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Obesity is a risk factor for asthma. Individuals with asthma and obesity often have poor asthma control and do not respond as well to therapies such as inhaled corticosteroids and long-acting bronchodilators. Weight loss improves asthma control, with a 5%-10% loss in body mass necessary and sufficient to lead to clinically relevant improvements. Preclinical studies have demonstrated the pathogenic contribution of adipocytes from obese mice to the augmented production of proinflammatory cytokines from airway epithelial cells and the salutary effects of diet-induced weight loss to decrease these consequences. However, the effects of adipocyte-derived products on airway epithelial function in human obesity remain incompletely understood. We utilized samples collected from a 12-mo longitudinal study of subjects with obesity undergoing weight loss (bariatric) surgery including controls without asthma and subjects with allergic and nonallergic obese asthma. Visceral adipose tissue (VAT) samples were collected during bariatric surgery and from recruited normal weight controls without asthma undergoing elective abdominal surgery. Human bronchial epithelial (HBEC3-KT) cells were exposed to plasma or conditioned media from cultured VAT adipocytes with or without agonists. Human bronchial smooth muscle (HBSM) cells were similarly exposed to adipocyte-conditioned media. Proinflammatory cytokines were augmented in supernatants from HBEC3-KT cells exposed to plasma as compared with subsequent visits. Whereas exposure to obese adipocyte-conditioned media induced proinflammatory responses, there were no differences between groups in both HBEC3-KT and HBSM cells. These data show that bariatric surgery and subsequent weight loss beneficially change the circulating factors that augment human airway epithelial and bronchial smooth muscle cell proinflammatory responses.NEW & NOTEWORTHY This longitudinal study following subjects with asthma and obesity reveals that weight loss following bariatric surgery decreases the capacity for plasma to augment proinflammatory cytokine secretion by human bronchial epithelial cells, implicating that circulating but not adipocyte-derived factors are important modulators in obese asthma.
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Asma , Cirurgia Bariátrica , Animais , Camundongos , Humanos , Estudos Longitudinais , Meios de Cultivo Condicionados , Obesidade/cirurgia , Obesidade/complicações , Cirurgia Bariátrica/efeitos adversos , Brônquios/patologia , Citocinas , Células Epiteliais/patologia , Redução de Peso/fisiologiaRESUMO
OBJECTIVE: Older adults with asthma (OAA) have elevated asthma morbidity rates. A six-session intervention based on self-regulation theory was shown to improve outcomes. However, wide-spread implementation was difficult due to the in-person design. Our objective was to determine the feasibility and acceptability of an updated intervention for OAA that is completely remote, includes a physician component, and utilizes shared decision-making (SDM). METHODS: A pilot study of 12 OAA with uncontrolled asthma and their asthma providers was conducted at three health centers. The remote intervention (titled SOAR) consisted of 4 sessions (2 groups and 2 individual). Asthma providers (both specialists and primary care) were sent updates of progress along with information on how to incorporate SDM into the visit. Implementation (feasibility, acceptability, and appropriateness) and clinical (asthma control, asthma quality of life, perceived control, depression, and self-confidence) outcomes were measured. RESULTS: SOAR was found to be feasible, acceptable, and appropriate, with values on validated implementation scales similar to those of in-person behavioral interventions. Asthma providers found the program helpful and intended to change care based on the updates. Asthma control scores improved significantly from baseline (14.2 to 16.8, p = 0.04), as did asthma quality of life (4.2 to 4.9, p = 0.03) and self-confidence to manage asthma (7.1 to 8.5, p = 0.02). There was no change in depression nor perceived control scores. CONCLUSION: A remote behavioral intervention appeared feasible and acceptable for OAA and their health care providers, and can improve outcomes. Larger scale implementation trials are warranted.
