Effect of anti-IL17 and/or Rho-kinase inhibitor treatments on vascular remodeling induced by chronic allergic pulmonary inflammation.

BACKGROUND AND AIMS: Expansion and morphological dysregulation of the bronchial vascular network occurs in asthmatic airways. Interleukin (IL) -17 and Rho-kinase (ROCK) are known to act in inflammation control and remodeling. Modulation of Rho-kinase proteins and IL-17 may be a promising approach for the treatment of asthma through the control of angiogenesis. Our objective was to analyze the effects of treatment with anti-IL17 and/or Rho-kinase inhibitor on vascular changes in mice with chronic allergic pulmonary inflammation. METHODS: Sixty-four BALB/c mice, with pulmonary inflammation induced by ovalbumin were treated with anti-IL17A (7.5/µg per dose, intraperitoneal) and/or Rho-kinase inhibitor (Y-27632-10 mg/kg, intranasal), 1 h before each ovalbumin challenge (22, 24, 26, and 28/days). Control animals were made to inhale saline. At the end of the protocol, lungs were removed, and morphometric analysis was performed to quantify vascular inflammatory, remodeling, and oxidative stress responses. RESULTS: Anti-IL17 or Rho-kinase inhibitor reduced the number of CD4+, CD8+, dendritic cells, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, Rho-kinase 1 and 2, transforming growth factor (TGF-ß), vascular endothelial growth factor (VEGF), nuclear factor (NF)-KappaB, iNOS, metalloproteinase (MMP)-9, MMP-12, metalloproteinase inhibitor-1 (TIMP-1), FOXP-3, signal transducer and activator of transcription 1 (STAT1) and phospho-STAT1-positive cells, and actin, endothelin-1, isoprostane, biglycan, decorin, fibronectin and the collagen fibers volume fraction compared with the ovalbumin group (p < 0.05). The combination treatment, when compared with anti-IL17, resulted in potentiation of decrease in the number of IL1ß- and dendritic cells-positive cells. When we compared the OVA-RHO inhibitor-anti-IL17 with OVA-RHO inhibitor we found a reduction in the number of CD8+ and IL-17, TGF-ß, and phospho-STAT1-positive cells and endothelin-1 in the vessels (p < 0.05). There was an attenuation in the number of ROCK 2-positive cells in the group with the combined treatment when compared with anti-IL17 or Rho-kinase inhibitor-treated groups (p < 0.05). CONCLUSION: We observed no difference in angiogenesis after treatment with Rho-kinase inhibitor and anti-IL17. Although the treatments did not show differences in angiogenesis, they showed differences in the markers involved in the angiogenesis process contributing to inflammation control and vascular remodeling.The reviews of this paper are available via the supplemental material section.

Effects of Aerobic Training Versus Breathing Exercises on Asthma Control: A Randomized Trial.

BACKGROUND: Aerobic training and breathing exercises are interventions that improve asthma control. However, the outcomes of these 2 interventions have not been compared. OBJECTIVE: To compare the effects of aerobic training versus breathing exercises on clinical control (primary outcome), quality of life, exercise capacity, and airway inflammation in outpatients with moderate-to-severe asthma. METHODS: Fifty-four asthmatics were randomized into either the aerobic training group (AG, n = 29) or the breathing exercise group (BG, n = 25). Both interventions lasted for 24 sessions (2/week, 40 minutes/session). Asthma clinical control (Asthma Control Questionnaire [ACQ]), quality of life (Asthma Quality of Life Questionnaire), asthma symptom-free days (ASFD), airway inflammation, exercise capacity, psychological distress (Hospital Anxiety and Depression Scale), daily-life physical activity (DLPA), and pulmonary function were evaluated before, immediately after, and 3 months after the intervention. RESULTS: Both interventions presented similar results regarding the ACQ score, psychological distress, ASFD, DLPA, and airway inflammation (P > .05). However, participants in the AG were 2.6 times more likely to experience clinical improvement at the 3-month follow-up than participants in the BG (P = .02). A greater proportion of participants in the AG also presented a reduction in the number of days without rescue medication use compared with BG (34% vs 8%; P = .04). CONCLUSIONS: Outpatients with moderate-to-severe asthma who participated in aerobic training or breathing exercise programs presented similar results in asthma control, quality of life, asthma symptoms, psychological distress, physical activity, and airway inflammation. However, a greater proportion of participants in the AG presented improvement in asthma control and reduced use of rescue medication.

