Immunophenotype in acute exacerbation of chronic obstructive pulmonary disease: a cross-sectional study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease, and the immune inflammatory response is thought to play an important role in pathogenesis. However, the immunophenotype of patients with COPD is unknown. Herein, we evaluated the immunophenotype of patients with acute exacerbation of COPD (AECOPD). METHODS: A cross-sectional study was conducted in West China Hospital from September 2018 to October 2019. The proportion of CD4 + T lymphocyte subtypes (Th1, Th2, Th17 and Treg) and levels of serum cytokines in the peripheral blood of patients with AECOPD, stable COPD (SCOPD), healthy smokers (HSs)and healthy controls (HCs) were evaluated. RESULTS: A total of 15 HCs, 19 HSs, 42 patients with SCOPD, and 55 patients with AECOPD were included. Compared to patients with SCOPD, Th1 cells, Th17 cells, Treg cell ratio, Th1/Th2 cell ratio, and the levels of C-reactive protein, interleukin (IL)-6, and IL-10 were significantly increased in patients with AECOPD (P < 0.001), while the proportion of Th2 cells was significantly reduced (P < 0.01). The proportion of Th17 cells was positively correlated with COPD Assessment Test score (r = 0.266, P = 0.009), modified Medical Research Council dyspnea score (r = 0.858, P < 0.0001), and Th1 cell ratio (r = 0.403, P < 0.0001) and negatively correlated with forced vital capacity (r = - 0.367, P = 0.009) and proportion of Th2 cells (r = - 0.655, P < 0.0001). CONCLUSIONS: The immunophenotype of patients with AECOPD shows abnormal activation of Th1, Th17, and Treg cells. There is a correlation between the proportion of Th17 cells and the severity of COPD; therefore, this may represent a novel index for the evaluation of COPD severity. TRIAL REGISTRATION: China Clinical Trials Registry, ChiCTR1800018452, registered 19 September 2018, https://www.chictr.org.cn/index.aspx .

Efficacy and safety of dupilumab for the treatment of uncontrolled asthma: a meta-analysis of randomized clinical trials.

BACKGROUND: Several recent clinical trials have assessed the effects of dupilumab in uncontrolled asthma, but reached no definite conclusion. We therefore conducted this meta-analysis to evaluate the overall efficacy and safety of dupilumab for the treatment of uncontrolled asthma. METHODS: All randomized controlled trials were included. Standard mean differences (SMD) or relative risks (RR) were calculated using Fixed-or random-effects models. RESULTS: Five studies involving 3369 patients were identified. Pooled analysis showed significant improvements in the first-second forced expiratory volume (FEV1) (SMD = 4.29, 95% CI: 2.78-5.81) and Asthma Quality of Life Questionnaire scores (SMD = 4.39, 95% CI: 1.44-7.34). Dupilumab treatments were also associated with significantly decreased 5-item Asthma Control Questionnaire scores (SMD = - 4.95, 95% CI: - 7.30 to - 2.60), AM and PM asthma symptom scores (SMD = - 5.09, 95% CI: - 6.40 to - 3.77; SMD = - 4.92, 95% CI: - 5.98 to - 3.86, respectively), and severe exacerbation risk (RR = 0.73; 95% CI: 0.67-0.79) compared with placebo, with similar incidence of adverse events (RR = 1.0; 95% CI: 0.96-1.04). CONCLUSION: Dupilumab treatment is relatively well-tolerated and could significantly improve FEV1, symptoms, asthma control, and quality of life, and reduced severe exacerbation risk in patients with uncontrolled asthma.

Long-term follow-up of self-expandable metallic stents in benign tracheobronchial stenosis: a retrospective study.

BACKGROUND: Self-expandable metallic stents (SEMSs) have enabled a approving management of malignant airway stenosis. However, the long-term efficacy and safety of this treatment in patients with benign airway stricture are unclear. We conducted this study to retrospectively determine the efficacy and long-term outcomes in patients who have undergone SEMS placement for benign tracheobronchial stenosis. METHODS: All patients treated with SEMSs from July 2003 to June 2016 were reviewed for symptomatic response, complications, and long-term outcomes. RESULTS: Total 131 stents were successfully deployed in 116 patients. Ninety-eight patients demonstrated clinical improvement after stent insertion (84.48%; 95% confidence interval [CI]: 77.89-91.07). Compared with uncovered stents, covered stents were associated with more sore throats complaints or chest pain (13.89% versus 28.81%, P = 0.036) and with higher incidences of major and minor granulation tissue formation and with recurrent stenosis (4.17% versus 15.25%, P = 0.029; 11.11% versus 37.29%, P < 0.0001 and 9.72% versus 28.81%, P = 0.005, respectively). Each covered and uncovered stent developing tissue hyperplasia required a median of 2 (range: 1-15) and 1(range: 1-7) fibrobronchoscope with electrocautery therapy, respectively. At follow-up (median: 1276 days; range: 2-4263), 68 patients had complete resolution, 15 remained under interventional treatment, 8 had bronchial occlusions, 7 underwent surgery, 14 were lost to follow-up, and 4 died of stent unrelated causes. CONCLUSION: SEMS placement achieved most clinical improvement among patients in our study, if adequate endotracheal measures were used to address stent-related complications. The use of permanent SEMSs for benign tracheobronchial stenosis was effective and safe for the majority of patients in a long-term follow-up. TRIAL REGISTRATION: The study has been retrospectively registered in the China Clinical Trial Registry on October 21, 2018 (Registry ID: ChiCTR1800019024 ).