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More than 50% of people with asthma in the United States are obese, and obesity often worsens symptoms of allergic asthma and impairs response to treatment. Based on previously established roles of the epithelial NADPH oxidase DUOX1 in allergic airway inflammation, we addressed the potential involvement of DUOX1 in altered allergic inflammation in the context of obesity. Intranasal house dust mite (HDM) allergen challenge of subjects with allergic asthma induced rapid secretion of IL-33, then IL-13, into the nasal lumen, responses that were significantly enhanced in obese asthmatic subjects (BMI >30). Induction of diet-induced obesity (DIO) in mice by high-fat diet (HFD) feeding similarly enhanced acute airway responses to intranasal HDM challenge, particularly with respect to secretion of IL-33 and type 2/type 3 cytokines, and this was associated with enhanced epithelial DUOX1 expression and was avoided in DUOX1-deficient mice. DIO also enhanced DUOX1-dependent features of chronic HDM-induced allergic inflammation. Although DUOX1 did not affect overall weight gain by HFD feeding, it contributed to glucose intolerance, suggesting a role in glucose metabolism. However, glucose intolerance induced by short-term HFD feeding, in the absence of adiposity, was not sufficient to alter HDM-induced acute airway responses. DIO was associated with enhanced presence of the adipokine leptin in the airways, and leptin enhanced DUOX1-dependent IL-13 and mucin production in airway epithelial cells. In conclusion, augmented inflammatory airway responses to HDM in obesity are associated with increases in airway epithelial DUOX1, and by increased airway epithelial leptin signaling.
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Asma , Intolerância à Glucose , Animais , Camundongos , Alérgenos , Asma/metabolismo , Dieta , Modelos Animais de Doenças , Oxidases Duais , Inflamação , Interleucina-13 , Interleucina-33 , Leptina , Obesidade , PyroglyphidaeRESUMO
Obesity is associated with severe, difficult-to-control asthma, and increased airway oxidative stress. Mitochondrial reactive oxygen species (mROS) are an important source of oxidative stress in asthma, leading us to hypothesize that targeting mROS in obese allergic asthma might be an effective treatment. Using a mouse model of house dust mite (HDM)-induced allergic airway disease in mice fed a low- (LFD) or high-fat diet (HFD), and the mitochondrial antioxidant MitoQuinone (MitoQ), we investigated the effects of obesity and ROS on HDM-induced airway inflammation, remodeling, and airway hyperresponsiveness (AHR). Obese allergic mice showed increased lung tissue eotaxin, airway tissue eosinophilia, and AHR compared with lean allergic mice. MitoQ reduced airway inflammation, remodeling, and hyperreactivity in both lean and obese allergic mice, and tissue eosinophilia in obese-allergic mice. Similar effects were observed with decyl triphosphonium (dTPP+), the hydrophobic cationic moiety of MitoQ lacking ubiquinone. HDM-induced oxidative sulfenylation of proteins was increased particularly in HFD mice. Although only MitoQ reduced sulfenylation of proteins involved in protein folding in the endoplasmic reticulum (ER), ER stress was attenuated by both MitoQ and dTPP+ suggesting the anti-allergic effects of MitoQ are mediated in part by effects of its hydrophobic dTPP+ moiety reducing ER stress. In summary, oxidative signaling is an important mediator of allergic airway disease. MitoQ, likely through reducing protein oxidation and affecting the UPR pathway, might be effective for the treatment of asthma and specific features of obese asthma.
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Asma , Eosinofilia , Animais , Asma/metabolismo , Pulmão/metabolismo , Obesidade/metabolismo , Inflamação/patologia , Pyroglyphidae , Eosinofilia/patologia , Modelos Animais de DoençasRESUMO
This report presents the proceedings from a workshop titled "Microbiome, Metabolism and Immunoregulation of Asthma" that was held virtually May 13 and 14, 2021. The workshop was jointly sponsored by the American Thoracic Society (Assembly on Allergy, Immunology, and Inflammation) and the National Institute of Allergy and Infectious Diseases. It convened an interdisciplinary group of experts with backgrounds in asthma immunology, microbiome science, metabolomics, computational biology, and translational pulmonary research. The main purpose was to identify key scientific gaps and needs to further advance research on microbial and metabolic mechanisms that may contribute to variable immune responses and disease heterogeneity in asthma. Discussions were structured around several topics, including 1) immune and microbial mechanisms of asthma pathogenesis in murine models, 2) the role of microbes in pediatric asthma exacerbations, 3) dysregulated metabolic pathways in asthma associated with obesity, 4) metabolism effects on macrophage function in adipose tissue and the lungs, 5) computational approaches to dissect microbiome-metabolite links, and 6) potential confounders of microbiome-disease associations in human studies. This report summarizes the major points of discussion, which included identification of specific knowledge gaps, challenges, and suggested directions for future research. These include questions surrounding mechanisms by which microbiota and metabolites shape host health versus an allergic or asthmatic state; direct and indirect influences of other biological factors, exposures, and comorbidities on these interactions; and ongoing technical and analytical gaps for clinical translation.