Streptococcus pneumoniae augments inflammatory process in asthma model without changing Th2 profile

Studies suggested that some aspects of asthma exacerbation by Spn infection remain unclear. Objective: to evaluate possible mechanism that worsen inflammation caused by Spn in an experimental model of chronic allergic inflammation. Methods: 30 BALB/c mice were divided in 4 groups: SAL (non-sensitized group), STREP (animals challenged with Spn), OVA (ovalbumin sensitized group), OVAST (OVA sensitized and challenged with Spn). OVA and OVAST groups received intraperitoneal injections of ovalbumin (OVA) solution (days 1 and 14). OVA challenges were performed on days 22, 24, 26, and 28. Afterwards, animals were challenged with pneumococcal strains M10 (11A)(50ul/bacteria in saline). After 12h, lung mechanics and bronchoalveolar lavage (BAL) were performed. Animals were euthanized, lungs removed for immunohistochemistry and morphometric analysis. Results: Challenge with Spn in OVA sensitized group induces an increase in of total cells (46.33±13.22x104cells/mL), neutrophils (23.70±14.39x104cells/mL), macrophages (7.70±2.03x104cells/mL) and eosinophils (14.52±13.88x104cells/mL) in BALF as well as increasing in polymorphonuclear cells (0.152±0.06mm2) and expression of IL-17 (12.12±2.67mm2) in peribronchovascular area in lung compared to OVA group (p<0.05). There were an increase in tissue damping (27.01±7.25cmH2O/mL/s(1-a)); expression of IL-5 (10.15±3.39mm2) and IL-13 (8.85±3.56mm2) in peribronchovascular area were observed in OVA groups compared to other groups (p<0.05). Conclusion: Challenge with Spn, in this model induces an increasing in lung inflammation by increasing IL-17 without changes in Th2 profile.

Inflammatory response to Streptococcus pneumoniae was attenuated by moderate aerobic exercise training

Moderate aerobic exercise training may alter immune system. Studies suggested that S. pneumoniae remained an important cause of mortality. Objective: To study mechanisms for attenuating inflammatory process involving pneumococcal infection by moderate aerobic exercise. Methods: 38Balb/C mice were divided into 4 groups: Control (C), Moderate Aerobic Exercise Training (MAT), S. pneumonia infection (IF), MAT+IF groups. Moderate intensity treadmill training was performed over 4weeks, 5x/week, 60min/session in MAT groups. After 72h of last exercise training, IF groups were challenged with pneumococcal strains M10 (11A; 50ul/bacteria in saline) and 12h after, lung function and bronchoalveolar lavage (BAL) were performed. Afterwards, animals were euthanized, lungs removed to proceed immunohistochemistry and morphometric analysis in lung parenchyma. Results: Bacterial inoculation resulted in increase in: total cells (77.66±54.02x104cells/mL), neutrophils (73.78±50.88x104cells/mL), resistance (0.77±0.08cmH2O.mL-1.s;) and elastance (31.86±8.16cmH2O.mL-1.s) of respiratory system and expression of IL-17 (817.88±217.59mm2)(p<0.05). MAT in animals submitted to bacterial challenge presented a decrease of these parameters (p<0.05). MAT+IF group showed an increase in expression of IL-1ra (886.04±274.07mm2), TLR2 (708.28±161.48mm2) and TLR4 (1444.11±723.92mm2) compared to IF group (p<0.05). Conclusion: These results suggest that MAT attenuated inflammatory process in an animal model of bacterial infection by increasing anti-inflammatory mediators, increasing Toll-like receptors that anticipated host defense, helping in resolution of inflammation.

High intensity interval training control inflammation in mice exposed to Streptococus pneumoniae

