Endothelin-1 induces connective tissue growth factor expression in human lung fibroblasts by disrupting HDAC2/Sin3A/MeCP2 corepressor complex.

BACKGROUND: Reduction of histone deacetylase (HDAC) 2 expression and activity may contribute to amplified inflammation in patients with severe asthma. Connective tissue growth factor (CTGF) is a key mediator of airway fibrosis in severe asthma. However, the role of the HDAC2/Sin3A/methyl-CpG-binding protein (MeCP) 2 corepressor complex in the regulation of CTGF expression in lung fibroblasts remains unclear. METHODS: The role of the HDAC2/Sin3A/MeCP2 corepressor complex in endothelin (ET)-1-stimulated CTGF production in human lung fibroblasts (WI-38) was investigated. We also evaluated the expression of HDAC2, Sin3A and MeCP2 in the lung of ovalbumin-induced airway fibrosis model. RESULTS: HDAC2 suppressed ET-1-induced CTGF expression in WI-38 cells. ET-1 treatment reduced HDAC2 activity and increased H3 acetylation in a time-dependent manner. Furthermore, overexpression of HDAC2 inhibited ET-1-induced H3 acetylation. Inhibition of c-Jun N-terminal kinase, extracellular signal-regulated kinase, or p38 attenuated ET-1-induced H3 acetylation by suppressing HDAC2 phosphorylation and reducing HDAC2 activity. Overexpression of both Sin3A and MeCP2 attenuated ET-1-induced CTGF expression and H3 acetylation. ET-1 induced the disruption of the HDAC2/Sin3A/MeCP2 corepressor complex and then prompted the dissociation of HDAC2, Sin3A, and MeCP2 from the CTGF promoter region. Overexpression of HDAC2, Sin3A, or MeCP2 attenuated ET-1-stimulated AP-1-luciferase activity. Moreover, Sin3A- or MeCP2-suppressed ET-1-induced H3 acetylation and AP-1-luciferase activity were reversed by transfection of HDAC2 siRNA. In an ovalbumin-induced airway fibrosis model, the protein levels of HDAC2 and Sin3A were lower than in the control group; however, no significant difference in MeCP2 expression was observed. The ratio of phospho-HDAC2/HDAC2 and H3 acetylation in the lung tissue were higher in this model than in the control group. Overall, without stimulation, the HDAC2/Sin3A/MeCP2 corepressor complex inhibits CTGF expression by regulating H3 deacetylation in the CTGF promoter region in human lung fibroblasts. With ET-1 stimulation, the HDAC2/Sin3A/MeCP2 corepressor complex is disrupted and dissociated from the CTGF promoter region; this is followed by AP-1 activation and the eventual initiation of CTGF production. CONCLUSIONS: The HDAC2/Sin3A/MeCP2 corepressor complex is an endogenous inhibitor of CTGF in lung fibroblasts. Additionally, HDAC2 and Sin3A may be of greater importance than MeCP2 in the pathogenesis of airway fibrosis.

Anti-IgE therapy inhibits chemotaxis, proliferation and transformation of circulating fibrocytes in patients with severe allergic asthma.

BACKGROUND AND OBJECTIVE: Circulating fibrocytes act as precursors of myofibroblasts, contribute to airway remodelling in chronic asthma and migrate to injured tissues by expressing CXCR4 and CCR7. Anti-IgE therapy improves severe allergic asthma (SAA) control and airway remodelling in T2-high SAA. The effects of anti-IgE therapy on fibrocyte activities were investigated in this study. METHODS: The expression of CCR7, CXCR4, ST2 and α-SMA (α-smooth muscle actin) in both circulating and cultured fibrocytes from all patients with asthma was measured, and was repeated after omalizumab treatment in SAA. Fibrocytes recruitment, proliferation and transformation were also measured in response to anti-IgE therapy. RESULTS: Omalizumab effectively improved asthma control and pulmonary function in T2-high SAA, associated with a decline in serum levels of IL-33 and IL-13. Omalizumab down-regulates CXCR4 and CCR7 expression of fibrocytes, which could suppress fibrocyte recruitment into the lungs. Omalizumab also suppressed the increased number of fibrocytes and α-SMA+ fibrocytes within the cultured non-adherent non-T (NANT) cells after 3-7 days of culture. The decrease in serum levels of IL-33 by omalizumab contributed to the effectiveness in inhibiting fibrocyte recruitment, proliferation and myofibroblast transformation through IL-33/ST2 axis. The elevated IL-13 expression in SAA patients potentiated the effects of IL-33 by increasing ST2 expression. CONCLUSION: Omalizumab reduced the number of circulating fibrocytes, cell and number of fibrocytes as well as α-SMA+ fibrocytes after 3-7 days of culture in SAA patients. IL-33 and IL-13 may be implicated in the effectiveness of omalizumab in inhibiting fibrocyte activation contributing partly to the clinical benefits in reducing lamina propria and basement membrane thickening.

