Effect of obesity on airway and systemic inflammation in adults with asthma: a systematic review and meta-analysis.

BACKGROUND: Obesity is associated with more severe asthma, however, the mechanisms responsible are poorly understood. Obesity is also associated with low-grade systemic inflammation; it is possible that this inflammation extends to the airways of adults with asthma, contributing to worse asthma outcomes. Accordingly, the aim of this review was to examine whether obesity is associated with increased airway and systemic inflammation and adipokines, in adults with asthma. METHODS: Medline, Embase, CINAHL, Scopus and Current Contents were searched till 11 August 2021. Studies reporting measures of airway inflammation, systemic inflammation and/or adipokines in obese versus non-obese adults with asthma were assessed. We conducted random effects meta-analyses. We assessed heterogeneity using the I2 statistic and publication bias using funnel plots. RESULTS: We included 40 studies in the meta-analysis. Sputum neutrophils were 5% higher in obese versus non-obese asthmatics (mean difference (MD)=5.0%, 95% CI: 1.2 to 8.9, n=2297, p=0.01, I2=42%). Blood neutrophil count was also higher in obesity. There was no difference in sputum %eosinophils; however, bronchial submucosal eosinophil count (standardised mean difference (SMD)=0.58, 95% CI=0.25 to 0.91, p<0.001, n=181, I2=0%) and sputum interleukin 5 (IL-5) (SMD=0.46, 95% CI=0.17 to 0.75, p<0.002, n=198, I2=0%) were higher in obesity. Conversely, fractional exhaled nitric oxide was 4.5 ppb lower in obesity (MD=-4.5 ppb, 95% CI=-7.1 ppb to -1.8 ppb, p<0.001, n=2601, I2=40%). Blood C reactive protein, IL-6 and leptin were also higher in obesity. CONCLUSIONS: Obese asthmatics have a different pattern of inflammation to non-obese asthmatics. Mechanistic studies examining the pattern of inflammation in obese asthmatics are warranted. Studies should also investigate the clinical relevance of this altered inflammatory response. PROSPERO REGISTERATION NUMBER: CRD42021254525.

Relationship between type 2 cytokine and inflammasome responses in obesity-associated asthma.

BACKGROUND: Obesity is a risk factor for asthma, and obese asthmatic individuals are more likely to have severe, steroid-insensitive disease. How obesity affects the pathogenesis and severity of asthma is poorly understood. Roles for increased inflammasome-mediated neutrophilic responses, type 2 immunity, and eosinophilic inflammation have been described. OBJECTIVE: We investigated how obesity affects the pathogenesis and severity of asthma and identified effective therapies for obesity-associated disease. METHODS: We assessed associations between body mass index and inflammasome responses with type 2 (T2) immune responses in the sputum of 25 subjects with asthma. Functional roles for NLR family, pyrin domain-containing (NLRP) 3 inflammasome and T2 cytokine responses in driving key features of disease were examined in experimental high-fat diet-induced obesity and asthma. RESULTS: Body mass index and inflammasome responses positively correlated with increased IL-5 and IL-13 expression as well as C-C chemokine receptor type 3 expression in the sputum of subjects with asthma. High-fat diet-induced obesity resulted in steroid-insensitive airway hyperresponsiveness in both the presence and absence of experimental asthma. High-fat diet-induced obesity was also associated with increased NLRP3 inflammasome responses and eosinophilic inflammation in airway tissue, but not lumen, in experimental asthma. Inhibition of NLRP3 inflammasome responses reduced steroid-insensitive airway hyperresponsiveness but had no effect on IL-5 or IL-13 responses in experimental asthma. Depletion of IL-5 and IL-13 reduced obesity-induced NLRP3 inflammasome responses and steroid-insensitive airway hyperresponsiveness in experimental asthma. CONCLUSION: We found a relationship between T2 cytokine and NLRP3 inflammasome responses in obesity-associated asthma, highlighting the potential utility of T2 cytokine-targeted biologics and inflammasome inhibitors.

An altered sputum macrophage transcriptome contributes to the neutrophilic asthma endotype.

