injection of LPS, and after 24 h the expression of TF and protease-activated receptors (PARs) on EC in lungs were assessed, alongside the extent of inflammation and injury. The expression of TF and PARs on the EC in lungs was upregulated after ALI. In the two strains of transgenic mice, expression of either of hTFPI or hirudin by EC was associated with significant reduction of inflammation, as assessed by the extent of leukocyte infiltration or the levels of proinflammatory cytokines, and promoted survival after LPS-induced ALI. The beneficial outcomes were associated with inhibition of the expression of chemokine CCL2 in lung tissues. The protection observed in the CD31-TFPI-transgenic strain was abolished by injection of an anti-hTFPI antibody, but not by prior engraftment of the transgenic strains with WT bone marrow, confirming that the changes observed were a specific transgenic expression of anticoagulants by EC. These results demonstrate that the inflammation in ALI is TF and thrombin dependent, and that expression of anticoagulants by EC significantly inhibits the development of ALI via repression of leukocyte infiltration, most likely via inhibition of chemokine gradients. These data enhance our understanding of the pathology of ALI and suggest a novel therapeutic strategy for treatment.

Co-existing pericardial and pleural malignant mesothelioma responding well to nedaplatin and pemetrexed: a case report.

Background: Malignant mesothelioma (MM) is a rare cancer with poor prognosis. It is less common that two serosal cavities are involved when the patient seeks medical attention firstly. The current first-line chemotherapy for advanced MM is a combination with cisplatin and pemetrexed. However, nedaplatin, a second-generation platinum-based antitumor agent, has the similar therapeutic effects as cisplatin but lower toxicity and higher water solubility. To our knowledge, this is the first case of co-existing pericardial and pleural MM treated with nedaplatin and pemetrexed and responding well. Case Description: A 33-year-old woman, who had worked in a kiln for more than 10 years, suffered from dyspnea and chest tightness for 6 days. Chest computed tomography (CT) showed a massive pericardial effusion. She was diagnosed tuberculous pericarditis and received 6 months antituberculosis treatment (rifampicin, isoniazide, pyrazinamide, ethambutol). But it was ineffective and she was re hospitalized again due to massive pleural effusion and pericardial effusion. She was diagnosed with co-existing pericardial and pleural MM finally based on pleural biopsy and cytology of pericardial effusion. She was responding well excitedly to chemotherapy with nedaplatin and pemetrexed with high tolerance. Bone marrow toxicity or recurrent massive pericardial or pleural effusion were not observed during chemotherapy. However, she gave up chemotherapy and has survived for 22 months, from the onset symptoms. Conclusions: In terms of clinical tolerance and less adverse reactions, we suggest that chemotherapy of nedaplatin with pemetrexed may be a more appropriate treatment in advanced MM. Further clinical trials are warrant.

Myeloid-Specific SIRT6 Deletion Protects Against Particulate Matter (PM2.5)-Induced Airway Inflammation.

Purpose: Particulate matter (PM2.5) is a common risk factor for airway inflammation. Alveolar macrophages play a critical role in airway inflammation. Sirtuin 6 (SIRT6) is a class Ill histone deacetylase that exerts an anti-inflammatory effect in airway diseases. However, the role of SIRT6 on PM2.5-induced airway inflammation in macrophages remains unclear. We aimed to determine whether SIRT6 protects against PM2.5-induced airway inflammation in macrophages. Methods: The effect of SIRT6 on PM2.5-induced airway inflammation was assessed by using THP1 cells or bone marrow-derived macrophages (BMDMs) exposed to PM2.5 in vitro and myeloid cell-specific SIRT6 conditional knockout mice (Sirt6fl/fl-LysMCre) in vivo. Results: PM2.5 increased SIRT6 expression in THP1 cells, but SIRT6 gene silencing decreased PM2.5 induced inflammatory cytokines in THP1 cells. Moreover, the expression of SIRT6 and inflammatory cytokines was also decreased in BMDMs with myeloid-specific deletion of SIRT6 after stimulation of PM2.5. In vivo, Sirt6fl/fl-LysMCre mice substantially decreased airway inflammation in response to PM2.5 exposure. Conclusion: Our results revealed that SIRT6 promotes the PM2.5-induced airway inflammation in macrophages and indicated that inhibition of SIRT6 in macrophages may represent therapeutic strategy for airway disorders induced by airborne particulate pollution.

Association between anticholinergic medication uses and the risk of pneumonia in elderly adults: a meta-analysis and systematic review.