Effects of vitamin D supplementation on the outcomes of patients with pulmonary tuberculosis: a systematic review and meta-analysis.

BACKGROUND: Vitamin D is involved in the host immune response toward Mycobacterium tuberculosis. However, the efficacy of vitamin D supplementation on sputum conversion, clinical response to treatment, adverse events, and mortality in patients with pulmonary tuberculosis (PTB) remains controversial. We aimed to clarify the efficacy and safety of vitamin D supplementation in PTB treatment. METHODS: We searched Medline, Embase, Cochrane Central Register of Controlled Trials, Web of Science for double-blind, randomized controlled trials of vitamin D supplementation in patients with PTB that reported sputum conversion, clinical response to treatment, adverse events, or mortality, published from database inception to November 26, 2017. This study was registered with PROSPERO, number CRD42018081236. RESULTS: A total of 1787 patients with active PTB receiving vitamin D supplementation along with standard anti-tuberculosis regimen were included in the eight trials with different doses of vitamin D ranging from 1000 IU/day to 600,000 IU/month at different intervals. Primary analysis revealed that vitamin D supplementation increased the proportion of sputum smear and culture conversions (OR 1.21, 95%CI 1.05~ 1.39, z = 2.69, P = 0.007; OR 1.22, 95%CI 1.04~ 1.43, z = 2.41, P = 0.02), but did not improve the time to sputum smear and culture conversions (HR 1.07, 95%CI 0.83~ 1.37, z = 0.50, P = 0.62; HR 0.97, 95%CI 0.76~ 1.23, z = 0.29, P = 0.77). In the secondary analysis, vitamin D improved serum 25(OH)D, plasma calcium concentration, lymphocyte count, and chest radiograph (MD 103.36, 95%CI 84.20~ 122.53, z = 10.57, P < 0.00001; SMD 0.26, 95%CI 0.15~ 0.37, z = 4.61, P < 0.00001; MD 0.09, 95%CI 0.03~ 0.14, z = 2.94, P = 0.003); MD -0.33, 95% CI -0.57~ - 0.08 z = 2.57, P = 0.01), but had no impact on adverse events, mortality and other indicators(TB score, BMI, mean mid-upper arm circumference, weight gain, CRP, ESR, and other blood cells) (P > 0.05). CONCLUSIONS: Vitamin D supplementation can be considered as a combination therapy in patients with PTB.

[Effects of diterpene phenol extract of Rosmarinus officinalis on TGFbeta1 and mRNA expressions of its signaling pathway molecules in the lung tissue of pulmonary fibrosis rats].