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Asma , Hipersensibilidade , Microbiota , Animais , Asma/etiologia , Criança , Humanos , Hipersensibilidade/complicações , Imunidade , Camundongos , National Institute of Allergy and Infectious Diseases (U.S.) , Estados UnidosRESUMO
BACKGROUND: Effectiveness of asthma treatment, including biologics, may be different in patients with higher body mass index (BMI). OBJECTIVE: To evaluate response to omalizumab (dosed by serum immunoglobulin E level and weight) by BMI category. METHODS: Pooled data from 2 randomized, double-blind, placebo-controlled studies of adults with moderate-to-severe allergic asthma were analyzed by BMI category (<25 kg/m2 [normal or underweight], n = 397; 25 to <30 kg/m2 [overweight], n = 330; ≥ 30 kg/m2 [obese], n = 268). Placebo-adjusted exacerbation rate reductions were evaluated by Poisson regression modeling. Changes from baseline in forced expiratory volume in 1 second, beclomethasone dipropionate (BDP) dose, Total Asthma Symptom Score, and Asthma Quality of Life Questionnaire were evaluated by analysis of covariance. RESULTS: Greater placebo-adjusted exacerbation rate reductions (95% confidence interval) were observed with increasing BMI (normal or underweight, -37.4% [-69.0% to 26.8%]; overweight, -52.7% [-78.4% to 3.7%]; obese, -71.9% [-86.9% to -39.5%]). There were no differences in forced expiratory volume in 1 second improvement between BMI categories at week 16 (normal or underweight, 76.2 [5.3-147.1] mL; overweight, 98.1 [13.9-182.4] mL; obese, 69.1 [-18.9 to 157.2] mL). No differences in BDP dose reduction (µg) were noted between BMI categories (normal or underweight, 23.0 [15.7-30.3]; overweight, 22.5 [13.5-31.5]; obese, 16.6 [5.8-27.3]). Fewer patients in the higher BMI categories eliminated BDP use. There were trends for smaller improvements with higher BMI in Total Asthma Symptom Score (normal/underweight, -0.52 [-0.82 to -0.22]; overweight, -0.50 [-0.80 to -0.20]; obese, -0.39 [-0.77 to 0.00]) and Asthma Quality of Life Questionnaire (normal or underweight, 0.34 [0.16-0.52]; overweight, 0.34 [0.13-0.55]; obese, 0.15 [-0.08 to 0.39]). CONCLUSION: Omalizumab provides benefit to patients with moderate-to-severe allergic asthma, regardless of BMI. TRIAL REGISTRATION: Studies 008/009 were conducted before clinical trial registration was required, and therefore clinical trial registration numbers are not available.
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Antiasmáticos , Asma , Adulto , Antiasmáticos/farmacologia , Antiasmáticos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Beclometasona/farmacologia , Beclometasona/uso terapêutico , Índice de Massa Corporal , Método Duplo-Cego , Volume Expiratório Forçado , Humanos , Obesidade/tratamento farmacológico , Omalizumab/farmacologia , Omalizumab/uso terapêutico , Sobrepeso , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Magreza/tratamento farmacológico , Resultado do TratamentoRESUMO
Asthma is a chronic disorder characterized by inflammation, mucus metaplasia, airway remodeling, and hyperresponsiveness. We recently showed that IL-1-induced glycolytic reprogramming contributes to allergic airway disease using a murine house dust mite model. Moreover, levels of pyruvate kinase M2 (PKM2) were increased in this model as well as in nasal epithelial cells from asthmatics as compared with healthy controls. Although the tetramer form of PKM2 converts phosphoenolpyruvate to pyruvate, the dimeric form of PKM2 has alternative, nonglycolysis functions as a transcriptional coactivator to enhance the transcription of several proinflammatory cytokines. In the current study, we examined the impact of PKM2 on the pathogenesis of house dust mite-induced allergic airways disease in C57BL/6NJ mice. We report, in this study, that activation of PKM2, using the small molecule activator, TEPP46, augmented PKM activity in lung tissues and attenuated airway eosinophils, mucus metaplasia, and subepithelial collagen. TEPP46 attenuated IL-1ß-mediated airway inflammation and expression of proinflammatory mediators. Exposure to TEPP46 strongly decreased the IL-1ß-mediated increases in thymic stromal lymphopoietin (TSLP) and GM-CSF in primary tracheal epithelial cells isolated from C57BL/6NJ mice. We also demonstrate that IL-1ß-mediated increases in nuclear phospho-STAT3 were decreased by TEPP46. Finally, STAT3 inhibition attenuated the IL-1ß-induced release of TSLP and GM-CSF, suggesting that the ability of PKM2 to phosphorylate STAT3 contributes to its proinflammatory function. Collectively, these results demonstrate that the glycolysis-inactive form of PKM2 plays a crucial role in the pathogenesis of allergic airways disease by increasing IL-1ß-induced proinflammatory signaling, in part, through phosphorylation of STAT3.