Hypoventilation patterns during bronchoscopic sedation and their clinical relevance based on capnographic and respiratory impedance analysis.

Capnography involves the measurement of end-tidal CO2 (EtCO2) values to detect hypoventilation in patients undergoing sedation. In a previous study, we reported that initiating a flexible bronchoscopy (FB) examination only after detecting signs of hypoventilation could reduce the risk of hypoxemia without compromising the tolerance of the patient for this type of intervention. We hypothesize that hypoventilation status could be determined with greater precision by combining thoracic impedance-based respiratory signals, RESP, and EtCO2 signals obtained from a nasal-oral cannula. Retrospective analysis was conducted on RESP and EtCO2 waveforms obtained from patients during the induction of sedation using propofol for bronchoscopic examination in a previous study. EtCO2 waveforms associated with hypoventilation were then compared with RESP patterns, patient variables, and sedation outcomes. Signals suitable for analysis were obtained from 44 subjects, 42 of whom presented indications of hypoventilation, as determined by EtCO2 waveforms. Two subtypes of hypoventilation were identified by RESP: central-predominant (n = 22, flat line RESP pattern) and non-central-predominant (n = 20, RESP pattern indicative of respiratory effort with upper airway collapse). Compared to cases of non-central-predominant hypoventilation, those presenting central-predominant hypoventilation during induction were associated with a lower propofol dose (40.2 ± 18.3 vs. 60.8 ± 26.1 mg, p = 0.009), a lower effect site concentration of propofol (2.02 ± 0.33 vs. 2.38 ± 0.44 µg/ml, p = 0.01), more rapid induction (146.1 ± 105.5 vs. 260.9 ± 156.2 s, p = 0.01), and lower total propofol dosage (96.6 ± 41.7 vs. 130.6 ± 53.4 mg, p = 0.04). Hypoventilation status (as revealed by EtCO2 levels) could be further classified by RESP into central-predominant or non-central-predominant types. It appears that patients with central-predominant hypoventilation are more sensitive to propofol during the induction of sedation. RESP values could be used to tailor sedation management specifically to individual patients.

Endotypes of severe allergic asthma patients who clinically benefit from anti-IgE therapy.

BACKGROUND: Omalizumab, a recombinant monoclonal anti-IgE antibody, was developed for the treatment of severe allergic asthma. Not all these patients respond to omalizumab. OBJECTIVE: This study aimed to evaluate whether the proinflammatory cytokine profiles in the severe allergic asthma patients were different between who responded and nonresponded to omalizumab therapy. METHODS: A prospective study was conducted to examine type 2 cytokines and epithelium-derived cytokines in the bronchial tissues by immunohistochemistry, Western blot and PCR analysis among patients with severe allergic asthma before and after omalizumab therapy. RESULTS: Fourteen of 23 patients with unstable severe allergic asthma improved their asthma control after 4 months of omalizumab treatment (Responders), while nine failed to improve (Non-Responders). Most of Responders were type 2-high endotype (12/14) with upregulated expression of IL-33, IL-25 and TSLP in their bronchial tissues, while most of Non-Responders were type 2-low endotype (8/9). Repeated bronchoscopic biopsy was done in nine responders after omalizumab treatment and showed a decline in IL-13, IL-33, IL-25 and TSLP expression in the bronchial tissues. Among 14 Responders who continued omalizuamb treatments to a total 12 months, six patients achieved a well control of asthma (ACT ≥ 23), while eight patients required additional treatment for asthma symptoms and had more rhinosinusitis comorbidities and a mixed eosinophilic and neutrophilic inflammation in their bronchial tissues. CONCLUSION: Most of the severe allergic asthma patients who benefited from omalizumab treatment were IL-33, IL-25 and TSLP aggravated type 2-high endotype. Rhinosinusitis or with a mixed eosinophilic and neutrophilic airway inflammation should be evaluated in patients who partially responded to omalizumab treatment.