OBJECTIVE: To investigate the regulative mechanism of the diterpene phenol extract of Rosmarinus Officinalis (DERO) on the imbalance of collagen metabolism of the lung tissue in pulmonary fibrosis rats. METHODS: Fifty healthy Sprague-Dawley rats were randomly divided into the normal saline group (NS), the bleomycin-induced lung injury group (BLM), the low dose DERO group (at the daily dose of 50 mg/kg), the moderate dose DERO group (at the daily dose of 100 mg/kg), and the high dose DERO group (at the daily dose of 200 mg/kg), 10 in each group (abbreviated as DERO 1, 2, 3, respectively). The pulmonary fibrosis rat model was prepared by disposable intratracheal instillation of bleomycin. DERO was administered by gastrogavage as intervention during the repairing process of lung injury. On the morning of the 29th day, the rats' lung tissue was extracted. The karyocyte number, collagen protein, type I collagen (collagen I) and transforming growth factor-beta type II receptor (TGFbetaR II), Smad4 mRNA expressions were semi-quantitatively determined using tissue microarray, HE staining, collagen fiber dyeing, immunohistochemical assay, and in situ hybridization. Using real-time fluorescent quantification RT-PCR, the mRNA expression of transforming growth factor-beta1 (TGF-beta1) were detected. RESULTS: Compared with the NS group, the collagen deposition of the lung tissue was obvious and the inflammatory infiltration was more severe in the BLM group (P < 0.05, P < 0.01). There was no statistical difference in the aforesaid 4 indices between the DERO1 group and the BLM group (P > 0.05). The collagen deposition and the inflammatory infiltration were obviously alleviated in the DERO2 and DERO3 groups (P < 0.05, P < 0.01). Compared with the NS group, the mRNA expressions of collagen-I, TGF-beta1 R II, Smad4, and TGF-beta1 were obviously up-regulated in the BLM group (P < 0.05, P < 0.01). Compared with the BLM group, the aforesaid four indices were not statistically changed in the DERO1 group (P > 0.05). But the mRNA expressions of collagen-I, TGF-beta1 R II, Smad4, and TGF-beta1 were obviously downregulated in the DERO2 and DERO3 groups (P < 0.05, P < 0.01). But the down-regulation of Smad4 expression was not obvious in the DERO2 and the DERO3 groups (P > 0.05). Compared with the DERO1 group, the mRNA expressions of collagen-I, TGF-beta1, R II, TGFbeta1 were all obviously lower in the DERO2 and the DERO3 groups (P < 0.05). But there was no statistical difference in the aforesaid 4 indices between the DERO2 group and the DERO3 group (P > 0.05). CONCLUSIONS: DERO could regulate imbalanced collagen metabolism of pulmonary fibrosis. It could inhibit excessive deposition of collagen fibers, especially excessive deposition of collagen- I. Its mechanisms might be realized by inhibiting up-regulation of TGF-beta1 and TGFbetaR II mRNA expressions, thus interfering the activation of TGF-beta-Smad signaling pathway on target genes, especially on type I procollagen target gene.

[The clinical value of combining multiple features of CT in discriminating between benign and malignant lung lesions].

OBJECTIVE: To develop a set of combined criteria of multiple features of chest CT for discriminating between benign and malignant lung lesions. METHODS: Patients whose chest CT showed abnormalities were recruited from the West China Hospital in March and April 2010. The patients were examined with bronchoscopy and the results of CT and pathology were compared. RESULTS: A total of 105 patients participated in this study and 85 had confirmed pathological results. The CT identified 27 cases of malignant lesions, 22 of which were confirmed by the pathology. The CT identified 58 cases of benign lesions, 55 of which were confirmed by the pathology. The set of combined criteria of multiple features of chest CT had an accuracy of 90.59%, a sensitivity of 88.00%, and a specificity of 91.67% in diagnosing benign and malignant lung lesions. CONCLUSION: The combined criteria of multiple imaging signs of CT have good clinical values for diagnosing malignant lung lesions.

[Effect of hypoxia on the expression and production of fractalkine in pulmonary artery smooth muscle cells and pulmonary microvascular endothelial cells].

OBJECTIVE: To investigate the effect of hypoxia on the expression and production of fractalkine (FKN) in cultured rat pulmonary artery smooth muscle cells (PASMCs) and pulmonary microvascular endothelial cells (PMVECs). METHODS: PASMCs and PMVECs from SD rat were cultured in vitro, and were exposed to hypoxia for 12 h,24 h and 48 h. The expressions of fractalkine mRNA and protein in PASMCs and PMVECs were measured by the methods of in situ hybridization and immunohistochemistry. The fractalkine concentrations in supernatant fluid of cultured PASMCs and PMVECs were measured by enzyme-linked immunosorbent assay. RESULTS: (1) Compared with the control group, the expression and production of fractalkine in PASMCs did not increase after the treatment of hypoxia for 12 hours (P > 0.05), but increased after being treated with hypoxia for 24 hours (P < 0.05), and became more significant after 48 hours (P < 0.01). (2) Compared with the control group, there were no differences of FKN concentrations in supernatant fluid of PMVECs, FKN mRNA and protein levels in PMVECs after being treated with hypoxia for 12 hours, 24 hours or 48 hours (P > 0.05). CONCLUSION: Hypoxia stimulates the synthesis and secretion of fractalkine in cultured rat PASMCs.

[The expression of thrombospondin-1 in serum and pulmonary arterioles of hypoxic pulmonary hypertension rats].