Assuntos
Asma/imunologia , Hipersensibilidade/imunologia , Pneumonia/imunologia , Piruvato Quinase/imunologia , Transdução de Sinais/imunologia , Remodelação das Vias Aéreas/fisiologia , Animais , Asma/metabolismo , Feminino , Hipersensibilidade/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/metabolismo , Pyroglyphidae/imunologia , Piruvato Quinase/metabolismoRESUMO
Obesity is a major risk factor for the development of asthma, and the prevalence of obesity is higher in people with asthma than in the general population. Obese people often have severe asthma-recent studies in the United States suggest that 60% of adults with severe asthma are obese. Multiple mechanisms link obesity and asthma, which are discussed in this article, and these pathways contribute to different phenotypes of asthma among people with obesity. From a practical aspect, changes in physiology and immune markers affect diagnosis and monitoring of disease activity in people with asthma and obesity. Obesity also affects response to asthma medications and is associated with an increased risk of co-morbidities such as gastroesophageal reflux disease, depression, and obstructive sleep apnea, all of which may affect asthma control. Obese people may be at elevated risk of exacerbations related to increased risk of severe disease in response to viral infections. Interventions that target improved dietary quality, exercise, and weight loss are likely to be particularly helpful for this patient population.
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Asma , Apneia Obstrutiva do Sono , Asma/tratamento farmacológico , Asma/epidemiologia , Asma/etiologia , Humanos , Obesidade/complicações , Obesidade/epidemiologia , Prevalência , Fatores de Risco , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/terapiaRESUMO
Obesity is a risk factor for the development of asthma and represents a difficult-to-treat disease phenotype. Aerobic glycolysis is emerging as a key feature of asthma, and changes in glucose metabolism are linked to leukocyte activation and adaptation to oxidative stress. Dysregulation of PKM2 (pyruvate kinase M2), the enzyme that catalyzes the last step of glycolysis, contributes to house dust mite (HDM)-induced airway inflammation and remodeling in lean mice. It remains unclear whether glycolytic reprogramming and dysregulation of PKM2 also contribute to obese asthma. The goal of the present study was to elucidate the functional role of PKM2 in a murine model of obese allergic asthma. We evaluated the small molecule activator of PKM2, TEPP46, and assessed the role of PKM2 using conditional ablation of the Pkm2 allele from airway epithelial cells. In obese C57BL/6NJ mice, parameters indicative of glycolytic reprogramming remained unchanged in the absence of stimulation with HDM. Obese mice that were subjected to HDM showed evidence of glycolytic reprogramming, and treatment with TEPP46 diminished airway inflammation, whereas parameters of airway remodeling were unaffected. Epithelial ablation of Pkm2 decreased central airway resistance in both lean and obese allergic mice in addition to decreasing inflammatory cytokines in the lung tissue. Lastly, we highlight a novel role for PKM2 in the regulation of glutathione-dependent protein oxidation in the lung tissue of obese allergic mice via a putative IFN-γ-glutaredoxin1 pathway. Overall, targeting metabolism and protein oxidation may be a novel treatment strategy for obese allergic asthma.