Differences between COPD patients and their families regarding willingness toward life-sustaining treatments.

BACKGROUND/PURPOSE: Patients with chronic obstructive pulmonary disease (COPD) receive more life-sustaining treatments (LSTs) than those with other diseases. The aims of this study were to explore the willingness of COPD patients and their families to consent to LSTs and compare the differences between their levels of willingness. METHODS: A cross-sectional survey was conducted, and structured questionnaires were used for data collection. RESULTS: A total of 219 valid samples were collected, including 109 patients and 110 families. Sixty percent of family members indicated that they did not know the intentions of the patient. Families were significantly more willing for patients to receive LSTs than the patients themselves. The level of willingness of patients and families varied according to the situation and LST interventions. When patients were in a vegetative state or medical treatments were futile, the willingness of COPD patients and their families to receive LSTs significantly decreased. Endotracheal intubation and external defibrillation were the least likely to be requested, whereas the willingness to receive medication injections and noninvasive ventilation was greatest. CONCLUSION: Communication between families and patients on the issue of LST should be facilitated. Adequate information on the patient's condition and possible LSTs should be provided to avoid COPD patients receiving inappropriate LSTs.

Effects of a Web-based Health Education Program on Quality of Life and Symptom Distress of Initially Diagnosed Advanced Non-Small Cell Lung Cancer Patients: A Randomized Controlled Trial.

Advanced non-small cell lung cancer (NSCLC) patients treated with chemotherapy experience functional decline and decreased quality of life. The purpose of this study was to evaluate the effects of a web-based health education program on global quality of life, quality of life-related functional dimensions, and symptom distress of initially diagnosed advanced non-small cell lung cancer patients. This study used a randomized, pre- and post-repeated measures design. A total of 55 participants were randomly assigned to an experimental group (n = 27) and a control group (n = 28). The experimental group participated in a web-based health education program, and the control group received usual care. Patients were assessed at 4 time points: baseline assessment (T0), and then 1, 2, and 3 months (T1, T2, and T3) after participating in the web-based health education program or receiving usual care. Patients in the experimental group had significantly greater global quality of life and emotional function, and significantly less top ten significant symptom distresses compared to those in the control group. There were no differences between the groups and within groups with respect to physical function, role function, cognitive function, and social function. The web-based health education can improve global quality of life, emotional function, and top ten significant symptom distresses in patients receiving chemotherapy during the first 3 months after initial diagnosis of advanced NSCLC. Web-based health education can improve quality of life and lessen distress of initially diagnosed NSCLC patients treated with chemotherapy.

Reduced suppressive effect of ß2-adrenoceptor agonist on fibrocyte function in severe asthma.

BACKGROUND: Patients with severe asthma have increased airway remodelling and elevated numbers of circulating fibrocytes with enhanced myofibroblastic differentiation capacity, despite being treated with high doses of corticosteroids, and long acting ß2-adrenergic receptor (AR) agonists (LABAs). We determined the effect of ß2-AR agonists, alone or in combination with corticosteroids, on fibrocyte function. METHODS: Non-adherent non-T cells from peripheral blood mononuclear cells isolated from healthy subjects and patients with non-severe or severe asthma were treated with the ß2-AR agonist, salmeterol, in the presence or absence of the corticosteroid dexamethasone. The number of fibrocytes (collagen I+/CD45+ cells) and differentiating fibrocytes (α-smooth muscle actin+ cells), and the expression of CC chemokine receptor 7 and of ß2-AR were determined using flow cytometry. The role of cyclic adenosine monophosphate (cAMP) was elucidated using the cAMP analogue 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) and the phosphodiesterase type IV (PDE4) inhibitor, rolipram. RESULTS: Salmeterol reduced the proliferation, myofibroblastic differentiation and CCR7 expression of fibrocytes from healthy subjects and non-severe asthma patients. Fibrocytes from severe asthma patients had a lower baseline surface ß2-AR expression and were relatively insensitive to salmeterol but not to 8-Br-cAMP or rolipram. Dexamethasone increased ß2-AR expression and enhanced the inhibitory effect of salmeterol on severe asthma fibrocyte differentiation. CONCLUSIONS: Fibrocytes from patients with severe asthma are relatively insensitive to the inhibitory effects of salmeterol, an effect which is reversed by combination with corticosteroids.