BACKGROUND: Neutrophilic asthma (NA) is a clinically important asthma phenotype, the cellular and molecular basis of which is not completely understood. Airway macrophages are long-lived immune cells that exert important homeostatic and inflammatory functions which are dysregulated in asthma. Unique transcriptomic programmes reflect varied macrophage phenotypes in vitro. We aimed to determine whether airway macrophages are transcriptomically altered in NA. METHODS: We performed RNASeq analysis on flow cytometry-isolated sputum macrophages comparing NA (n = 7) and non-neutrophilic asthma (NNA, n = 13). qPCR validation of RNASeq results was performed (NA n = 13, NNA n = 23). Pathway analysis (PANTHER, STRING) of differentially expressed genes (DEGs) was performed. Gene set variation analysis (GSVA) was used to test for enrichment of NA macrophage transcriptomic signatures in whole sputum microarray (cohort 1 - controls n = 16, NA n = 29, NNA n = 37; cohort 2 U-BIOPRED - controls n = 16, NA n = 47, NNA n = 57). RESULTS: Flow cytometry-sorting significantly enriched sputum macrophages (99.4% post-sort, 44.9% pre-sort, p < .05). RNASeq analysis confirmed macrophage purity and identified DEGs in NA macrophages. Selected DEGs (SLAMF7, DYSF, GPR183, CSF3, PI3, CCR7, all p < .05 NA vs. NNA) were confirmed by qPCR. Pathway analysis of NA macrophage DEGs was consistent with responses to bacteria, contribution to neutrophil recruitment and increased expression of phagocytosis and efferocytosis factors. GSVA demonstrated neutrophilic macrophage gene signatures were significantly enriched in whole sputum microarray in NA vs. NNA and controls in both cohorts. CONCLUSIONS: We demonstrate a pathophysiologically relevant sputum macrophage transcriptomic programme in NA. The finding that there is transcriptional activation of inflammatory programmes in cell types other than neutrophils supports the concept of NA as a specific endotype.

Neutrophilic asthma features increased airway classical monocytes.

BACKGROUND: Monocytes and macrophages are critical innate immune cells of the airways. Despite their differing functions, few clinical studies discriminate between them and little is known about their regulation in asthma. OBJECTIVE: We aimed to distinguish and quantify macrophages, monocytes and monocyte subsets in induced sputum and blood and examine their relationship with inflammatory and clinical features of asthma. METHODS: We applied flow cytometry to distinguish macrophages, monocytes and subsets in sputum and blood (n = 53; 45 asthma, 8 non-asthma) and a second asthma sputum cohort (n = 26). Monocyte subsets were identified by surface CD14/CD16 (CD14++ CD16- classical, CD14+ CD16+ intermediate and CD14+ CD16++ non-classical monocytes). Surface CD206, a marker of monocyte tissue differentiation, was measured in sputum. Relationship to airway inflammatory phenotype (neutrophilic n = 9, eosinophilic n = 14, paucigranulocytic n = 22) and asthma severity (severe n = 12, non-severe n = 33) was assessed. RESULTS: Flow cytometry- and microscope-quantified sputum differential cell proportions were significantly correlated. Sputum macrophage number was reduced (p = .036), while classical monocyte proportion was increased in asthma vs non-asthma (p = .032). Sputum classical monocyte number was significantly higher in neutrophilic vs paucigranulocytic asthma (p = .013). CD206- monocyte proportion and number were increased in neutrophilic vs eosinophilic asthma (p < .001, p = .013). Increased sputum classical and CD206- monocyte numbers in neutrophilic asthma were confirmed in the second cohort. Blood monocytes did not vary with airway inflammatory phenotype, but blood classical monocyte proportion and number were increased in severe vs non-severe asthma (p = .022, p = .011). CONCLUSION AND CLINICAL RELEVANCE: Flow cytometry allowed distinction of sputum macrophages, monocytes and subsets, revealing compartment-specific dysregulation of monocytes in asthma. We observed an increase in classical and CD206- monocytes in sputum in neutrophilic asthma, suggesting co-recruitment of monocytes and neutrophils to the airways in asthma. Our data suggest further investigation of how airway monocyte dysregulation impacts on asthma-related disease activity is merited.

Relationship of sputum mast cells with clinical and inflammatory characteristics of asthma.