Assuntos
Asma/enzimologia , Asma/patologia , Hipersensibilidade/enzimologia , Hipersensibilidade/patologia , Inflamação/enzimologia , Inflamação/patologia , Piruvato Quinase/metabolismo , Animais , Asma/complicações , Asma/parasitologia , Hiper-Reatividade Brônquica/complicações , Dieta Hiperlipídica , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Glutationa/metabolismo , Glicólise , Homeostase/efeitos dos fármacos , Hipersensibilidade/complicações , Hipersensibilidade/parasitologia , Mediadores da Inflamação/metabolismo , Pulmão/enzimologia , Pulmão/patologia , Camundongos Endogâmicos C57BL , Camundongos Obesos , Modelos Biológicos , Piridazinas/administração & dosagem , Piridazinas/farmacologia , Pyroglyphidae , Pirróis/administração & dosagem , Pirróis/farmacologiaRESUMO
Although recognized as an important endocrine organ, little is known about the mechanisms through which adipose tissue can regulate inflammatory responses in distant tissues, such as lung that are affected by obesity. To explore potential mechanisms, male C57BL/6J mice were provided either high-fat diet, low-fat diet, or were provided a high-fat diet then switched to the low-fat diet to promote weight loss. Visceral adipocytes were then cultured in vitro to generate conditioned media (CM) that was used to treat both primary (mouse tracheal epithelial cells; MTECs) and immortalized (mouse-transformed club cells; MTCCs) airway epithelial cells. Adiponectin levels were greatly depressed in the CM from both obese and diet-switched adipocytes relative to mice continually fed the low-fat diet. MTECs from mice with obesity secreted higher baseline levels of inflammatory cytokines than MTECs from lean or diet-switched mice. MTECs treated with obese adipocyte CM increased their secretion of these cytokines compared with MTECs treated with lean CM. Diet-switched CM modestly decreased the production of cytokines compared with obese CM, and these effects were recapitulated when the CM was used to treat MTCCs. Adipose stromal vascular cells from mice with obesity expressed genes consistent with an M1 macrophage phenotype and decreased eosinophil abundance compared with lean stromal vascular fraction, a profile that persisted in the lean diet-switched mice despite substantial weight loss. Soluble factors secreted from obese adipocytes exert a proinflammatory effect on airway epithelial cells, and these alterations are attenuated by diet-induced weight loss, which could have implications for the airway dysfunction related to obese asthma and its mitigation by weight loss.
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Adipócitos/fisiologia , Tecido Adiposo/citologia , Células Epiteliais/fisiologia , Inflamação/complicações , Obesidade/induzido quimicamente , Animais , Linhagem Celular , Técnicas de Cocultura , Dieta Hiperlipídica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sistema Respiratório/citologiaRESUMO
BACKGROUND AND OBJECTIVE: Late-onset non-allergic asthma in obesity is characterized by an abnormally compliant, collapsible lung periphery; it is not known whether this abnormality exists in proximal airways. We sought to compare collapsibility of central airways between lean and obese individuals with and without asthma. METHODS: A cross-sectional study comparing luminal area and shape (circularity) of the trachea, left mainstem bronchus, right bronchus intermedius and right inferior lobar bronchus at RV and TLC by CT was conducted. RESULTS: In 11 lean controls (BMI: 22.4 (21.5, 23.8) kg/m2 ), 10 lean individuals with asthma (23.6 (22.0, 24.8) kg/m2 ), 10 obese controls (45.5 (40.3, 48.5) kg/m2 ) and 21 obese individuals with asthma (39.2 (35.8, 42.9) kg/m2 ), lumen area and circularity increased significantly with an increase in lung volume from RV to TLC for all four airways (P < 0.05 for all). Changes in area and circularity with lung volume were similar in obese individuals with and without asthma, and both obese groups had severe airway collapse at RV. In multivariate analysis, change in lumen area was related to BMI and change in circularity to waist circumference, but neither was related to asthma diagnosis. CONCLUSION: Excessive collapse of the central airways is related to obesity, and occurs in both obese controls and obese asthma. Increased airway collapse could contribute to ventilation abnormalities in obese individuals particularly at lower lung volumes, and complicate asthma in obese individuals.
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Asma , Asma/complicações , Brônquios/diagnóstico por imagem , Estudos Transversais , Humanos , Pulmão/diagnóstico por imagem , Obesidade/complicações , FenótipoRESUMO
The 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group was coordinated and supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health. It is designed to improve patient care and support informed decision making about asthma management in the clinical setting. This update addresses six priority topic areas as determined by the state of the science at the time of a needs assessment, and input from multiple stakeholders:A rigorous process was undertaken to develop these evidence-based guidelines. The Agency for Healthcare Research and Quality's (AHRQ) Evidence-Based Practice Centers conducted systematic reviews on these topics, which were used by the Expert Panel Working Group as a basis for developing recommendations and guidance. The Expert Panel used GRADE (Grading of Recommendations, Assessment, Development and Evaluation), an internationally accepted framework, in consultation with an experienced methodology team for determining the certainty of evidence and the direction and strength of recommendations based on the evidence. Practical implementation guidance for each recommendation incorporates findings from NHLBI-led patient, caregiver, and clinician focus groups. To assist clincians in implementing these recommendations into patient care, the new recommendations have been integrated into the existing Expert Panel Report-3 (EPR-3) asthma management step diagram format.