Obstructive sleep apnoea accelerates FEV1 decline in asthmatic patients.

BACKGROUND: Although the prevalence of both obstructive sleep apnoea (OSA) and asthma are both increasing, little is known about the impact of OSA on the natural history of lung function in asthmatic patients. METHODS: A total of 466 patients from our sleep laboratory were retrospectively enrolled. Of them, 77 patients (16.5%) had asthma with regular follow-up for more than 5 years. Their clinical characteristics, pulmonary function, emergency room visits, and results of polysomnography results were analysed. RESULTS: The patients were divided into three groups according to the severity of the apnoea-hypopnea index (AHI). The decline in FEV1 among asthma patients with severe OSA (AHI > 30/h) was 72.4 ± 61.7 ml/year (N = 34), as compared to 41.9 ± 45.3 ml/year (N = 33, P = 0.020) in those with mild to moderate OSA (5 < AHI ≤ 30) and 24.3 ± 27.5 ml/year (N = 10, P = 0.016) in those without OSA (AHI ≤ 5). For those patients with severe OSA, the decline of FEV1 significantly decreased after continuous positive airway pressure (CPAP) treatment. After multivariate stepwise linear regression analysis, only AHI was remained independent factor for the decline of FEV1 decline. CONCLUSIONS: Asthmatic patients with OSA had substantially greater declines in FEV1 than those without OSA. Moreover, CPAP treatment alleviated the decline of FEV1 in asthma patients with severe OSA.

Different perceptions of narrative medicine between Western and Chinese medicine students.

BACKGROUND: Western medicine is an evidence-based science, whereas Chinese medicine is more of a healing art. To date, there has been no research that has examined whether students of Western and Chinese medicine differentially engage in, or benefit from, educational activities for narrative medicine. This study fills a gap in current literature with the aim of evaluating and comparing Western and Chinese Medicine students' perceptions of narrative medicine as an approach to learning empathy and professionalism. METHODS: An initial 10-item questionnaire with a 5-point Likert scale was developed to assess fifth-year Western medical (MS) and traditional Chinese medical (TCMS) students' perceptions of a 4-activity narrative medicine program during a 13-week internal medicine clerkship. Exploratory factor analysis was undertaken. RESULTS: The response rate was 88.6% (412/465), including 270 (65.5%) MSs and 142 (34.5%) TCMSs, with a large reliability (Cronbach alpha = 0.934). Three factors were extracted from 9 items: personal attitude, self-development/reflection, and emotional benefit, more favorable in terms of enhancement of self-development/reflection. The perceptions of narrative medicine by scores between the two groups were significantly higher in TCMSs than MSs in all 9-item questionnaire and 3 extracted factors. CONCLUSIONS: Given the different learning cultures of medical education in which these student groups engage, this suggests that undertaking a course in Chinese medicine might enhance one's acceptance to, and benefit from, a medical humanities course. Alternatively, Chinese medicine programmes might attract more humanities-focused students.

Efficacy of omalizumab (Xolair®) in patients with moderate to severe predominately chronic oral steroid dependent asthma in Taiwan: a retrospective, population-based database cohort study.