OBJECTIVE: To conduct a meta-analysis and systematic review on the association between anticholinergic medication uses and the risk of pneumonia in elderly adults. MATERIALS AND METHODS: Medical databases were searched included PubMed, Web of Science, EBSCO and Google Scholar (up to December 7, 2022). Studies evaluating association between anticholinergic medication uses and the risk of pneumonia in elderly adults were included. Studies without available data were excluded. We made meta-analysis by using adjusted odds ratio (aOR) with 95% confidence intervals (CIs) from random-effects model. The risk of bias was assessed using ROBINS-I tool and statistical heterogeneity using the I2 statistic. Registration: INPLASY202330070. RESULTS: A total of six studies with 107,012 participants were included. Meta-analysis results showed that anticholinergic medication uses was related with an increased risk of pneumonia (aOR = 1.59; 95%CI, 1.32-1.92) and stroke-associated pneumonia (aOR = 2.02; 95%CI, 1.76-2.33). Moreover, risk estimates of pneumonia for high-potency anticholinergics (aOR = 1.96; 95%CI, 1.22-3.14) were higher than those for low-potency anticholinergics (aOR = 1.58; 95%CI, 1.27-1.97). And increased risk of pneumonia was associated with the anticholinergic medication uses within 30 days (aOR = 2.13; 95%CI, 1.33-3.43), within 90 days (aOR = 2.03; 95%CI, 1.26-3.26) and chronic use (aOR = 1.65; 95%CI, 1.09-2.51). CONCLUSIONS: The risk of pneumonia is increased in elderly adults with anticholinergic medication, especially with higher-potency anticholinergic drugs and in the initiation phase of anticholinergic medication. Clinicians should monitor their use in older patients carefully, especially when the pneumonia-related signs and symptoms are identified.

Anticholinergic medication could increase the risk of pneumonia in elderly adults.The risk of pneumonia was higher in the initiation phase of anticholinergic medication and when the older patients was medicated with higher-potency anticholinergic drugs.Clinicians should monitor anticholinergic drugs use in older patients carefully, especially when the pneumonia-related signs and symptoms are identified.

Prenatal and postnatal exposure to Bisphenol A and Asthma: a systemic review and meta-analysis.

BACKGROUND: Bisphenol A (BPA) is a plasticizer with high production and ubiquitous usage in polycarbonate plastics and epoxy resins. The association between prenatal or postnatal exposure to BPA and childhood wheeze/asthma has not been well established. Our study aimed to provide further justification for the current studies. METHODS: Studies were searched from PubMed, Web of Science, Scopus and Embase from inception until Sep 15, 2020. Meta-analysis was performed to calculate pooled adjusted odds ratios (aOR). The methodological quality of included studies was assessed by using the Newcastle Ottawa Scale (NOS). RESULTS: Of 2,814 screened articles, 9 studies with 3,885 participants were included in the final analysis. When all studies were pooled, postnatal exposure to BPA was associated with a higher risk of childhood asthma (aOR =1.43; 95% CI: 1.28-1.59) or childhood wheeze (aOR =1.38; 95% CI: 1.18-1.62). Prenatal exposure to BPA had a small but significant increased risk of childhood asthma (aOR =1.17; 95% CI: 1.01-1.34). An increased risk of childhood wheeze was related to prenatal exposure to BPA at 16 weeks' gestation (aOR =1.29; 95% CI: 1.07-1.55), but not at 26 weeks' gestation (aOR =1.07; 95% CI: 0.88-1.29) nor at random-time gestation (aOR =1.02; 95% CI: 0.89-1.16). CONCLUSIONS: Prenatal and postnatal exposure to BPA was related to an increased risk of childhood asthma. However, only postnatal and early gestational exposure (at 16 weeks) to BPA could induce the risk of childhood wheeze, but not late gestational exposure (at 26 weeks).

Prevalence and risk factors of mental distress in China during the outbreak of COVID-19: A national cross-sectional survey.

OBJECTIVE: As a result of the pandemic of COVID-19, the public have been experiencing psychological distress. However, the prevalence of psychological distress during the COVID-19 pandemic remains unknown. Our objective was to evaluate the prevalence of psychological distress during COVID-19 outbreak and their risk factors, especially their internal paths and causality. METHODS: A nationwide cross-sectional survey of the prevalence of mental disorders was conducted. We used Hospital Anxiety and Depression Scale (HADS) to estimate the prevalence of anxiety and depression. The internal paths and the causality of the psychological health were analyzed using a structural equation modeling (SEM) approach. RESULTS: A total of 24,789 respondents completed the survey. We found that the overall prevalence of anxiety, depression, combination of anxiety, and depression were 51.6% (95% CI: 51.0-52.2), 47.5% (95% CI: 46.9-48.1), and 24.5% (95% CI: 24.0-25.0), respectively. The risk of psychological disorders in men was higher than that in women. The status of psychological health was different across different age groups, education levels, occupations, and income levels. The SEM analysis revealed that inadequate material supplies, low income, low education, lack of knowledge or confidence of the epidemic, and lack of exercise are major risk factors for psychological distress. CONCLUSIONS: The evidence from this survey poses serious challenges related to the high prevalence of psychological distress, but also offers strategies to deal with the mental health problems caused by the COVID-19 pandemic.