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Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Humanos , Guias de Prática Clínica como AssuntoRESUMO
Mitochondria regulate a myriad of cellular functions. Dysregulation of mitochondrial control within airway epithelial cells has been implicated in the pro-inflammatory response to allergens in asthma patients. Because of their multifaceted nature, mitochondrial structure must be tightly regulated through fission and fusion. Dynamin Related Protein 1 (DRP1) is a key driver of mitochondrial fission. During allergic asthma, airway epithelial mitochondria appear smaller and structurally altered. The role of DRP1-mediated mitochondrial fission, however, has not been fully elucidated in epithelial response to allergens. We used a Human Bronchial Epithelial Cell line (HBECs), primary Mouse Tracheal Epithelial Cells (MTECs), and conditional DRP1 ablation in lung epithelial cells to investigate the impact of mitochondrial fission on the pro-inflammatory response to house dust mite (HDM) in vitro and in vivo. Our data suggest that, following HDM challenge, mitochondrial fission is rapidly upregulated in airway epithelial cells and precedes production of pro-inflammatory cytokines and chemokines. Further, deletion of Drp1 in lung epithelial cells leads to decreased fission and enhanced pro-inflammatory signaling in response to HDM in vitro, as well as enhanced airway hyper-responsiveness (AHR), inflammation, differential mucin transcription, and epithelial cell death in vivo. Mitochondrial fission, therefore, regulates the lung epithelial pro-inflammatory response to HDM.
Assuntos
Alérgenos/farmacologia , Dinaminas/fisiologia , Dinâmica Mitocondrial/genética , Hipersensibilidade Respiratória/genética , Mucosa Respiratória/efeitos dos fármacos , Animais , Brônquios/efeitos dos fármacos , Brônquios/fisiologia , Células Cultivadas , Dinaminas/genética , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Transgênicos , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/metabolismo , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismoRESUMO
BACKGROUND: Body habitus, pneumoperitoneum, and Trendelenburg positioning may each independently impair lung mechanics during robotic laparoscopic surgery. This study hypothesized that increasing body mass index is associated with more mechanical strain and alveolar collapse, and these impairments are exacerbated by pneumoperitoneum and Trendelenburg positioning. METHODS: This cross-sectional study measured respiratory flow, airway pressures, and esophageal pressures in 91 subjects with body mass index ranging from 18.3 to 60.6 kg/m2. Pulmonary mechanics were quantified at four stages: (1) supine and level after intubation, (2) with pneumoperitoneum, (3) in Trendelenburg docked with the surgical robot, and (4) level without pneumoperitoneum. Subjects were stratified into five body mass index categories (less than 25, 25 to 29.9, 30 to 34.9, 35 to 39.9, and 40 or higher), and respiratory mechanics were compared over surgical stages using generalized estimating equations. The optimal positive end-expiratory pressure settings needed to achieve positive end-expiratory transpulmonary pressures were calculated. RESULTS: At baseline, transpulmonary driving pressures increased in each body mass index category (1.9 ± 0.5 cm H2O; mean difference ± SD; P < 0.006), and subjects with a body mass index of 40 or higher had decreased mean end-expiratory transpulmonary pressures compared with those with body mass index of less than 25 (-7.5 ± 6.3 vs. -1.3 ± 3.4 cm H2O; P < 0.001). Pneumoperitoneum and Trendelenburg each further elevated transpulmonary driving pressures (2.8 ± 0.7 and 4.7 ± 1.0 cm H2O, respectively; P < 0.001) and depressed end-expiratory transpulmonary pressures (-3.4 ± 1.3 and -4.5 ± 1.5 cm H2O, respectively; P < 0.001) compared with baseline. Optimal positive end-expiratory pressure was greater than set positive end-expiratory pressure in 79% of subjects at baseline, 88% with pneumoperitoneum, 95% in Trendelenburg, and ranged from 0 to 36.6 cm H2O depending on body mass index and surgical stage. CONCLUSIONS: Increasing body mass index induces significant alterations in lung mechanics during robotic laparoscopic surgery, but there is a wide range in the degree of impairment. Positive end-expiratory pressure settings may need individualization based on body mass index and surgical conditions.