OBJECTIVE: To investigate the expression of thrombospondin-1 (TSP-1) in serum and pulmonary arterioles of rats with hypoxic pulmonary hypertension. METHODS: Twenty male Wistar rats were divided into two groups and exposed to air and isobaric hypoxia for 3 weeks respectively. The mean pulmonary artery pressure (mPAP) was measured by right cardiac catheterization. The rates of wall thickness/external diameter (WT%) and wall area/total vascular area (WA%) were calculated. The TSP-1 level in serum was measured by enzyme-linked immunosorbent assay. TSP-1 mRNA expression in lung tissue was evaluated by quantitative PCR. RESULTS: The pulmonary artery pressure increased in the hypoxia exposed rats. The chronic hypoxia also elicited the thicking of the wall and the narrowing of the lumen of pulmonary arterioles. It led to the increases of pulmonary artery pressure, the index of right ventricular hypertrophy [RV/(LV+S)], WA% and WT% compared to the controls [mPAP:(2.86 +/- 0.39) kPa vs. (1.35 +/- 40.28) kPa; RV/(LV+ S): (43.53 +/- 3.38)% vs. (23.68 +/- 3.48)%; WT%: (35.24 +/- 11.20)% vs. (23.63 +/- 9.74)%; WA%: (55.09 +/- 12.38)% vs. (41.62 +/- 12.83)% respectively, P<0.05]. In hypoxic group, the expression of TSP-1 mRNA in the lung was significantly up-regulated, the expression level of TSP-1 in serum was higher than that in control group (P<0.01). Linear correlation analysis showed that TSP-1 mRNA was positively associated with WT%, WA% and mPAP (r= 0.748, 0.686, 0.942 respectively, P<0.05). CONCLUSION: The TSP-1 may play an important role in the pathogenesis process of hypoxic pulmonary vascular remodeling and pulmonary hypertension.

[Expression of thrombospondin-1 in the lung of hypoxic pulmonary hypertension rats].

OBJECTIVE: To investigate the expression of thrombospondin-1(TSP-1) in the lung of hypoxia-induced pulmonary hypertension rats. METHODS: Thirty male Wistar rats were divided into two groups, pulmonary hypertension group and control group. The mice in experimental group were exposed to isobaric hypoxia for 3 weeks, and those in control group were exposed to air. The pulmonary artery pressure was measured by right cardiac catheterization. The expression of TSP-1 and TGF-beta1 in the lungs of rats were measured by immunohistochemical staining. The histological sections of the lungs were examined using a computerized image analyzer. RESULTS: After the induction of hypoxia for 3 weeks, the rats had pulmonary artery pressure increased with the thickening of the wall and the narrowing of the lumen of pulmonary arterioles. In the experimental group, the mean pulmonary artery pressure (mPAP) was (2.86 +/- 0.39) kPa, the index of right ventricular hypertrophy RV/(LV+S) was (43.53 +/- 3.38)%, the ratio of vascular wall thickness/vascular external diameter (WA%) was (55.09 +/- 12.38)%, and the ratio of vascular wall area/total vascular area (WT%) was (35.24 +/- 11.2)%, which all were significantly increased in comparison with those of control group [mPAP (1.35 +/- 0.28) kPa, RV/(LV+S) (23.68 +/- 3.48)%, WT% (23.63 +/- 9.74)%, WA% (41.62 +/- 12.83)%, respectively. P < 0.05). The positive staining of TSP-1 (1.32 +/- 0.04 vs. 0.96 +/- 0.03) and TGF-beta1 (1.38 +/- 0.05 vs. 1.04 +/- 0.04) in the wall of pulmonary arteriole of the rats exposed to hypoxia were significantly stronger than those of control rats (P < 0.01). CONCLUSION: The expression of TSP-1 appears to be increased in hypoxic pulmonary hypertension rats, which may contribute to the pathogenesis of hypoxic pulmonary vascular remodeling.

Clinical features of asthma with comorbid bronchiectasis: A systematic review and meta-analysis.

BACKGROUND: This meta-analysis aimed to systematically estimate the prevalence of comorbid bronchiectasis in patients with asthma and to summarize its clinical impact. METHODS: Embase, PubMed, and Cochrane Library electronic databases were searched to identify relevant studies published from inception until March 2020. STUDY SELECTION: Studies were included if bronchiectasis was identified by high-resolution computed tomography. Outcomes included the prevalence of bronchiectasis and its association with demographic characteristics and indicators of asthma severity, including results of lung function tests and the number of exacerbations. RESULTS: Five observational studies with 839 patients were included. Overall, the mean prevalence of bronchiectasis in patients with asthma was 36.6% (307/839). Patients with comorbid bronchiectasis had lower forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) (MD: -2.71; 95% CI: -3.72 to -1.69) and more frequent exacerbations (MD: 0.68; 95% CI: 0.03 to 1.33) than those with asthma alone, and there was no significant difference of sex, duration of asthma and serum levels of immunoglobulin(Ig)Es between asthmatic patients with or without bronchiectasis. CONCLUSION: The presence of bronchiectasis in patients with asthma was associated with greater asthma severity. There are important therapeutic implications of identifying bronchiectasis in asthmatic patients.

[Effects of mechanical force on expressions of intercellular adhesion molecule-1 in cultured human alveolar type 2 cells].