Hematological indices as simple, inexpensive and practical severity markers of obstructive sleep apnea syndrome: a meta-analysis.

BACKGROUND: Clinical detection of inflammatory markers is useful to assess the degree of nocturnal hypoxia and predict the presence of complications in obstructive sleep apnea syndrome (OSAS) patients. Nowadays, some researchers proposed that hematological parameters could be substituted for novel disease-specific biochemical markers (such as C-reactive protein) because they were comparatively cheap, simple and practical. But there was a contradiction whether the hematological parameters were positively correlated with the OSAS severity. METHODS: Medical databases were searched included PubMed, Web of Science, Scopus, Cochrane Library, Clinical Trial, Embase and Google Scholar (up to March 29, 2018). We used weighted mean differences (WMDs) with 95% confidence intervals (CIs) from random-effects model. RESULTS: Seventeen studies were included in this meta-analysis and results were presented by different hematological parameters. Pooled analysis showed that OSAS was associated with a high level of WBC (white blood cell, 11 studies, 2,206 subjects, WMD: 0.58; 95% CI: 0.31 to 0.85; P<0.0001), NLR (neutrophil-to-lymphocyte ratio, 5 studies, 1416 subjects, WMD: 0.46; 95% CI: 0.13 to 0.80; P=0.007), MPV (mean platelet volume, 8 studies, 1,854 subjects, WMD: 0.63; 95% CI: 0.29 to 0.98; P=0.0004), PDW (platelet distribution width, 6 studies, 1,911 subjects, WMD: 0.76; 95% CI: 0.47 to 1.06; P<0.00001), PLR (platelet-to-lymphocyte ratio, 3 studies, 998 subjects, WMD: 21.76; 95% CI: 8.54 to 34.99; P=0.001), RDW (red cell distribution width, 5 studies, 1,701 subjects, WMD: 0.31; 95% CI: 0.11 to 0.51; P=0.002) and HCT (hematocrit, 3 studies, 662 subjects, WMD: 1.58; 95% CI: 0.52 to 2.64; P=0.003). But OSAS was associated with a low level of LYM (lymphocyte, 5 studies, 1,285 subjects, WMD: -0.27; 95% CI: -0.49 to -0.06; P=0.01). There was a gradual rising trend from mild OSAS to severe OSAS existed in all subgroups. CONCLUSIONS: Hematological indices are comparatively Simple, Inexpensive and Practical Severity Markers of OSAS including WBC, LYM, NLR, MPV, PDW, PLR, RDW and HCT.

Heated humidification did not improve compliance of positive airway pressure and subjective daytime sleepiness in obstructive sleep apnea syndrome: A meta-analysis.

INTRODUCTION: We performed a meta-analysis on whether heated humidification during positive airway pressure (PAP) could improve compliance and subjective daytime sleepiness in obstructive sleep apnea syndrome (OSAS) patients. MATERIALS AND METHODS: We searched PubMed, EMBASE, Medline, Cochrane Library, Clinical Trials, Web of Science and Scopus from inception to Oct 29, 2017. We made meta-analysis on the all available randomized controlled trials (RCTs) which assessed effects of heated humidification intervention on PAP compliance and subjective daytime sleepiness, by subgroups of automatic adjusting positive airway pressure/ continuous positive airway pressure (APAP/CPAP) usage and patients with/without upper airway symptoms prior to PAP therapy. RESULTS: A total of nine RCTs were evaluated finally in this meta-analysis. When all the studies were pooled, heated humidification did not improve PAP usage time [weighted mean difference(WMD) = 13.28, 95% confidence interval(CI): -5.85 to 32.41, P = 0.17] or Epworth sleepiness scale (ESS) score (WMD = -0.63, 95% CI: -1.32 to 0.07, P = 0.08). In terms of PAP usage time, heated humidification failed to enhance compliance in both APAP (WMD = 22.34, 95%CI: -21.08 to 65.77, P = 0.31) or CPAP subgroup (WMD = 11.09, 95%CI: -10.21 to 32.40, P = 0.31) and it was also ineffective among patients with upper airway symptoms prior to PAP therapy (WMD = 22.74, 95% CI: -7.77 to 53.24, P = 0.14) or without (WMD = 13.22, 95%CI: -35.84 to 62.29, P = 0.60). In terms of ESS score, heated humidification did not reduce ESS scores in both APAP (WMD = -1.59, 95% CI: -3.81 to 0.64, P = 0.16) or CPAP subgroup (WMD = -0.39, 95% CI: -1.16 to 0.37, P = 0.32) and it was also helpless among patients with upper airway symptoms prior to PAP therapy (WMD = -1.17, 95% CI: -3.10 to 0.75, P = 0.23) or without (WMD = -0.30, 95%CI: -2.25 to 1.66, P = 0.76). CONCLUSION: Heated humidification during PAP therapy improves neither the compliance nor ESS scores in OSAS patients, no matter what types of PAP or whether the patients had upper airway symptoms prior to PAP therapy. But to the population with upper airway symptoms and the APAP users, the conclusions were limited because of small sample size and possible selection bias. More attentions should be paid to these potentially possible benefited subgroups.