BACKGROUND: Mast cells (MCs) are innate immune cells that regulate atopic and non-atopic inflammation in the airways. MCs play a critical role in the pathogenesis of asthma, yet their relationship to airway and systemic inflammation and clinical characteristics of asthma is poorly understood. OBJECTIVE: To quantify MCs in induced sputum samples and understand their relationship to airway and circulatory immune cells, and clinical variables in asthma. METHODS: We employed flow cytometry of sputum samples to quantify MCs, basophils and other immune cells in 51 participants (45 asthma and 6 non-asthma controls). Relationship of MCs to airway (n = 45) and blood (n = 19) immune cells, participant demographics, asthma history, spirometry and airways hyperresponsiveness (AHR) to hypertonic saline was determined by correlation and comparison of cut-off-based sputum MC high vs low participants. RESULTS: Mast cells, basophils and eosinophils were increased in asthma vs non-asthma control sputum. In asthma sputum, MCs, basophils and eosinophils were significantly intercorrelated, and MCs and basophils were elevated in participants with eosinophilic asthma. MCs and basophils, but not eosinophils, correlated with AHR. Sputum MC high asthma was characterized by an increased proportion of participants with uncontrolled asthma and reduced FEV1 and FVC. Trends towards similar clinical associations with elevated MCs were observed in a paucigranulocytic subpopulation (n = 15) lacking airway eosinophilia or neutrophilia. Receiver operator characteristic (ROC) analysis showed peripheral blood eosinophil (PBE) count predicted elevated sputum eosinophils and basophils, but not MCs. CONCLUSIONS AND CLINICAL RELEVANCE: Sputum MCs are elevated in asthma, and their measurement may be useful as they relate to key clinical features of asthma (spirometry, asthma control, AHR). PBE count did not predict airway MC status, suggesting direct measurement of airway MCs by sensitive methods such as flow cytometry should be further developed.

Saturated fatty acids, obesity, and the nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in asthmatic patients.

BACKGROUND: Both obesity and high dietary fat intake activate the nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome. OBJECTIVE: We aimed to examine NLRP3 inflammasome activity in the airways of obese asthmatic patients after macronutrient overload and in immune cells challenged by inflammasome triggers. METHODS: Study 1 was a cross-sectional observational study of nonobese (n = 51) and obese (n = 76) asthmatic adults. Study 2 was a randomized, crossover, acute feeding study in 23 asthmatic adults (n = 12 nonobese and n = 11 obese subjects). Subjects consumed 3 isocaloric meals on 3 separate occasions (ie, saturated fatty acid, n-6 polyunsaturated fatty acid, and carbohydrate) and were assessed at 0 and 4 hours. For Studies 1 and 2, airway inflammation was measured based on sputum differential cell counts, IL-1ß protein levels (ELISA), and sputum cell gene expression (Nanostring nCounter). In Study 3 peripheral blood neutrophils and monocytes were isolated by using Ficoll density gradient and magnetic bead separation and incubated with or without palmitic acid, LPS, or TNF-α for 24 hours, and IL-1ß release was measured (ELISA). RESULTS: In Study 1 NLRP3 and nucleotide oligomerization domain 1 (NOD1) gene expression was upregulated, and sputum IL-1ß protein levels were greater in obese versus nonobese asthmatic patients. In Study 2 the saturated fatty acid meal led to increases in sputum neutrophil percentages and sputum cell gene expression of Toll-like receptor 4 (TLR4) and NLRP3 at 4 hours in nonobese asthmatic patients. In Study 3 neutrophils and monocytes released IL-1ß when challenged with a combination of palmitic acid and LPS or TNF-α. CONCLUSION: The NLRP3 inflammasome is a potential therapeutic target in asthmatic patients. Behavioral interventions that reduce fatty acid exposure, such as weight loss and dietary saturated fat restriction, warrant further exploration.

Role of Obesity in Asthma: Mechanisms and Management Strategies.