BACKGROUND: Omalizumab (Xolair®), a recombinant monoclonal anti-IgE antibody, has demonstrated efficacy in clinical trials conducted in patients with moderate to severe persistent allergic asthma. We aimed to investigate the efficacy, discontinuation and medical resource utilization of omalizumab in the real-life setting in Taiwan. METHODS: This study was a retrospective, population-based database cohort study using the Taiwan NHIRD from 2007 to 2011 assessing the efficacy of omalizumab therapy over 4 months on changes in asthma medication, asthma control, frequency of exacerbations and hospitalization rates at baseline and after omalizumab discontinuation. RESULTS: There was a reduction in asthma medication post omalizumab therapy and severe exacerbations and hospitalizations from baseline (31.2%, n = 282) to the end of follow-up (11.8%, n = 144, p < 0.001). Nearly all the patients received chronic oral corticosteroids at baseline (92.4%). The number of ER visits decreased from 1.13 ± 2.04 to 0.29 ± 0.83, and the mean number of admissions decreased from 5.93 ± 16.16 to 2.75 ± 12.02 from baseline to the end of follow-up (p < 0.001). After discontinuation of omalizumab, the cost of ER medical expenses decreased from New Taiwan dollars (NTD) 3934 at 2 months to NTD 2860 at 12 months. CONCLUSIONS: Patients who received omalizumab therapy for over 4 months were more likely to reduce the use of other asthma medications and less likely to experience an asthma exacerbation, ER visits, and hospitalization, even after the discontinuation of omalizumab. These data suggest that omalizumab has efficacy in improving health outcomes in patients with moderate to severe predominately chronic oral steroid dependent asthma in the real-life setting in Taiwan.

Increased phenotypic differentiation and reduced corticosteroid sensitivity of fibrocytes in severe asthma.

BACKGROUND: Patients with severe asthma are less responsive to corticosteroid therapy and show increased airway remodeling. The mesenchymal progenitors, fibrocytes, may be involved in the remodeling of asthmatic airways. We propose that fibrocytes in severe asthma are different from those in nonsevere asthma. OBJECTIVES: To examine the survival, myofibroblastic differentiation, and C-C chemokine receptor 7 (CCR7) expression in blood fibrocytes from patients with severe and nonsevere asthma and study the effect of corticosteroids on fibrocyte function. METHODS: The nonadherent non-T-cell fraction of blood mononuclear cells was isolated from healthy subjects and patients with nonsevere and severe asthma. Total and differentiating fibrocytes were identified by their expression of CD45, collagen I, and α-smooth muscle actin using flow cytometry. The expression of CCR7 and of the glucocorticoid receptor was measured by using flow cytometry. RESULTS: Increased numbers of circulating fibrocytes, with greater myofibroblastic differentiation potential, were observed in patients with severe asthma. Dexamethasone induced apoptosis, leading to reduction in the number of cultured fibrocytes and total nonadherent non-T cells from healthy subjects and patients with nonsevere asthma but not from patients with severe asthma. Dexamethasone reduced CCR7 expression in fibrocytes from patients with nonsevere asthma but not from patients with severe asthma. Glucocorticoid receptor expression was attenuated in fibrocytes from patients with severe asthma. CONCLUSIONS: Patients with severe asthma have elevated numbers of circulating fibrocytes that show enhanced myofibroblastic differentiation and that are less responsive to the effects of corticosteroids.

Fibrocyte trafficking in patients with chronic obstructive asthma and during an acute asthma exacerbation.

BACKGROUND: Fibrocytes express several chemokine receptors (CCR7 and CXCR4) that regulate their recruitment and trafficking into tissue-damage sites in response to specific chemokine gradients (CCL19 and CXCL12). OBJECTIVE: We investigated whether these chemoattractants and S100A9, through the receptor for advanced glycation end-products (RAGE; ie, its receptor), are involved in fibrocyte trafficking in patients with chronic obstructive asthma (COA) and during an acute exacerbation (AE) in patients without airflow obstruction (Asthma AE group). METHODS: We collected peripheral blood from 14 asthmatic patients with normal pulmonary function, 14 patients with COA, 11 patients in the Asthma AE group, and 14 healthy subjects. Isolated circulating fibrocytes were used for migration assay. Expression of CCR7, CXCR4, S100A9, and RAGE in fibrocytes was measured by using flow cytometry. CCL19 and CXCL12 expression in bronchial tissues was determined by using immunohistochemistry and RT-PCR. RESULTS: There were higher numbers of circulating fibrocytes in patients in the Asthma AE group and patients with COA. The expression of CXCL12 in bronchial tissues and CXCR4 in circulating fibrocytes was higher in the Asthma AE group and, to a lesser extent, in patients with COA. The expression of CCL19 in bronchial tissues and CCR7 in fibrocytes was higher in patients with COA. CXCL12/CXCR4 and CCL19/CCR7 enhanced fibrocyte transmigration in the Asthma AE group and in patients with COA, respectively. The upregulated expression of S100A9 and RAGE in fibrocytes of patients in the Asthma AE group and those with COA contributes to the enhanced basal migratory motility of fibrocytes. CONCLUSION: The CXCR4/CXCL12 axis contributes to chemotaxis of fibrocytes in patients in the Asthma AE group, whereas the CCR7/CCL19 axis plays an important role in patients with COA. S100A9 enhances the basal migratory motility of fibrocytes from patients in the Asthma AE group and patients with COA.