S.pneumoniae is an important cause of pneumonia. Exercise training is a stimulator of immune system. High Intensity Interval Training (HIIT) have been gain adepts, although their benefits remain unclear. Objective: Evaluate if HIIT prior to S.pneumoniae infection in mice alters lung inflammation. Methods: 38Balb/C mice were divided into 4 groups: Sedentary (SED),HIIT (HIIT), Infection (IF),HIIT+infection (HIIT/IF). HIIT was performed in a treadmill altering 26 session: 1min of 75%¨maximum capacity training and 30s of 50% maximum capacity training, over 4w, 5x/w. 72h after last training, IF groups were challenged with pneumococcal strains M10 (11A)(50 ul/bacteria in saline).Lung function and bronchoalveolar lavage (BAL) were performed 12h after challenge. Afterwards, animals were euthanized, lungs removed to immunohistochemistry and morphometric analysis in lung parenchyma. Results: Pneumococcal inoculation induces an increase in lung resistance (0.74±0.07cmH2O.mL-1.s) and elastance (31.86±8.16 cmH2O.mL-1.s) of respiratory system, in total cells (77.66±54.02x104cells/mL) and neutrophils (73.47±50.88x104cells/mL) in BALF, expression of IL-17 (817.88±217.59mm2) and collagen fibers content in lung parenchyma (17.24±4.54%) (p<0.05). HIIT in inoculated animals resulted in a reduction of all parameters (p<0.05), except for lung resistance. HIIT groups presented increasing expression of IL-1ra (698.64±432.42mm2), CuZnSOD (576.42±138.18mm2), IL-33 (990.07±212.47mm2)(p<0.001). Conclusion: HIIT attenuated inflammatory process induced by S.pneumoniae, increasing antiinflammatory mediators and antioxidant enzymes, reducing proinflammatory mediators.

Author Correction: Effects of the serine protease inhibitor rBmTI-A in an experimental mouse model of chronic allergic pulmonary inflammation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Effects of the serine protease inhibitor rBmTI-A in an experimental mouse model of chronic allergic pulmonary inflammation.

To evaluate whether a recombinant serine protease inhibitor (rBmTI-A) modulates inflammation in an experimental model of chronic allergic lung inflammation. Balb/c mice were divided into four groups: SAL (saline), OVA (sensitized with ovalbumin), SAL + rBmTI-A (control treated with rBmTI-A) and OVA + rBmTI-A (sensitized with ovalbumin and treated with rBmTI-A). The animals received an intraperitoneal injection of saline or ovalbumin, according to the group. The groups received inhalation with saline or ovalbumin and were treated with rBmTI-A or saline by nasal instillation. After 29 days, we evaluated the respiratory mechanics; bronchoalveolar lavage fluid (BALF); cytokines; MMP-9, TIMP-1; eosinophils; collagen and elastic fibre expression in the airways; and the trypsin-like, MMP-1, and MMP-9 lung tissue proteolytic activity. Treatment with rBmTI-A reduced the trypsin-like proteolytic activity, the elastance and resistance maximum response, the polymorphonuclear cells, IL-5, IL-10, IL-13 and IL-17A in the BALF, the expression of IL-5, IL-13, IL-17, CD4+, MMP-9, TIMP-1, eosinophils, collagen and elastic fibres in the airways of the OVA + rBmTI-A group compared to the OVA group (p < 0.05). rBmTI-A attenuated bronchial hyperresponsiveness, inflammation and remodelling in this experimental model of chronic allergic pulmonary inflammation. This inhibitor may serve as a potential therapeutic tool for asthma treatment.

The Th17/Treg Cytokine Imbalance in Chronic Obstructive Pulmonary Disease Exacerbation in an Animal Model of Cigarette Smoke Exposure and Lipopolysaccharide Challenge Association.

We proposed an experimental model to verify the Th17/Treg cytokine imbalance in COPD exacerbation. Forty C57BL/6 mice were exposed to room air or cigarette smoke (CS) (12 ± 1 cigarettes, twice a day, 30 min/exposure and 5 days/week) and received saline (50 µl) or lipopolysaccharide (LPS) (1 mg/kg in 50 µl of saline) intratracheal instillations. We analyzed the mean linear intercept, epithelial thickness and inflammatory profiles of the bronchoalveolar lavage fluid and lungs. We evaluated macrophages, neutrophils, CD4+ and CD8+ T cells, Treg cells, and IL-10+ and IL-17+ cells, as well as STAT-3, STAT-5, phospho-STAT3 and phospho-STAT5 levels using immunohistochemistry and IL-17, IL-6, IL-10, INF-γ, CXCL1 and CXCL2 levels using ELISA. The study showed that CS exposure and LPS challenge increased the numbers of neutrophils, macrophages, and CD4+ and CD8+ T cells. Simultaneous exposure to CS/LPS intensified this response and lung parenchymal damage. The densities of Tregs and IL-17+ cells and levels of IL-17 and IL-6 were increased in both LPS groups, while IL-10 level was only increased in the Control/LPS group. The increased numbers of STAT-3, phospho-STAT3, STAT-5 and phospho-STAT5+ cells corroborated the increased numbers of IL-17+ and Treg cells. These findings point to simultaneous challenge with CS and LPS exacerbated the inflammatory response and induced diffuse structural changes in the alveolar parenchyma characterized by an increase in Th17 cytokine release. Although the Treg cell differentiation was observed, the lack of IL-10 expression and the decrease in the density of IL-10+ cells observed in the CS/LPS group suggest that a failure to release this cytokine plays a pivotal role in the exacerbated inflammatory response in this proposed model.