Assuntos
Índice de Massa Corporal , Laparoscopia/métodos , Respiração com Pressão Positiva/métodos , Mecânica Respiratória/fisiologia , Procedimentos Cirúrgicos Robóticos/métodos , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Laparoscopia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Respiração com Pressão Positiva/efeitos adversos , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Volume de Ventilação Pulmonar/fisiologia , Lesão Pulmonar Induzida por Ventilação Mecânica/etiologia , Lesão Pulmonar Induzida por Ventilação Mecânica/prevenção & controleRESUMO
PURPOSE: Hypercapnic respiratory failure (HRF) is a frequent cause of hospitalization and a common comorbidity in hospitalized patients. There are few studies addressing what factors might predict poor outcomes in this patient population. The purpose of the current study was to investigate characteristics and outcomes of patients hospitalized with HRF. METHODS: A study of patients ≥ 18 years admitted with HRF in a 1-year period. Patients with limited life expectancy related to other conditions, and those with a non-respiratory cause of HRF, were excluded. RESULTS: 202 subjects met eligibility criteria: 24% had a diagnosis of obstructive sleep apnea, 6% obesity hypoventilation, 46% chronic obstructive pulmonary disease, and 10% asthma. Fifteen (7%) died during the index admission. Forty-one patients (23%) were readmitted within 30 days: peripheral vascular disease [adjusted odds ratio (aOR) 4.78, CI 1.45-15.74] and tachycardia (aOR 2.97, CI 1.22-7.26) were associated with an increased risk of readmission. Sixty-six patients (36%) died after discharge. Risk of death was increased in older patients (aOR 1.32, CI 1.13-1.54 per 5 years), those with peripheral vascular disease (aOR 12.56, CI 2.35-67.21), higher Charlson co-morbidity index (aOR 1.39, CI 1.09-1.76), use of home oxygen (aOR 4.03, CI 1.89-8.57), and those who had been readmitted (aOR 3.07, CI 1.46-6.43). CONCLUSIONS: Hospitalization for HRF is associated with a high morbidity and mortality. Our observation that home oxygen use was associated with increased mortality suggests that oxygen use could be a risk factor for death in patients with HRF.
Assuntos
Hospitalização , Hipercapnia/terapia , Mortalidade , Readmissão do Paciente/estatística & dados numéricos , Insuficiência Respiratória/terapia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Feminino , Insuficiência Cardíaca/epidemiologia , Humanos , Hipercapnia/epidemiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Síndrome de Hipoventilação por Obesidade/epidemiologia , Oxigenoterapia , Doenças Vasculares Periféricas/epidemiologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Insuficiência Respiratória/epidemiologia , Fatores de Risco , Apneia Obstrutiva do Sono/epidemiologiaRESUMO
Importance: Asthma is a major public health problem worldwide and is associated with excess morbidity, mortality, and economic costs associated with lost productivity. The National Asthma Education and Prevention Program has released the 2020 Asthma Guideline Update with updated evidence-based recommendations for treatment of patients with asthma. Objective: To report updated recommendations for 6 topics for clinical management of adolescents and adults with asthma: (1) intermittent inhaled corticosteroids (ICSs); (2) add-on long-acting muscarinic antagonists; (3) fractional exhaled nitric oxide; (4) indoor allergen mitigation; (5) immunotherapy; and (6) bronchial thermoplasty. Evidence Review: The National Heart, Lung, and Blood Advisory Council chose 6 topics to update the 2007 asthma guidelines based on results from a 2014 needs assessment. The Agency for Healthcare Research and Quality conducted systematic reviews of these 6 topics based on literature searches up to March-April 2017. Reviews were updated through October 2018 and used by an expert panel (n = 19) that included asthma content experts, primary care clinicians, dissemination and implementation experts, and health policy experts to develop 19 new recommendations using the GRADE method. The 17 recommendations for individuals aged 12 years or older are reported in this Special Communication. Findings: From 20â¯572 identified references, 475 were included in the 6 systematic reviews to form the evidence basis for these recommendations. Compared with the 2007 guideline, there was no recommended change in step 1 (intermittent asthma) therapy (as-needed short-acting ß2-agonists [SABAs] for rescue therapy). In step 2 (mild persistent asthma), either daily low-dose ICS plus as-needed SABA therapy or as-needed concomitant ICS and SABA therapy are recommended. Formoterol in combination with an ICS in a single inhaler (single maintenance and reliever therapy) is recommended as the preferred therapy for moderate persistent asthma in step 3 (low-dose ICS-formoterol therapy) and step 4 (medium-dose ICS-formoterol therapy) for both daily and as-needed therapy. A short-term increase in the ICS dose alone for worsening of asthma symptoms is not recommended. Add-on long-acting muscarinic antagonists are recommended in individuals whose asthma is not controlled by ICS-formoterol therapy for step 5 (moderate-severe persistent asthma). Fractional exhaled nitric oxide testing is recommended to assist in diagnosis and monitoring of symptoms, but not alone to diagnose or monitor asthma. Allergen mitigation is recommended only in individuals with exposure and relevant sensitivity or symptoms. When used, allergen mitigation should be allergen specific and include multiple allergen-specific mitigation strategies. Subcutaneous immunotherapy is recommended as an adjunct to standard pharmacotherapy for individuals with symptoms and sensitization to specific allergens. Sublingual immunotherapy is not recommended specifically for asthma. Bronchial thermoplasty is not recommended as part of standard care; if used, it should be part of an ongoing research effort. Conclusions and Relevance: Asthma is a common disease with substantial human and economic costs globally. Although there is no cure or established means of prevention, effective treatment is available. Use of the recommendations in the 2020 Asthma Guideline Update should improve the health of individuals with asthma.