Vocal cord dysfunction diagnosed by four-dimensional dynamic volume computed tomography in patients with difficult-to-treat asthma: A case series.

Patients with asthma may also have vocal cord dysfunction (VCD), which leads to poor control of the asthma. Once patients are diagnosed with difficult-to-treat asthma with poor control, VCD should be excluded or treated accordingly. The gold standard for diagnosis of VCD is to perform a laryngoscopy. However, this procedure is invasive and may not be suitable for patients with difficult-to-treat asthma. Four-dimensional (4D) dynamic volume computed tomography (CT) is a noninvasive method for quantification of laryngeal movement, and can serve as an alternative for the diagnosis of VCD. Herein, we present a series of five cases with difficult-to-treat asthma patients who were diagnosed with VCD by 4D dynamic volume CT. Clinicians should be alert to the possibility of VCD when poor control is noted in patients with asthma. Early diagnosis by noninvasive 4D dynamic volume CT can decrease excessive doses of inhaled corticosteroids.

Adjuvant treatment with a mammalian target of rapamycin inhibitor, sirolimus, and steroids improves outcomes in patients with severe H1N1 pneumonia and acute respiratory failure.

OBJECTIVES: Severe H1N1 pneumonia with acute respiratory failure results in infiltration of lungs due to the presence of hyperactive immune cells. Rapamycin and corticosteroids inhibit this immune response by blocking the activation of T and B cells. DESIGN: Open-label prospective randomized controlled trial. SETTING: A tertiary medical center, Chang Gung Memorial Hospital, located in Taiwan. PATIENTS: Between 2009 and 2011, of 4,012 H1N1-infected patients, 38 patients with severe H1N1 pneumonia and acute respiratory failure were enrolled. MEASUREMENTS AND MAIN RESULTS: Thirty-eight patients with confirmed H1N1 pneumonia and on mechanical ventilatory support were randomized to receive adjuvant treatment of corticosteroids with an mTOR inhibitor, either with sirolimus (Rapamune 2 mg/d) (sirolimus group, n = 19) for 14 days or without sirolimus (nonsirolimus group, n = 19). The clinical values measured included PaO2/FIO2, Sequential Organ Failure Assessment score, duration of ventilatory support, and mortality. The baseline demography was similar between the two groups. After treatment, the PaO2/FIO2 values on day 3 (167.5 [95% CI, 86.7-209.2 mm Hg], n = 19 vs 106.8 [95% CI, 73.0-140.7 mm Hg], n = 19; p = 0.025] and day 7 (241.6 [95% CI, 185.2-297.9 mm Hg], n = 19 vs 147.0 [95% CI, 100.7-193.7 mm Hg], n = 17; p = 0.008) in the sirolimus group were significantly better over the nonsirolimus group. Similarly, the Sequential Organ Failure Assessment score on day 3 (4.3 [95% CI, 3.1-5.5]; p = 0.029) and day 7 (5.9 [95% CI, 4.8-6.9], n = 19 and 6.2 [95% CI, 4.7-7.8], n = 17, respectively) significantly improved in the sirolimus group. The liberation from a mechanical ventilator at 3 months was also better in the sirolimus combined with corticosteroids treatment. Similarly, the duration of ventilator use was significantly shorter in the sirolimus group (median, 7 vs 15 d; p = 0.03 by log-rank test). In the sirolimus combined with corticosteroids treatment group, a rapid clearance of virus also occurred after 7 days of treatment. CONCLUSIONS: In patients with severe H1N1 pneumonia, early adjuvant treatment with corticosteroids and an mTOR inhibitor was associated with improvement in outcomes, such as hypoxia, multiple organ dysfunction, virus clearance, and shortened liberation of ventilator and ventilator days.

NF-κB repressing factor downregulates basal expression and mycobacterium tuberculosis induced IP-10 and IL-8 synthesis via interference with NF-κB in monocytes.