OBJECTIVE: To explore the expression of intercellular adhesion molecule-1 (ICAM-1) in cultured human alveolar type 2 cells (A549) stimulated by mechanical force in vitro. METHODS: Cells were divided into 3 groups: a tensile stress group, a compressive stress group and a control group. The four-point bending system was used to stimulate A549 cells. The cells were stimulated by tensile stress or compressive stress respectively at the same magnitude of 1000 microstrain for 6 h. Sham cells in control group were not subjected to mechanical loading. The protein level and mRNA level of ICAM-1 were measured by Western blot and RT-PCR. Then an inhibitor was added to further explore the possible mechanism. The cells were divided into a tensile stress+inhibitor group, a compressive stress + inhibitor group and a control group. The cells were pretreated with PD98059, a specific inhibitor of extracellular signal-regulated kinase (ERK) for 60 min, and then stimulated respectively by tensile stress or compressive stress at the same magnitude of 1000 microstrain for 6 h or were not subjected to mechanical loading. ICAM-1 protein and mRNA concentrations were determined by Western blot and RT-PCR, respectively. The data were analyzed by one-way ANOVA and Student-Newman-Keuls were used to compare 2 means. RESULTS: The expression of ICAM-1 protein in the tensile stress group (1.16+/-0.07) or the compressive stress group (1.05+/-0.02) were significantly higher than that of the control group (0.78+/-0.07, F=3.31, P<0.05), and the expression of ICAM-1 mRNA in the tensile stress group (1.42+/-0.05) or the compressive stress group (1.27+/-0.05) were also significantly higher than that of the control group (0.13+/-0.04, F=23.1, P<0.01). After pretreated with PD98059 for 60 min, the expression of ICAM-1 protein in the tensile stress group (1.62+/-0.10) was significantly higher than that of the control group (0.50+/-0.03, q=3.75, P<0.05), while there was no significant difference between the compressive stress group (0.60+/-0.03, q=0.32, P>0.05) and the control group. At the transcription level, the expression of ICAM-1 in the tensile stress group (1.57+/-0.03) was significantly higher than that of the control group (0.35+/-0.29, q=3.51, P<0.05), while there was no significant difference between the compressive stress group (0.46+/-0.03, q=0.32, P>0.05) and the control group. CONCLUSIONS: Mechanical forces upregulate the expression of ICAM-1 in A549 cells. PD98059 partly inhibits the upregulation of ICAM-1 induced by mechanical forces. ERK pathway may be partly involved in signal transduction of mechanical force induced expression of ICAM-1 in A549 cells.

Peripheral Blood Eosinophil as a Biomarker in Outcomes of Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

Purpose: Mounting evidence suggests that eosinophil levels correlate with the effects of therapy and phenotype for chronic obstructive pulmonary disease (COPD). This study aimed to clarify the relationship between eosinophil levels and clinical outcomes in patients with acute exacerbation of COPD (AECOPD). Methods: A prospective, multicenter, observational cohort study was performed in three teaching hospitals. Patients were grouped by quartile percentage (0, 0.7, 2.55) and absolute blood eosinophils count (0, 0.05×109/L, 0.17×109/L) and divided into four numbered groups ranked from low to high. Results: The study included 493 AECOPD patients. In the percentile-ranked groups, patients in Group 1 experienced significantly longer hospital stays, higher rates of both noninvasive mechanical ventilation (NIMV), and heart failure than those in Group 4 (12 days vs 10 days, p = 0.005; 29.5% vs 23.6%, p = 0.007; 48.4% vs 28.5%, p = 0.001). Group 1 also had higher frequencies of respiratory failure and pulmonary heart disease compared to Groups 3 and 4 (54.8% vs 34.8%, p = 0.002; 54.8% vs 35%, p = 0.003). In the absolute count-ranked groups, patients in Group 1 had significantly higher rates of NIMV than those in Group 3 (41.1% vs 21.7%, p = 0.001), had higher rates of heart failure, respiratory failure, and pulmonary heart disease than those in Group 3 and 4 (48.1% vs 30.2%, p = 0.003; 48.1% vs 30.4%, p = 0.005; 50.8% vs 32.2%, p = 0.004; 50.8% vs 34.1%, p = 0.008; 51.9% vs 34.1%, p = 0.004; 51.9% vs 33%, p = 0.003). There were outcome differences among the admitting hospital of stays in the absolute count groups (p = 0.002), but the differences were not significant in a pairwise comparison. The proportion of ICU admissions and mortality was different in two cohorts with no difference in a pairwise comparison. Conclusion: Patients with lower eosinophil counts experienced poorer clinical outcomes. Eosinophil levels may be a helpful marker to predict outcomes in AECOPD.

Prevalence and Baseline Clinical Characteristics of Eosinophilic Chronic Obstructive Pulmonary Disease: A Meta-Analysis and Systematic Review.

Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with different clinical and pathophysiological characteristics. Cumulative evidence shows that eosinophil levels may be connected to the therapeutic effects and phenotype of COPD. However, the prevalence of eosinophilic inflammation in COPD and the baseline characteristics of eosinophilic COPD remain unknown. Our study investigated the prevalence of COPD with eosinophil levels of >2% and the characteristics of eosinophilic COPD. Methods: We searched the Cochrane Central Library, Medline, Embase, and the Web of Science for trials of eosinophil and COPD published from database inception to May 1, 2019. Results: In total, 40,112 COPD patients that were involved in 19 trials were included in the final analysis. The prevalence of eosinophilic COPD ranged from 18.84 to 66.88%, with an average prevalence of 54.95% across all studies. We found that men, ex-smokers, individuals with a history of ischemic heart disease, and individuals with a higher body mass index (BMI) were at higher risk of eosinophilic COPD (OR 1.36, 95% CI 1.26-1.46, P < 0.00001; OR 1.23, 1.12-1.34, P < 0.0001; OR 1.31, 1.14-1.50, P = 0.001; MD 0.70, 0.27-1.12, P = 0.001). There was, however, a lower proportion of GOLD stage I patients among those with eosinophilic COPD (OR 0.84, 0.73-0.96, P = 0.01). No significant differences were found in terms of age, current smoker status, pack-years smoked, percent of predicted forced expiratory volume in 1 s, hypertension, diabetes, or other GOLD stages between the two groups (P > 0.05). Conclusions: Our analysis suggests that eosinophilic inflammation is prevalent in COPD. Eosinophilic COPD was more likely to occur in men, ex-smokers, those with a higher BMI, and those with a high risk of some comorbidity; however, a lower proportion of patients with eosinophilic COPD experienced mild airflow limitations.

Efficacy and Safety of CFTR Corrector and Potentiator Combination Therapy in Patients with Cystic Fibrosis for the F508del-CFTR Homozygous Mutation: A Systematic Review and Meta-analysis.

INTRODUCTION: Cystic fibrosis (CF) is a progressive, genetic disease that causes persistent lung infections and limits the ability to breathe over time. The combination of a cystic fibrosis transmembrane conductance regulator (CFTR) corrector and potentiator has provided a benefit by decreasing sweat chloride concentration in CF for the F508del-CFTR homozygous mutation, but it remains controversial in lung function, nutritional status, clinical score and safety. METHODS: The authors performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of combination therapy on lung function, nutritional status, clinical score and safety in CF for the F508del-CFTR homozygous mutation. Web of Science, Cochrane Central Register of Controlled Trials, Medline, and Embase were searched. The registered PROSPERO number was CRD42018085875. RESULTS: Five RCTs, including a total of 1637 participants with the F508del-CFTR homozygous mutation who accepted CFTR corrector and potentiator combination therapy along with basic treatment were enrolled in this analysis. Primary analysis revealed that combination therapy improved the percent of predicted FEV1 (ppFEV1) (MD 2.38, 1.62-3.15, P < 0.00001), Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score (MD 2.59, 0.96-4.22, P = 0.002) and body-mass index (BMI) (MD 0.21, 0.03-0.39, P = 0.02). In the secondary analysis, combination therapy had no impact on the number of participants reporting adverse events (OR 0.88, 0.58-1.33, P = 0.53), but increased the proportion of discontinued treatments due to adverse events (OR 2.71, 1.3-5.63, P = 0.008). CONCLUSIONS: CFTR corrector and potentiator combination therapy effectively improves lung function, nutritional status and clinical score in CF patients with the F508del-CFTR homozygous mutation, and has an acceptable safety profile.

Acute pulmonary inflammation is inhibited in CXCR3 knockout mice after short-term cigarette smoke exposure.

AIM: CXCR3, via binding its specific ligand CXCL10, plays an important role in cigarette smoke (CS)-induced pulmonary inflammation. CXCR3 is preferentially expressed in activated T cells (chiefly CD8+ T cells). The purpose of this study was to investigate the role of CXCR3 in CS-induced pulmonary injury using CXCR3 gene-deficient (CXCR3-/-) mice. METHODS: Differences in the infiltration of inflammatory cells and CD8+ T cells and the expression of inflammatory mediators and chemokines in the bronchoalveolar lavage fluid and lungs at the mRNA and protein levels were compared between CXCR3-/- mice and wild-type (WT) mice at 2 h after 3 d of CS exposure. RESULTS: Compared with their WT counterparts, the CXCR3-/- mice showed alleviated inflammation, as evidenced by fewer inflammatory cells, particularly cytotoxic CD8+ T cells, in bronchoalveolar lavage fluid and lung tissues. At both the mRNA and protein levels, there were significantly lower levels of inflammatory and chemotactic cytokines, including TNF-alpha, interleukin-8, interferon-gamma, transforming growth factor-beta1, and CXCL10 in the CXCR3-/- mice. CONCLUSION: Our data show that CXCR3 is important in recruiting inflammatory cells (particularly CD8+ T cells) into the airways and lungs, as well as initiating inflammatory and fibrotic cytokines release at 2 h following a short-term CS insult. CXCR3 could be a novel target for the treatment of pulmonary inflammation induced by CS.