Effect of Anti-IL17 Antibody Treatment Alone and in Combination With Rho-Kinase Inhibitor in a Murine Model of Asthma.

Background: Interleukin-17 (IL-17) and Rho-kinase (ROCK) play an important role in regulating the expression of inflammatory mediators, immune cell recruitment, hyper-responsiveness, tissue remodeling, and oxidative stress. Modulation of IL-17 and ROCK proteins may represent a promising approach for the treatment of this disease. Objective: To study the effects of an anti-IL17 neutralizing antibody and ROCK inhibitor treatments, separately and in combination, in a murine model of chronic allergy-induced lung inflammation. Methods: Sixty-four BALBc mice, were divided into eight groups (n = 8): SAL (saline-instilled); OVA (exposed-ovalbumin); SAL-RHOi (saline and ROCK inhibitor), OVA-RHOi (exposed-ovalbumin and ROCK inhibitor); SAL-anti-IL17 (saline and anti-IL17); OVA-anti-IL17 (exposed-ovalbumin and anti-IL17); SAL-RHOi-anti-IL17 (saline, ROCK inhibitor and anti-IL17); and OVA-RHOi-anti-IL17 (exposed-ovalbumin, anti-IL17, and ROCK inhibitor). A 28-day protocol of albumin treatment was used for sensitization and induction of pulmonary inflammation. The anti-IL17A neutralizing antibody (7.5 µg per treatment) was administered by intraperitoneal injection and ROCK inhibitor (Y-27632) intranasally (10 mg/kg), 1 h prior to each ovalbumin challenge (days 22, 24, 26, and 28). Results: Treatment with the anti-IL17 neutralizing antibody and ROCK inhibitor attenuated the percentage of maximal increase of respiratory system resistance and respiratory system elastance after challenge with methacholine and the inflammatory response markers evaluated (CD4+, CD8+, ROCK1, ROCK2, IL-4, IL-5, IL-6, IL-10 IL-13, IL-17, TNF-α, TGF-ß, NF-κB, dendritic cells, iNOS, MMP-9, MMP-12, TIMP-1, FOXP3, isoprostane, biglycan, decorin, fibronectin, collagen fibers content and gene expression of IL-17, VAChT, and arginase) compared to the OVA group (p < 0.05). Treatment with anti-IL17 and the ROCK inhibitor together resulted in potentiation in decreasing the percentage of resistance increase after challenge with methacholine, decreased the number of IL-5 positive cells in the airway, and reduced, IL-5, TGF-ß, FOXP3, ROCK1 and ROCK2 positive cells in the alveolar septa compared to the OVA-RHOi and OVA-anti-IL17 groups (p < 0.05). Conclusion: Anti-IL17 treatment alone or in conjunction with the ROCK inhibitor, modulates airway responsiveness, inflammation, tissue remodeling, and oxidative stress in mice with chronic allergic lung inflammation.

Can inflammatory markers in induced sputum be used to detect phenotypes and endotypes of pediatric severe therapy-resistant asthma?

BACKGROUND: The phenotypes and endotypes of severe therapy-resistant asthma (STRA) have not been fully elucidated in children. The aim of the present study was to investigate inflammatory markers in the induced sputum of children with STRA and to compare them with those present in a group of children who achieved control. METHODS: A prospective cohort of children (6-18 years of age) diagnosed with severe asthma (GINA criteria) who had undergone treatment for at least 6 months was comprehensively followed for 3 months. Inhalation technique, adherence to treatment, ACT score, and main comorbidities were assessed. Induced sputum samples were collected for cytology analysis and quantitative assessment of cytokines; the participants also underwent spirometry, plethysmography, and fractional exhaled nitric oxide (FeNO) measurement. RESULTS: Forty patients were included (average age 12.8 years; 62.5% male); of these, 13 (32.5%) were classified as STRA at the end of follow-up. There were no significant differences between the STRA and control groups in demographic data, functional test results, or FeNO levels. The eosinophilic inflammatory pattern predominated in both groups; however, the STRA group showed a proportionally higher percentage of sputum neutrophils (P < 0.05). The median sputum levels of the cytokines IL-10, GM-CSF, IFN-γ, and TNF-α were significantly higher in the STRA group (P < 0.05). GM-CSF and TNF-α levels showed inverse correlations with ACT scores. CONCLUSION: The presence of neutrophils, the cytokines IL-10, and IFN-γ and, more particularly, TNF-α, and GM-CSF in the sputum may play an important role in the pathophysiological mechanism of STRA in children and adolescents. Specific antagonists for these cytokines may represent a future therapeutic strategy.