PURPOSE OF REVIEW: Obesity is a commonly reported comorbidity in asthma, particularly in severe asthma. Obese asthmatics are highly symptomatic with a poor quality of life, despite using high-dose inhaled corticosteroids. While the clinical manifestations have been documented, the aetiologies of obese-asthma remain unclear. RECENT FINDINGS: Several potential mechanisms have been proposed, including poor diet quality, physical inactivity and consequent accrual of excess adipose tissue. Each of these factors independently activates inflammatory pathways, potentially exerting effects in the airways. Because the origins of obesity are multifactorial, it is now believed there are multiple obese-asthma phenotypes, with varied aetiologies and clinical consequences. In this review, we will describe the clinical implications of obesity in people with asthma, our current understanding of the mechanisms driving this association and describe recently proposed obese-asthma phenotypes. We will then discuss how asthma management is complicated by obesity, and provide graded recommendations for the management of obesity in this population.

Should we treat obesity in COPD? The effects of diet and resistance exercise training.

BACKGROUND AND OBJECTIVE: Obesity is an established risk factor for poor health outcomes, but paradoxically in chronic obstructive pulmonary disease (COPD), it is associated with improved survival and lung function. A major evidence gap exisits to inform treatment recommendations for patients with COPD who are obese. We aimed to determine the effect of weight reduction involving a low-energy diet utilizing a partial meal replacement plan, coupled with resistance exercise training in obese COPD patients. METHODS: In a proof of concept before-after clinical trial, obese (body mass index ≥30 kg/m(2) ) COPD patients received a 12 week weight reduction programme involving meal replacements, dietary counselling by a dietitian and resistance exercise training prescribed and supervised by a physiotherapist. Patients were reviewed face to face by the dietitian and physiotherapist every 2 weeks for counselling. RESULTS: Twenty-eight participants completed the intervention. Mean (standard deviation) body mass index was 36.3 kg/m(2) (4.6) at baseline and reduced by 2.4 kg/m(2) ((1.1) P < 0.0001) after the intervention. Importantly, skeletal muscle mass was maintained. Clinical outcomes improved with weight loss including exercise capacity, health status, dyspnea, strength and functional outcomes. There was also a significant reduction in the body mass index, obstruction, dyspnea and exercise score (BODE). Systemic inflammation measured by C-reactive protein however did not change. CONCLUSION: In obese COPD patients, dietary energy restriction coupled with resistance exercise training results in clinically significant improvements in body mass index, exercise tolerance and health status, whilst preserving skeletal muscle mass. This novel study provides a framework for development of guidelines for the management of obese COPD patients and in guiding future research.

Macrophage activation, age and sex effects of immunometabolism in obese asthma.

Obese asthma is characterised by infiltration of adipose tissue by activated macrophages and mast cells. The aim of this study was to examine the age and sex effects of immunometabolism in obese asthma. Obese and non-obese asthmatic children and adults underwent spirometry, body composition assessment by dual energy X-ray absorptiometry and measurement of serum soluble CD163 (sCD163), tryptase, C-reactive protein (CRP) and other adipocytokines. Plasma CRP (p<0.01) and leptin (p<0.01) were elevated in obese asthmatic adults, and sCD163 (p=0.003) was elevated in obese asthmatic children. We observed significantly higher sCD163 in obese female children compared to obese female adults and male children, and higher CRP in obese female adults compared to obese male children and adults. Serum tryptase concentrations were not significantly different across age groups. sCD163 positively correlated with the proportion of android fat in obese female children (r=0.70, p=0.003) and obese female adults (r=0.65, p=0.003). In obese female children, sCD163 was inversely associated with forced expiratory volume in 1 s % predicted (r=-0.55, p=0.02) and was positively associated with the Asthma Control Questionnaire (r=0.57, p=0.02). Obese children with asthma have sex-specific macrophage activation, which may contribute to worse asthma control and lung function. The heterogeneous systemic inflammatory profile across age and sex suggests the existence of sub-phenotypes in obese asthma at the molecular level.

Acute exercise is associated with reduced exhaled nitric oxide in physically inactive adults with asthma.