Acid-Suppressive Drug Use During Pregnancy and the Risk of Childhood Asthma: A Meta-analysis.

CONTEXT: The association between acid-suppressive drug exposure during pregnancy and childhood asthma has not been well established. OBJECTIVE: To conduct a systematic review and meta-analysis on this association to provide further justification for the current studies. DATA SOURCES: We searched PubMed, Medline, Embase, the Cochrane Database of Systematic Reviews, EBSCO Information Services, Web of Science, and Google Scholar from inception until June 2017. STUDY SELECTION: Observational studies in which researchers assessed acid-suppressive drug use during pregnancy and the risk of childhood asthma were included. DATA EXTRACTION: Of 556 screened articles, 8 population-based studies were included in the final analyses. RESULTS: When all the studies were pooled, acid-suppressive drug use in pregnancy was associated with an increased risk of asthma in childhood (relative risk [RR] = 1.45; 95% confidence interval [CI] 1.35-1.56; I2 = 0%; P < .00001). The overall risk of asthma in childhood increased among proton pump inhibitor users (RR = 1.34; 95% CI 1.18-1.52; I2 = 46%; P < .00001) and histamine-2 receptor antagonist users (RR = 1.57; 95% CI 1.46-1.69; I2 = 0%; P < .00001). LIMITATIONS: None of the researchers in the studies in this meta-analysis adjusted for the full panel of known confounders in these associations. CONCLUSIONS: The evidence suggests that prenatal, maternal, acid-suppressive drug use is associated with an increased risk of childhood asthma. This information may help clinicians and parents to use caution when deciding whether to take acid-suppressing drugs during pregnancy because of the risk of asthma in offspring.

IDH1 R132H Mutation Enhances Cell Migration by Activating AKT-mTOR Signaling Pathway, but Sensitizes Cells to 5-FU Treatment as NADPH and GSH Are Reduced.

AIM OF STUDY: Mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene were recently discovered in vast majority of World Health Organization (WHO) grade II/III gliomas. This study is to understand the effects of IDH1 R132H mutation in gliomagenesis and to develop new strategies to treat glioma with IDH1 R132H mutation. MATERIALS AND METHODS: Over expression of IDH1 R132H in U87MG cells was done by transfecting cells with IDH1 R132H plasmid. MTT assay, scratch repair assay and western blot were performed to study effects of IDH1 R132H mutation on cell proliferation, migration, regulating AKT-mTOR signaling pathway and cell death respectively. NADP+/NADPH and GSH quantification assays were performed to evaluate effects of IDH1 R132H mutation on the production of antioxidant NADPH and GSH. RESULTS: We found that over expression of IDH1 R132H mutation decreased cell proliferation consistent with previous reports; however, it increased cell migration and enhanced AKT-mTOR signaling pathway activation. Mutations in isocitrate dehydrogenase (IDH) 1 also change the function of the enzymes and cause them to produce 2-hydroxyglutarate and not produce NADPH. We tested the level of NADPH and GSH and demonstrated that IDH1 R132H mutant stable cells had significantly low NADPH and GSH level compared to control or IDH1 wild type stable cells. The reduced antioxidants (NADPH and GSH) sensitized U87MG cells with IDH R132H mutant to 5-FU treatment. CONCLUSION: Our study highlights the important role of IHD1 R132H mutant in up- regulating AKT-mTOR signaling pathway and enhancing cell migration. Furthermore, we demonstrate that IDH1 R132H mutation affects cellular redox status and sensitizes gliomas cells with IDH1 R132H mutation to 5FU treatment.