Prophylactic and therapeutic treatment with the flavonone sakuranetin ameliorates LPS-induced acute lung injury.

Sakuranetin is the main isolate flavonoid from Baccharis retusa (Asteraceae) leaves and exhibits anti-inflammatory and antioxidative activities. Acute respiratory distress syndrome is an acute failure of the respiratory system for which effective treatment is urgently necessary. This study investigated the preventive and therapeutic effects of sakuranetin on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. Animals were treated with intranasal sakuranetin 30 min before or 6 h after instillation of LPS. Twenty-four hours after ALI was induced, lung function, inflammation, macrophages population markers, collagen fiber deposition, the extent of oxidative stress, and the expression of matrix metalloprotease-9 (MMP-9), tissue inhibitor of MMP-9 (TIMP-1) and NF-κB were evaluated. The animals began to show lung alterations 6 h after LPS instillation, and these changes persisted until 24 h after LPS administration. Preventive and therapeutic treatment with sakuranetin reduced the neutrophils in the peripheral blood and in the bronchial alveolar lavage. Sakuranetin treatment also reduced macrophage populations, particularly that of M1-like macrophages. In addition, sakurnaetin treatment reduced keratinocyte-derived chemokines (IL-8 homolog) and NF-κB levels, collagen fiber formation, MMM-9 and TIMP-1-positive cells, and oxidative stress in lung tissues compared with LPS animals treated with vehicle. Finally, sakuranetin treatment also reduced total protein, and the levels of TNF-α and IL-1ß in the lung. This study shows that sakuranetin prevented and reduced pulmonary inflammation induced by LPS. Because sakuranetin modulates oxidative stress, the NF-κB pathway, and lung function, it may constitute a novel therapeutic candidate to prevent and treat ALI.

A randomized, controlled, crossover study in patients with mild and moderate asthma undergoing treatment with traditional Chinese acupuncture.

OBJECTIVES: This study sought to verify the effects of acupuncture as an adjuvant treatment for the control of asthma. METHODS: This was a randomized, controlled, crossover trial conducted at the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. A total of 74 patients with mild/moderate, persistent asthma were randomized into two therapeutic groups: Group A - 31 patients underwent 10 real weekly acupuncture sessions, followed by a 3-week washout period and 10 sham weekly acupuncture sessions; and Group B - 43 patients underwent 10 sham weekly acupuncture sessions, followed by a 3-week washout period and 10 real weekly acupuncture sessions. Patients used short- and long-acting ß-2 agonists and inhaled corticosteroids when necessary. Prior to treatment and after each period of 10 treatment sessions, the patients were evaluated for spirometry, induced sputum cell count, exhaled nitric oxide (NO) and with the Short Form 36 (SF-36) and Questionnaire on Quality of Life-Asthma (QQLA) questionnaires. Daily peak flow and symptom diaries were registered. The level of significance adopted was 5% (α=0.05). RESULTS: In Group B, after real acupuncture, there was a decrease in eosinophils (p=0.035) and neutrophils (p=0.047), an increase in macrophages (p=0.001) and an improvement in peak flow (p=0.01). After sham acupuncture treatment, patients experienced less coughing (p=0.037), wheezing (p=0.013) and dyspnea (p=0.014); similarly, after real acupuncture, patients reported less coughing (p=0.040), wheezing (p=0.012), dyspnea (p<0.001) and nocturnal awakening episodes (p=0.009). In Group A, there was less use of rescue medication (p=0.043). After the sham procedure, patients in Group A experienced less coughing (p=0.007), wheezing (p=0.037), dyspnea (p<0.001) and use of rescue medication (p<0.001) and after real acupuncture, these patients showed improvements in functional capacity (p=0.004), physical aspects (p=0.002), general health status (p<0.001) and vitality (p=0.019). Sham acupuncture also led to significant differences in symptoms, but these were not different from those seen with real acupuncture. Spirometry and exhaled NO levels did not show a difference between sham and real acupuncture treatment. In addition, no significant difference was demonstrated between treatments regarding the quality of life evaluation. CONCLUSION: Real and sham acupuncture have different effects and outcomes on asthma control. The crossover approach was not effective in this study because both interventions led to improvement of asthma symptoms, quality of life and inflammatory cell counts. Thus, sham acupuncture cannot serve as a placebo in trials with acupuncture as the main intervention for asthma.