BACKGROUND: Although exercise has multiple health benefits, relatively little attention has been paid to its potential therapeutic effects in those with asthma. OBJECTIVE: To examine the effects of acute exercise on inflammation in physically inactive and active adults with asthma. METHODS: Fourteen adults with asthma (n = 6 physically inactive, n = 8 physically active) completed (1) 30 minutes of moderate-intensity exercise on a treadmill and (2) 30 minutes of rest in random order, with 4 weeks between sessions. Exhaled nitric oxide (eNO) was measured before and after the intervention (0, 0.5, 1, 2, 4, and 24 hours). Blood inflammatory mediators were measured before and after the intervention (0, 2, and 24 hours). RESULTS: Physically inactive participants had a significant decrease in eNO 4 hours after exercise (-4.8 ppb, -6.4 to -0.5 ppb, P = .028), which was not observed in physically active participants (P = .362). Interluekin-1 receptor antagonist increased in the physically inactive group 2 hours after exercise, with this increase strongly correlated with the decrease in eNO at 4 hours (R = -0.685, P = .007) and 24 hours (R = -0.659, P = .014) after exercise. Interleukin-6 was increased significantly 2 hours after exercise in physically inactive participants. Blood neutrophils and nuclear factor erythroid 2-like 2 gene expression were increased 2 hours after exercise in the overall cohort. CONCLUSION: This study demonstrates that acute moderate-intensity exercise is associated with decreased eNO in physically inactive adults with asthma and suggests that interluekin-1 receptor antagonist could have a role in mediating this effect. The attenuated response in physically active participants might be due to the sustained anti-inflammatory effects of exercise training. Future studies should investigate the impact of exercise intensity and exercise training on airway inflammation in those with asthma. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au), registration number ACTRN12613001014741.

Determinants of weight loss success utilizing a meal replacement plan and/or exercise, in overweight and obese adults with asthma.

BACKGROUND AND OBJECTIVE: While weight loss has been shown to reduce obesity-related comorbidity, many weight loss treatments fail. Factors that enhance weight loss success are unknown, particularly in those with asthma. The aim of the study was to identify patient characteristics that predict weight loss success in adults with asthma. METHODS: Baseline and change in asthma characteristics and eating behaviours were investigated for relationships with weight loss and fat loss using multiple linear regression, in 38 overweight and obese adults with asthma randomized to dietary, exercise or combined interventions targeting weight loss for 10 weeks. RESULTS: Mean ± standard deviation weight loss was 6.6 ± 5.1 kg. Greater %weight loss and %fat loss was achieved in those with poorer asthma-related quality of life at baseline ((rs = 0.398, P = 0.015) and (rs = 0.455, P = 0.005) respectively), with 1.7% greater absolute weight loss at week 10 corresponding to each one unit reduction in the asthma-related quality of life score at baseline. Furthermore, a lower baseline forced expiratory volume in 1 s/forced vital capacity correlated with greater weight loss (rs = 0.398, P = 0.015). Male sex was associated with a 3.6 kg greater weight loss (P = 0.087). Reducing emotional eating during the programme was associated with greater weight loss in women (rs = 0.576, P = 0.010). CONCLUSIONS: This study demonstrates that individuals with more severe asthma at baseline are more successful in achieving weight loss, which could be a consequence of greater motivation and could be used as a motivational tool within the clinical setting. Gender tailoring of weight loss programmes may be useful to enhance weight loss success. Future studies are urgently needed to establish predictors of long-term weight loss maintenance in those with asthma.

Associations between program outcomes and adherence to Social Cognitive theory tasks: process evaluation of the SHED-IT community weight loss trial for men.

BACKGROUND: Despite rising international rates of obesity, men remain reluctant to participate in weight loss research. There is a lack of evidence to guide the development of effective weight loss interventions that engage men. The objective of this study was to provide a comprehensive process evaluation of the SHED-IT (Self-Help, Exercise and Diet using Information Technology) weight loss program for men, as delivered in the SHED-IT community weight loss trial, and to identify key components associated with success. METHODS: In an assessor-blinded randomised controlled trial, 159 overweight and obese men (BMI 25.0-40.0 kg/m2) were randomised to one of two gender-tailored weight loss interventions with no face-to-face contact, or a control group. The interventions were informed by Bandura's Social Cognitive Theory (SCT) with men encouraged to complete a Support Book containing SCT-based tasks including goal setting, reward setting, creation of social support strategies and self-monitoring of: i) weight, ii) physical activity, and iii) diet. At post-test, compliance with SCT tasks was examined and men also completed a process evaluation questionnaire. RESULTS: Both SHED-IT intervention groups demonstrated greater weight loss during the intervention compared to the control, with no difference between intervention groups. Most men engaged with the SCT tasks although compliance declined over time and utilisation of social support networks and reward selection was poor. In a multiple regression model, the number of goals set (ß [95% CI] = -0.3 [-0.6, -0.1], p = 0.01) and the number of weight records documented (ß [95% CI] = -0.2 [-0.4, -0.0], p = 0.03) independently predicted weight loss. The process evaluation indicated that men found the programs to be supportive, enjoyable and beneficial. CONCLUSIONS: This process evaluation provides valuable information to inform the development of obesity treatment strategies that engage men. Future studies with men should include a strong focus on self-monitoring and goal setting to enhance behaviour change and improve treatment effects. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000699066.