BACKGROUND: Our previous study showed NF-κB repressing factor (NKRF) downregulates IP-10 and IL-8 synthesis in the peripheral blood mononuclear cells and alveolar macrophages of TB patients with high bacterial loads. However, the mechanism underlying the repressive effect of NKRF is not fully understood. RESULTS: The levels of IP-10, IL-8 and NKRF were significantly up-regulated in THP-1 cells treated with heated mycobacterium tuberculosis (H. TB). NKRF inhibited NF-κB-mediated IP-10 and IL-8 synthesis and release induced by H. TB. The repressive effect of NKRF is mediated via interference with NF-κB (p65) binding and RNA polymerase II recruitment to promoter sites of IP-10 and IL-8. CONCLUSIONS: We have elucidated that direct contact with MTb induces IP-10, IL-8 and a concomitant increase in NKRF in THP-1 cells. The up-regulated NKRF serves as an endogenous repressor for IP-10 and IL-8 synthesis to hinder host from robust response to MTb infection.

The endothelin A receptor mediates fibrocyte differentiation in chronic obstructive asthma. The involvement of connective tissue growth factor.

RATIONALE: Fibrocytes possess increased differentiability into α-smooth muscle actin (α-SMA)(+) myofibroblasts in chronic obstructive asthma (COA) and contribute to pulmonary fibrosis. Endothelin-1 (ET-1) induces matrix-associated gene expression through the ETA receptor (ETAR) and promotes fibroblast differentiation. However, the mechanism of fibrocyte differentiation remains unclear. OBJECTIVES: To define the roles of the ETAR and connective tissue growth factor (CTGF) expression in fibrocytes in the development of fibrosis in COA. METHODS: Blood nonadherent non-T (NANT) cells were isolated, and fibrocytes expressing CD45, collagen I, CTGF, ETAR, or α-SMA were identified by flow cytometry. MEASUREMENTS AND MAIN RESULTS: We showed the accumulation of fibrocytes in bronchial walls and overexpression of CTGF in fibrocytes from patients with COA. After being cultured, CTGF was increased in fibrocytes from patients with COA, but not from those of normal participants or patients with asthma without obstruction. Serum levels of ET-1 and the expression of the ETAR in fibrocytes were significantly higher in patients with COA compared with normal participants and patients with asthma without obstruction. Treatment with the ETAR antagonist (BQ123), but not ETBR antagonist (BQ788), reduced the expression of CTGF and α-SMA in fibrocytes and fibrocyte differentiation in patients with COA. Furthermore, treatment with BQ123 or an anti-CTGF antibody attenuated α-SMA expression induced by ET-1 in fibrocytes from normal participants. CONCLUSIONS: Our findings demonstrate for the first time that the ETAR pathway is vital for CTGF expression, which results in fibrocyte differentiation in COA, and suggests that an ETAR antagonist may be a potential antifibrotic agent in preventing the development of fibrosis in patients with COA.

Mobile-phone-based home exercise training program decreases systemic inflammation in COPD: a pilot study.

BACKGROUND: Moderate-intensity exercise training improves skeletal muscle aerobic capacity and increased oxidative enzyme activity, as well as exercise tolerance in COPD patients. METHODS: To investigate whether the home-based exercise training program can reduce inflammatory biomarkers in patients with COPD, twelve patients using mobile phone assistance and 14 with free walk were assessed by incremental shuttle walk test (ISWT), spirometry, strength of limb muscles, and serum C-reactive protein (CRP) and inflammatory cytokines. RESULTS: Patients in the mobile phone group improved their ISWT walking distance, with decrease in serum CRP after 2 months, and sustained at 6 months. Patients in the control group had no improvement. Serum IL-8 in the mobile phone group was significantly reduced at 2, 3 and 6 months after doing home exercise training compared to baseline. IL-6 and TNF-α were significantly elevated at 3 and 6 months in control group, while there were no changes in mobile phone group. The strength of limb muscles was significantly greater compared to baseline at 3 and 6 months in the mobile phone group. CONCLUSIONS: A mobile-phone-based system can provide an efficient home endurance exercise training program with improved exercise capacity, strength of limb muscles and a decrease in serum CRP and IL-8 in COPD patients. Decreased systemic inflammation may contribute to these clinical benefits. (Clinical trial registration No.: NCT01631019).