A randomized, controlled, crossover study in patients with mild and moderate asthma undergoing treatment with traditional Chinese acupuncture

OBJECTIVES:This study sought to verify the effects of acupuncture as an adjuvant treatment for the control of asthma.METHODS:This was a randomized, controlled, crossover trial conducted at the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. A total of 74 patients with mild/moderate, persistent asthma were randomized into two therapeutic groups: Group A - 31 patients underwent 10 real weekly acupuncture sessions, followed by a 3-week washout period and 10 sham weekly acupuncture sessions; and Group B - 43 patients underwent 10 sham weekly acupuncture sessions, followed by a 3-week washout period and 10 real weekly acupuncture sessions. Patients used short- and long-acting β-2 agonists and inhaled corticosteroids when necessary. Prior to treatment and after each period of 10 treatment sessions, the patients were evaluated for spirometry, induced sputum cell count, exhaled nitric oxide (NO) and with the Short Form 36 (SF-36) and Questionnaire on Quality of Life-Asthma (QQLA) questionnaires. Daily peak flow and symptom diaries were registered. The level of significance adopted was 5% (α=0.05).RESULTS:In Group B, after real acupuncture, there was a decrease in eosinophils (p=0.035) and neutrophils (p=0.047), an increase in macrophages (p=0.001) and an improvement in peak flow (p=0.01). After sham acupuncture treatment, patients experienced less coughing (p=0.037), wheezing (p=0.013) and dyspnea (p=0.014); similarly, after real acupuncture, patients reported less coughing (p=0.040), wheezing (p=0.012), dyspnea (p<0.001) and nocturnal awakening episodes (p=0.009). In Group A, there was less use of rescue medication (p=0.043). After the sham procedure, patients in Group A experienced less coughing (p=0.007), wheezing (p=0.037), dyspnea (p<0.001) and use of rescue medication (p<0.001) and after real acupuncture, these patients showed improvements in functional capacity (p=0.004), physical aspects (p=0.002), general health status (p<0.001) and vitality (p=0.019). Sham acupuncture also led to significant differences in symptoms, but these were not different from those seen with real acupuncture. Spirometry and exhaled NO levels did not show a difference between sham and real acupuncture treatment. In addition, no significant difference was demonstrated between treatments regarding the quality of life evaluation.CONCLUSION:Real and sham acupuncture have different effects and outcomes on asthma control. The crossover approach was not effective in this study because both interventions led to improvement of asthma symptoms, quality of life and inflammatory cell counts. Thus, sham acupuncture cannot serve as a placebo in trials with acupuncture as the main intervention for asthma.

Aerobic training decreases bronchial hyperresponsiveness and systemic inflammation in patients with moderate or severe asthma: a randomised controlled trial.

BACKGROUND: The benefits of aerobic training for the main features of asthma, such as bronchial hyperresponsiveness (BHR) and inflammation, are poorly understood. We investigated the effects of aerobic training on BHR (primary outcome), serum inflammatory cytokines (secondary outcome), clinical control and asthma quality of life (Asthma Quality of Life Questionnaire (AQLQ)) (tertiary outcomes). METHODS: Fifty-eight patients were randomly assigned to either the control group (CG) or the aerobic training group (TG). Patients in the CG (educational programme+breathing exercises (sham)) and the TG (same as the CG+aerobic training) were followed for 3 months. BHR, serum cytokine, clinical control, AQLQ, induced sputum and fractional exhaled nitric oxide (FeNO) were evaluated before and after the intervention. RESULTS: After 12 weeks, 43 patients (21 CG/22 TG) completed the study and were analysed. The TG improved in BHR by 1 doubling dose (dd) (95% CI 0.3 to 1.7 dd), and they experienced reduced interleukin 6 (IL-6) and monocyte chemoattractant protein 1 (MCP-1) and improved AQLQ and asthma exacerbation (p<0.05). No effects were seen for IL-5, IL-8, IL-10, sputum cellularity, FeNO or Asthma Control Questionnaire 7 (ACQ-7; p>0.05). A within-group difference was found in the ACQ-6 for patients with non-well-controlled asthma and in sputum eosinophil and FeNO in patients in the TG who had worse airway inflammation. CONCLUSIONS: Aerobic training reduced BHR and serum proinflammatory cytokines and improved quality of life and asthma exacerbation in patients with moderate or severe asthma. These results suggest that adding exercise as an adjunct therapy to pharmacological treatment could improve the main features of asthma. TRIAL REGISTRATION NUMBER: NCT02033122.