[The effect of breviscapine on the pulmonary arterial pressure and the expression of Rho-kinase in pulmonary arterioles of hypoxic rats].

OBJECTIVE: To observe the effect of breviscapine on the pulmonary artery pressure and the Rho-kinase and Rho-kinase mRNA in pulmonary arterioles of rats treated with hypoxia, and therefore to explore the mechanisms of breviscapine on hypoxic pulmonary hypertension. METHODS: Eighteen adult male SD rats were randomly divided into 3 groups. One group was exposed to air (normal group), the second group was exposed to isobaric hypoxia for 3 weeks (hypoxic group), and the third group was exposed to hypoxia for 3 weeks and treated with breviscapine (preventive group). Cardiac catheterization was used to measure the mean pulmonary arterial pressure (mPAP). The heart was isolated, and the right ventricle (RV), left ventricle plus ventricular septum (LV + S) were weighed to calculate the ratio RV/(LV + S). The ratio of vascular wall thickness/vascular external diameter (WT%) and the ratio of vascular wall area/total vascular area (WA%) were measured by image analysis. The quantity of Rho-kinase and Rho-kinase mRNA in rat pulmonary arterioles were determined by immunohistochemistry and in situ hybridization respectively. RESULTS: The mPAP in the preventive group [(19.83 +/- 1.47) mm Hg, 1 mm Hg = 0.133 kPa] was significantly lower than that of the hypoxic group [(27.3 +/- 5.0) mm Hg], t = 4.28, P < 0.05. The RV/(LV + S) in the preventive group (0.29 +/- 0.03) was significantly lower than that in the hypoxic group (0.34 +/- 0.05, t = 2.39, P < 0.05). The WT% and WA% in the preventive group (25 +/- 5 and 45 +/- 5, respectively) were significantly lower than those in the hypoxic group (36 +/- 12 and 59 +/- 13, respectively, t = 4.89, 5.89, P < 0.05). The positive staining of ROCKI and ROCKII on pulmonary arterioles in the preventive group (1.18 +/- 0.10 and 1.30 +/- 0.12, respectively) were significantly lower than those in the hypoxic group (1.29 +/- 0.08 and 1.63 +/- 0.24, respectively, t = 3.90, 5.82, P < 0.05). The positive staining of ROCKI mRNA and ROCKII mRNA in the preventive group (1.23 +/- 0.13 and 1.22 +/- 0.06, respectively) were significantly lower than those in the hypoxic group (1.37 +/- 0.13 and 1.59 +/- 0.31, respectively, t = 3.94, 5.83, P < 0.05). CONCLUSION: Breviscapine was shown to prevent hypoxic pulmonary hypertension and decrease Rho-kinase and Rho-kinase mRNA.

[The prophylactic effect of thymosin alpha 1 on the acute exacerbation of chronic obstructive pulmonary disease].

OBJECTIVES: To investigate the prophylactic effect of thymosin alpha 1 and its mechanism on patients with chronic obstructive pulmonary disease. METHODS: Eighty patients with chronic obstructive pulmonary disease were divided into two groups. In the treatment group, 42 patients received thymosin alpha 1 1.6 mg hypodermic injection, quague die alterna, for 10 times. All patients were followed for 6 months, and were assessed the number and days of patients with acute exacerbation at 3 and 6 months. In two groups, before treatment and 3 and 6 months after treatment, the pulmonary function tests were measured, and the blood samples were collected for the measurement of the blood IgA, IgG, IgM, CD3, CD4 and CD8 levels. RESULTS: In the treatment group, the number and days of patients with acute exacerbation were significantly lower in comparison with those of the control group. After treatment of thymosin alpha 1, blood CD4 and CD4/CD8 levels were significantly increased. CONCLUSION: Thymosin alpha 1 has a good protection for the acute exacerbation of chronic obstructive pulmonary disease, by incresing body cellular immune activity.

[Effect of simvastatin on endothelin-1 expression in endothelial cell cultured hypoxically].