Effects of Moderate- versus Vigorous-Intensity Exercise Training on Asthma Outcomes in Adults.

BACKGROUND: The therapeutic effects of exercise has prompted calls for it to be embedded into standard asthma care, but evidence informing the optimal exercise intensity is lacking. OBJECTIVE: This study aimed to compare the effects of moderate- and vigorous-intensity aerobic exercise training on asthma outcomes and inflammation. METHODS: This was a 12-week randomised controlled trial in 46 adults with asthma randomised to either 1) 45min moderate-intensity exercise training three times/week, 2) 30min vigorous-intensity exercise training three times/week, or 3) control group. Asthma-related quality of life (AQLQ), asthma control (ACQ), cardiorespiratory fitness, body composition, and airway and systemic inflammation were assessed pre- and post-intervention. RESULTS: Forty-one participants completed the study (89% retention). The moderate-intensity group had a statistically and clinically significant improvement in AQLQ [0.63 (0.33 to 0.93) p<0.001) and ACQ [-0.51 (-0.83 to -0.19), p=0.003] relative to control. The vigorous-intensity group had a statistically, but not clinically, significant improvement in AQLQ [0.46 (0.14 to 0.80, p=0.007] and ACQ [-0.36 (-0.69 to -0.02, p=0.040] relative to control. Following moderate-intensity training, there was a reduction in sputum macrophage [-1341 (-2491 to -191)x104/mL, p=0.024] and lymphocyte [-114 (-220 to -8)x104/mL, p=0.036] counts relative to control. A reduction in android fat mass, but not a change in fitness, was associated with improved AQLQ (rs=-0.341, p=0.030) and reduced sputum IL-6 (rs=0.422, p=0.013). CONCLUSION: Our findings suggest that both moderate-intensity and vigorous-intensity aerobic exercise training are associated with improvements in clinical asthma outcomes, and therefore both intensities could be recommended as an adjuvant asthma therapy.

Protein Intake and Physical Activity Levels as Determinants of Sarcopenia Risk in Community-Dwelling Older Adults.

Community screening for sarcopenia is complex, with barriers including access to specialized equipment and trained staff to conduct body composition, strength and function assessment. In the current study, self-reported dietary protein intake and physical activity (PA) in adults ≥65 years was assessed relative to sarcopenia risk, as determined by body composition, strength and physical function assessments, consistent with the European Working Group on Sarcopenia in Older People (EWGSOP) definition. Of those screened (n = 632), 92 participants (77% female) were assessed as being at high risk of developing sarcopenia on the basis of dietary protein intake ≤1 g∙kg-1∙day-1 [0.9 (0.7-0.9) g∙kg-1∙day-1] and moderate intensity physical activity <150 min.week-1. A further 31 participants (65% female) were defined as being at low risk, with both protein intake [1.2 (1.1-1.5) g∙kg-1∙day-1] and PA greater than the cut-off values. High-risk participants had reduced % lean mass [53.5 (7.8)% versus 54.8 (6.1)%, p < 0.001] and impaired strength and physical function. Notably, high-risk females exhibited greater deficits in lean mass and strength, with minimal differences between groups for males. In community-dwelling older adults, self-reported low protein intake and low weekly PA is associated with heightened risk for sarcopenia, particularly in older women. Future research should determine whether early intervention in older adults with low protein intake and PA attenuates functional decline.

Relationship between body composition, inflammation and lung function in overweight and obese asthma.