Collagenase mRNA Overexpression and Decreased Extracellular Matrix Components Are Early Events in the Pathogenesis of Emphysema.

To describe the progression of parenchymal remodeling and metalloproteinases gene expression in earlier stages of emphysema, mice received porcine pancreatic elastase (PPE) instillation and Control groups received saline solution. After PPE instillation (1, 3, 6 hours, 3 and 21 days) we measured the mean linear intercept, the volume proportion of types I and III collagen, elastin, fibrillin and the MMP-1, -8, -12 and -13 gene expression. We observed an initial decrease in type I (at the 3rd day) and type III collagen (from the 6th hour until the 3rd day), in posterior time points in which we detected increased gene expression for MMP-8 and -13 in PPE groups. After 21 days, the type III collagen fibers increased and the type I collagen values returned to similar values compared to control groups. The MMP-12 gene expression was increased in earlier times (3 and 6 hours) to which we detected a reduced proportion of elastin (3 days) in PPE groups, reinforcing the already established importance of MMP-12 in the breakdown of ECM. Such findings will be useful to better elucidate the alterations in ECM components and the importance of not only metalloelastase but also collagenases in earlier emphysema stages, providing new clues to novel therapeutic targets.

Respiratory rehabilitation: a physiotherapy approach to the control of asthma symptoms and anxiety.

OBJECTIVES: The objectives of this study were to verify the degree of anxiety, respiratory distress, and health-related quality of life in a group of asthmatic patients who have experienced previous panic attacks. Additionally, we evaluated if a respiratory physiotherapy program (breathing retraining) improved both asthma and panic disorder symptoms, resulting in an improvement in the health-related quality of life of asthmatics. METHODS: Asthmatic individuals were assigned to a chest physiotherapy group that included a breathing retraining program held once a week for three months or a paired control group that included a Subtle Touch program. All patients were assessed using the Diagnostic and Statistical Manual of Mental Disorders IV, the Sheehan Anxiety Scale, the Quality of Life Questionnaire, and spirometry parameter measurements. RESULTS: Both groups had high marks for panic disorder and agoraphobia, which limited their quality of life. The Breathing Retraining Group program improved the clinical control of asthma, reduced panic symptoms and agoraphobia, decreased patient scores on the Sheehan Anxiety Scale, and improved their quality of life. Spirometry parameters were unchanged. CONCLUSION: Breathing retraining improves the clinical control of asthma and anxiety symptoms and the health-related quality of life in asthmatic patients.

Respiratory rehabilitation: a physiotherapy approach to the control of asthma symptoms and anxiety

OBJECTIVES: The objectives of this study were to verify the degree of anxiety, respiratory distress, and health-related quality of life in a group of asthmatic patients who have experienced previous panic attacks. Additionally, we evaluated if a respiratory physiotherapy program (breathing retraining) improved both asthma and panic disorder symptoms, resulting in an improvement in the health-related quality of life of asthmatics. METHODS: Asthmatic individuals were assigned to a chest physiotherapy group that included a breathing retraining program held once a week for three months or a paired control group that included a Subtle Touch program. All patients were assessed using the Diagnostic and Statistical Manual of Mental Disorders IV, the Sheehan Anxiety Scale, the Quality of Life Questionnaire, and spirometry parameter measurements. RESULTS: Both groups had high marks for panic disorder and agoraphobia, which limited their quality of life. The Breathing Retraining Group program improved the clinical control of asthma, reduced panic symptoms and agoraphobia, decreased patient scores on the Sheehan Anxiety Scale, and improved their quality of life. Spirometry parameters were unchanged. CONCLUSION: Breathing retraining improves the clinical control of asthma and anxiety symptoms and the health-related quality of life in asthmatic patients.

Cigarette smoke dissociates inflammation and lung remodeling in OVA-sensitized and challenged mice.