OBJECTIVE: To observe the role of simvasatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in synthesis and excretion of endothelin-1 (ET-1) in endothelial cell cultured hypoxically. METHODS: Human umbilical vein endothelial cells were hypoxically cultured and treated with simvastatin by different concentrations (0, 1.0, 2.5, 5.0, 10.0 micromol/L) and different times (12, 24, 48 h). Mevalonate was used to intervent the effect of simvastatin. Reverse transcription-polymerase chain reaction (RT-PCR)and enzyme-linked immunoadsorbent assay (ELISA) were adopted to measure ET-1 mRNA and ET-1 in supernatant fluid of endothelial cell culture. RESULTS: (1) There were no changes of ET-1 mRNA and ET-1 expression after the hypoxically cultured endothelial cell were incubated with 1 MICROmol/L simvastatin, but ET-1 expression decreased without significant difference compared to control (0 micromol/L simvastatin) when interfered with 2.5 micromol/L simvastatin. The decreases of ET-1 mRNA and ET-1 expression became more obvious when expression were interfered by 5 micromol/Land 10 micromol/L simvastatin (P < 0.01). (2) ET-1 mRNA and ET-1 expression decreased at 12 h after the endothelial cells were incubated with 10 micromol/L simvastatin, which became more fewer at 24 h and reached the minimum expression at 48 h (P < 0.01). (3) The inhibition effect of simvastatin on ET-1 mRNA and ET-1 expression of endothelial cells could be prevented by mevalonate with concentration of 100 micromol/L. CONCLUSION: Simvastatin can inhibit ET-1 expression in endothelial cell cultured hypoxically.

[The change of fractalkine in lung tissue of rat with hypoxic pulmonary hypertension].

OBJECTIVE: To evaluate the role of fractalkine in the pathogenesis of hypoxic pulmonary hypertension. METHODS: Twenty male SD rats were randomly divided into control group and hypoxic group. Rats in hypoxic group were exposed to hypoxia for 3 weeks. Mean pulmonary arterial pressure (mPAP) was measured by a right cardiac catheterization. The thickness of pulmonary arterioles was measured with a computerized image analyzer. The rates of wall thickness/external diameter (WT%) and wall area/total vascular area (WA%) were calculated. The fractalkine level in lung tissue were measured by enzyme-linked immunosorbent assay. Fractalkine mRNA expression in lung were observed by reverse transcriptase-polymerase chain reaction. RESULTS: The rat mPAP of hypoxic group was higher than that of the control group [(28.7 +/- 3.8) mmHg vs (16.3 +/- 2.1) mmHg, P < 0.01]. The WT% and WA% were increased significantly in hypoxic group than in control group (WT%: (21.28 +/- 4.60)% vs (10.20 +/- 1.56)%, WA%: (67.08 +/- 9.44)% vs (38.11 +/- 42.30)%, P < 0.01, respectively]. In hypoxic group, the expression of fractalkine mRNA in the lung was significantly up-regulated [(0.49 +/- 0.05) vs (0.29 +/- 0.02), P < 0.01], the expression level of fractalkine in lung tissue was higher than that in control group [(7622.6 +/- 938.4) pg/mL vs (4168.5 +/- 403.5) pg/mL, P < 0.01. Linear correlation analyses showed that fractalkine mRNA and protein were positively associated with WA% and WT% (P < 0.05). CONCLUSION: The synthesis and release of fractalkine are increase in the lung tissue of chronic hypoxic rats, and fractalkine may play an important role in hypoxic pulmonary hypertension.

Anti-interleukin 5 Therapy for Eosinophilic Asthma: a Meta-analysis of Randomized Clinical Trials.

Recently, more and more clinical trials have been performed to evaluate the effects of anti-interleukin (IL)-5 antibodies in eosinophilic asthma. However, a confirm conclusion has not been well established. We therefore sought to conduct a meta-analysis to assess the overall efficacy and safety of anti-interleukin 5 treatments in eosinophilic asthma. RCTs of anti-interleukin 5 treatments in eosinophilic asthma published up to June 2016 in PubMed, Embase, Cochrane library databases, and CBM, which reported pulmonary functions, quality-of-life scores, asthmatic exacerbations, and adverse events were included. Fixed-effect models were used to calculate mean difference, relative risks (RR), and 95 % CIs. Twelve studies involving 3340 patients were identified. Pooled analysis revealed significant improvements in FEV1 (nine trials, 1935 subjects; MD = 0.12; 95 % CI, 0.08-0.16), and Asthma Quality-of-Life Questionnaire scores (five trials, 1334 subjects; MD = 0.23; 95 % CI, 0.13-0.34). Anti-interleukin 5 treatment was also associated with significantly decreased exacerbation risk than placebo (six trials, 875 subjects; RR = 0.52; 95 % CI, 0.46 to 0.59) and a lower incidence of adverse events (eight trials, 1754 subjects; RR = 0.93; 95 % CI, 0.89 to 0.97). Anti-interleukin 5 treatment is well tolerated and could significantly improve FEV1, quality of life, and reduced exacerbations risk in patients with eosinophilic asthma. Further trials are necessary to assess the baseline blood eosinophil count to identify the optimal patients of eosinophilic asthma that could benefit from anti-interleukin 5 therapy.