BACKGROUND: The obese-asthma phenotype is not well defined. The aim of this study was to examine both mechanical and inflammatory influences, by comparing lung function with body composition and airway inflammation in overweight and obese asthma. METHODS: Overweight and obese (BMI 28-40 kg/m(2)) adults with asthma (n = 44) completed lung function assessment and underwent full-body dual energy x-ray absorptiometry. Venous blood samples and induced sputum were analysed for inflammatory markers. RESULTS: In females, android and thoracic fat tissue and total body lean tissue were inversely correlated with expiratory reserve volume (ERV). Conversely in males, fat tissue was not correlated with lung function, however there was a positive association between android and thoracic lean tissue and ERV. Lower body (gynoid and leg) lean tissue was positively associated with sputum %neutrophils in females, while leptin was positively associated with android and thoracic fat tissue in males. CONCLUSIONS: This study suggests that both body composition and inflammation independently affect lung function, with distinct differences between males and females. Lean tissue exacerbates the obese-asthma phenotype in females and the mechanism responsible for this finding warrants further investigation.

Exercise Training Programs Improve Cardiorespiratory and Functional Fitness in Adults With Asthma: A SYSTEMATIC REVIEW AND META-ANALYSIS.

PURPOSE: This systematic review aimed to identify the characteristics and determine the effects of exercise interventions on improving health-related physical fitness in adults with asthma. REVIEW METHODS: A systematic search was completed in MEDLINE, CINAHL, Embase, and SPORTDiscus for peer-reviewed publications of experimental studies that investigated the effects of an exercise training intervention on performance-based health-related physical fitness outcomes in adults with asthma. Two reviewers independently screened studies for inclusion according to predetermined criteria and performed data extraction and quality assessment of included studies. SUMMARY: Forty-five articles were included, in which results for 39 unique studies were reported. Subjects (n = 2135) were aged 22 ± 4 to 71 ± 11 yr with mild-severe asthma. Most exercise programs used aerobic exercise, either alone or in combination with resistance or breathing/stretching exercises. The most common exercise program characteristics were supervised moderate-to-vigorous intensity aerobic exercise performed for 30-45 min 3 d/wk. Meta-analyses revealed significant improvements in cardiorespiratory fitness (V˙o2peak: unstandardized mean difference [MD] 3.1 mL/kg/min, 95% CI, 1.9-4.3), functional fitness (walking distance: MD 41 m, 95% CI, 27-54), and overall health-related physical fitness (standardized mean difference [SMD] 0.67, 95% CI, 0.46-0.89) in favor of groups who underwent experimental exercise training interventions. Aerobic exercise elicited superior improvements in health-related physical fitness compared with breathing/stretching exercise (SMD 0.47, 95% CI, 0.14-0.81).Supervised exercise training programs, particularly those aerobic in nature, are effective in eliciting clinically meaningful improvements in cardiorespiratory and functional fitness in adults with asthma.PROSPERO registration ID number = CRD42018092828.

Comparing the Effect of Acute Moderate and Vigorous Exercise on Inflammation in Adults with Asthma: A Randomized Controlled Trial.

Rationale: Exercise is associated with improvements in asthma; however, the mechanisms responsible are not clear. Exercise induces changes in systemic inflammation, and it is possible that these inflammatory effects extend to the airways of people with asthma. Studies in healthy adults suggest inflammatory responses are dependent on exercise intensity: Although acute moderate exercise is antiinflammatory, acute vigorous exercise appears to be neutral or proinflammatory. The effect of exercise intensity on inflammation has not been investigated in people with asthma. Objectives: To compare acute changes in airway and systemic inflammation after a bout of moderate or vigorous exercise in physically inactive adults with asthma and to establish whether these effects differ according to asthma phenotype. Methods: Participants were randomized to either 1) control (no intervention), 2) 45 minutes of moderate exercise, or 3) 30 minutes of vigorous exercise. Induced sputum and blood samples were collected at baseline and 4 hours after intervention. Results: Fifty-six participants (75% female; mean age, 33.4 [9.9] yr) completed the trial. Moderate exercise induced a significant reduction in sputum eosinophil count (-173 [-337 to -10]; P = 0.032) and sputum percentage eosinophils (-2.2 [-4.9 to 0.5]; P = 0.049) relative to control. Vigorous exercise had no effect on airway inflammation. The antiinflammatory effects of moderate exercise were greatest in participants with eosinophilic asthma, with larger reductions in sputum eosinophils and larger increases in plasma interleukin (IL)-1ra than seen in participants with noneosinophilic asthma. Vigorous exercise induced a systemic proinflammatory response in participants with eosinophilic asthma, indicated by an increase in serum IL-5 and IL-1ß; however, this had no effect on airway inflammation. Conclusions: Exercise intensity modifies the acute inflammatory response to exercise in adults with asthma. Although a bout of moderate exercise is associated with a reduction in eosinophilic airway inflammation, vigorous exercise has no effect on airway inflammation. Interestingly, the effects of moderate exercise vary by asthma phenotype, with greater antiinflammatory effects in participants with eosinophilic asthma. Future studies should examine the impact of exercise training at different intensities on inflammation and clinical asthma outcomes. Clinical trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12615000294550).