Assuntos
Corticosteroides/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Imunoterapia , Agonistas Muscarínicos/administração & dosagem , Administração por Inalação , Administração Oral , Adolescente , Adulto , Albuterol/administração & dosagem , Asma/diagnóstico , Asma/terapia , Criança , Terapia Combinada , Gerenciamento Clínico , Combinação de Medicamentos , Fumarato de Formoterol/administração & dosagem , HumanosRESUMO
BACKGROUND AND OBJECTIVE: Obesity produces restrictive effects on lung function. We previously reported that obese patients with asthma exhibit a propensity towards small airway closure during methacholine challenge which improved with weight loss. We hypothesized that increased abdominal adiposity, a key contributor to the restrictive effects of obesity on the lung, mediates this response. This study investigates the effect of body mass index (BMI) versus waist circumference (WC) on spirometric lung function, sensitivity to airway narrowing and closure, and airway closure during bronchoconstriction in patients with asthma. METHODS: Participants underwent spirometry and methacholine challenge. Sensitivity to airway closure and narrowing was assessed from the dose-response slopes of the forced vital capacity (FVC) and the ratio of forced expiratory volume in 1 s (FEV1 ) to FVC, respectively. Airway closure during bronchoconstriction (closing index) was computed as the percent reduction in FVC divided by the percent reduction in FEV1 at maximal bronchoconstriction. RESULTS: A total of 116 asthmatic patients (56 obese) underwent methacholine challenge. Spirometric lung function was inversely related to WC (P < 0.05), rather than BMI. Closing index increased significantly during bronchoconstriction in obese patients and was related to increasing BMI (P = 0.01), but not to WC. Sensitivity to airway closure and narrowing was not associated with BMI or WC. CONCLUSION: Although WC is associated with restrictive effects on baseline lung function, increased BMI, rather than WC, predisposes to airway closure during bronchoconstriction. These findings suggest that obesity predisposes to airway closure during bronchoconstriction through mechanisms other than simple mass loading.
Assuntos
Broncopatias , Testes de Provocação Brônquica/métodos , Obesidade Abdominal , Espirometria/métodos , Circunferência da Cintura , Adulto , Índice de Massa Corporal , Broncopatias/diagnóstico , Broncopatias/fisiopatologia , Broncoconstrição/fisiologia , Constrição Patológica , Suscetibilidade a Doenças/diagnóstico , Suscetibilidade a Doenças/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal/diagnóstico , Obesidade Abdominal/fisiopatologiaRESUMO
BACKGROUND AND OBJECTIVE: The reduction of forced expiratory volume in 1 s (FEV1 ) in response to methacholine challenge in asthma may reflect two components: airway narrowing, assessed by the change in FEV1 /forced vital capacity (FVC), and airway closure, assessed by the change in FVC. The purpose of this study was to determine the degree and determinants of airway closure in response to methacholine in a large group of asthmatic patients participating in studies conducted by the American Lung Association-Airways Clinical Research Centers (ALA-ACRC). METHODS: We used the methacholine challenge data from participants in five studies of the ALA-ACRC to determine the closing index, defined as the contribution of airway closure to the decrease in FEV1 , and calculated as %ΔFVC/%ΔFEV1 . RESULTS: There were a total of 936 participants with asthma, among whom the median closing index was 0.67 relative to that of a published healthy population of 0.54. A higher closing index was associated with increased age (10-year increments) (0.04, 95% CI = 0.02, 0.05, P < 0.005) and obesity (0.07, 95% CI = 0.03, 0.10, P < 0.001). There was no association between the closing index and asthma control. CONCLUSION: Our findings confirm that airway closure in response to methacholine occurs in a large, diverse population of asthmatic participants, and that increased airway closure is associated with older age and obesity. These findings suggest that therapies targeting airway closure may be important in patients with a high closing index.