We evaluated the effects of cigarette smoke (CS) on lung inflammation and remodeling in a model of ovalbumin (OVA)-sensitized and OVA-challenged mice. Male BALB/c mice were divided into 4 groups: non-sensitized and air-exposed (control); non-sensitized and exposed to cigarette smoke (CS), sensitized and air-exposed (OVA) (50 µg+OVA 1% 3 times/week for 3 weeks) and sensitized and cigarette smoke exposed mice (OVA+CS). IgE levels were not affected by CS exposure. The increases in total bronchoalveolar fluid cells in the OVA group were attenuated by co-exposure to CS, as were the changes in IL-4, IL-5, and eotaxin levels as well as tissue elastance (p<0.05). In contrast, only the OVA+CS group showed a significant increase in the protein expression of IFN-γ, VEGF, GM-CSF and collagen fiber content (p<0.05). In our study, exposure to cigarette smoke in OVA-challenged mice resulted in an attenuation of pulmonary inflammation but led to an increase in pulmonary remodeling and resulted in the dissociation of airway inflammation from lung remodeling.

Effects of aerobic training on psychosocial morbidity and symptoms in patients with asthma: a randomized clinical trial.

BACKGROUND: Asthma symptoms reduce patients' daily activities, impair their health-related quality of life (HRQoL), and increase their reports of anxiety and depression, all of which seem to be related to a decrease in asthma control. Aerobic exercise training is known to improve aerobic fitness and reduce dyspnea in asthmatics; however, its effect in reducing psychologic distress and symptoms remains poorly understood. We evaluated the role of an aerobic training program in improving HRQoL (primary aim) and reducing psychologic distress and asthma symptoms (secondary aims) for patients with moderate or severe persistent asthma. METHODS: A total of 101 patients were randomly assigned to either a control group or an aerobic training group and studied during the period between medical consultations. Control group patients (educational program plus breathing exercises) (n = 51) and training group patients (educational program plus breathing exercises plus aerobic training) (n = 50) were followed twice a week during a 3-month period. HRQoL and levels of anxiety and depression were quantified before and after treatment. Asthma symptoms were evaluated monthly. RESULTS: At 3 months, the domains (physical limitations, frequency of symptoms, and psychosocial) and total scores of HRQoL significantly improved only in the training group patients (P < .001); the number of asthma-symptom-free days and anxiety and depression levels also significantly improved in this group (P < .001). In addition, a linear relationship between improvement in aerobic capacity and the days without asthma symptoms was observed (r = 0.47; P < .01). CONCLUSIONS: Our results suggest that aerobic training can play an important role in the clinical management of patients with persistent asthma. Further, they may be especially useful for patients with higher degrees of psychosocial distress. TRIAL REGISTRATION: clinicaltrials.gov; Identifier: NCT-00989365.

Non-asthmatic patients show increased exhaled nitric oxide concentrations.

OBJECTIVE: Evaluate whether exhaled nitric oxide may serve as a marker of intraoperative bronchospasm. INTRODUCTION: Intraoperative bronchospasm remains a challenging event during anesthesia. Previous studies in asthmatic patients suggest that exhaled nitric oxide may represent a noninvasive measure of airway inflammation. METHODS: A total of 146,358 anesthesia information forms, which were received during the period from 1999 to 2004, were reviewed. Bronchospasm was registered on 863 forms. From those, three groups were identified: 9 non-asthmatic patients (Bronchospasm group), 12 asthmatics (Asthma group) and 10 subjects with no previous airway disease or symptoms (Control group). All subjects were submitted to exhaled nitric oxide measurements (parts/billion), spirometry and the induced sputum test. The data was compared by ANOVA followed by the Tukey test and Kruskal-Wallis followed by Dunn's test. RESULTS: The normal lung function test results for the Bronchospasm group were different from those of the asthma group (p <0.05). The median percentage of eosinophils in induced sputum was higher for the Asthma [2.46 (0.45-6.83)] compared with either the Bronchospasm [0.55 (0-1.26)] or the Control group [0.0 (0)] (p <0.05); exhaled nitric oxide followed a similar pattern for the Asthma [81.55 (57.6-86.85)], Bronchospasm [46.2 (42.0 -62.6] and Control group [18.7 (16.0-24.7)] (p< 0.05). CONCLUSIONS: Non-asthmatic patients with intraoperative bronchospasm detected during anesthesia and endotracheal intubation showed increased expired nitric oxide.