The Impact of Meal Dietary Inflammatory Index on Exercise-Induced Changes in Airway Inflammation in Adults with Asthma.

Research suggests exercise may reduce eosinophilic airway inflammation in adults with asthma. The Dietary Inflammatory Index (DII®) quantifies the inflammatory potential of the diet and has been associated with asthma outcomes. This study aimed to determine whether the DII of a meal consumed either before or after exercise influences exercise-induced changes in airway inflammation. A total of 56 adults with asthma were randomised to (1) 30-45 min moderate-vigorous exercise, or (2) a control group. Participants consumed self-selected meals, two hours pre- and two hours post-intervention. Energy-adjusted DII (E-DIITM) was determined for each meal, with meals then characterised as "anti-inflammatory" or "pro-inflammatory" according to median DII. Induced sputum cell counts were measured pre- and four hours post-intervention. Participants consuming an anti-inflammatory meal two hours post-exercise had a decrease in sputum %eosinophils (-0.5 (-2.0, 0.3)%) compared with participants who consumed a pro-inflammatory meal two hours post-exercise (0.5 (0, 3.0)%, p = 0.009). There was a positive correlation between the E-DII score of the post-exercise meal and change in sputum %eosinophils (rs = 0.478, p = 0.008). The E-DII score of the meal consumed two hours pre-exercise had no effect on sputum %eosinophils (p = 0.523). This study suggests an anti-inflammatory meal two hours post-exercise augments exercise-induced improvements in eosinophilic airway inflammation in adults with asthma.

Airway monocyte modulation relates to tumour necrosis factor dysregulation in neutrophilic asthma.

BACKGROUND: Dysregulation of tumour necrosis factor-α (TNF-α) signalling is implicated in neutrophilic asthma. TNF-α signalling involves membrane-bound and soluble ligand (TNF-α) and receptors (TNFRs); however, little is known about how these proteins are altered in asthma. We hypothesised that intercompartment-, immune cell- and/or asthma inflammatory phenotype-dependent regulation could relate to TNF dysregulation in neutrophilic asthma. METHODS: Measurements were made in 45 adults with asthma (36 non-neutrophilic, 9 neutrophilic) and 8 non-asthma controls. Soluble TNF-α, TNF receptor 1 (TNFR1) and TNFR2 were quantified in plasma and sputum supernatant by ELISA, and membrane-bound TNF-α/TNFR1/TNFR2 measured on eosinophils, neutrophils, monocytes, and macrophages in blood and sputum by flow cytometry. Marker expression was compared between inflammatory phenotypes and compartments, and relationship of membrane-bound and soluble TNF markers and immune cell numbers tested by correlation. RESULTS: Soluble sputum TNFR1 and TNFR2 were increased in neutrophilic versus non-neutrophilic asthma (p=0.010 and p=0.029). Membrane-bound TNF-α expression was upregulated on sputum versus blood monocytes, while TNFR1 and TNFR2 levels were reduced on airway versus blood monocytes and neutrophils. Soluble TNFR1 and TNFR2 in sputum significantly correlated with the number of airway monocytes (p=0.016, r=0.358 and p=0.029, r=0.327). CONCLUSION: Our results imply that increased sputum soluble TNF receptor levels observed in neutrophilic asthma relate to the increased recruitment of monocytes and neutrophils into the airways and their subsequent receptor shedding. Monocytes also increase TNF-α ligand expression in the airways. These results suggest an important contribution of airway monocytes to the altered inflammatory milieu in neutrophilic asthma.