Going to extremes of lung volume.
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Diving↗
Biomedical subjects
Charles G Irvin
Publications and source records attributed to Charles G Irvin.
Predicting episodes of poor asthma control in treated patients with asthma.
BACKGROUND: Asthma exacerbations are dangerous, expensive, and difficult to anticipate. OBJECTIVE: To characterize patients with asthma who had asthma episodes and exacerbations during 4 weeks of observation. METHODS: A total of 2032 volunteers with asthma (age, 3-64 years; 62% female subjects) were studied over two 2-week intervals after flu vaccine and placebo. Baseline data, including several asthma questionnaires, were analyzed for prediction of subsequent asthma events as recorded on diaries detailing peak flow, medication use, and health care use. RESULTS: During 28 days of diary collection, 43.2% of participants had at least 1 episode of poor asthma control. Most episodes were characterized by increased use of rescue medications or reductions in peak flow, but nearly 15% of participants had exacerbations characterized by use of systemic corticosteroids, unscheduled health care visits, or both. Episode frequency was highest in children <10 years of age. Additional risk factors were smoking, African American ethnicity, low lung function, and past history of severe asthma. The best predictors were symptom questionnaires, and a simple questionnaire concerning the preceding 2 weeks worked as well as more complex questionnaires or those reflecting longer periods. In regression analyses, questionnaire results, smoking, lung function, ethnicity, and asthma history all were associated with asthma episodes in people older than 10 years, whereas only asthma history was predictive in those <10 years. CONCLUSION: Symptom questionnaires are predictive of subsequent asthma episodes in people older than age 10 years, but not in younger people. CLINICAL IMPLICATIONS: Simple assessments may be helpful in identifying patients most at risk for future asthma episodes.
Adolescent↗
Intrinsic and antigen-induced airway hyperresponsiveness are the result of diverse physiological mechanisms.
Airway hyperresponsiveness (AHR) is a defining feature of asthma. We have previously shown, in mice sensitized and challenged with antigen, that AHR is attributable to normal airway smooth muscle contraction with exaggerated airway closure. In the present study we sought to determine if the same was true for mice known to have intrinsic AHR, the genetic strain of mice, A/J. We found that A/J mice have AHR characterized by minimal increase in elastance following aerosolized methacholine challenge compared with mice (BALB/c) that have been antigen sensitized and challenged [concentration that evokes 50% change in elastance (PC(50)): 22.9 +/- 5.7 mg/ml for A/J vs. 3.3 +/- 0.4 mg/ml for antigen-challenged and -sensitized mice; P < 0.004]. Similar results were found when intravenous methacholine was used (PC(30) 0.22 +/- 0.08 mg/ml for A/J vs. 0.03 +/- 0.004 mg/ml for antigen-challenged and -sensitized mice). Computational model analysis revealed that the AHR in A/J mice is dominated by exaggerated airway smooth muscle contraction and that when the route of methacholine administration was changed to intravenous, central airway constriction dominates. Absorption atelectasis was used to provide evidence of the lack of airway closure in A/J mice. Bronchoconstriction during ventilation with 100% oxygen resulted in a mean 9.8% loss of visible lung area in A/J mice compared with 28% in antigen-sensitized and -challenged mice (P < 0.02). We conclude that the physiology of AHR depends on the mouse model used and the route of bronchial agonist administration.
Administration, Inhalation↗
Effect of obesity on clinical presentation and response to treatment in asthma.
Obesity is a risk factor for being diagnosed with asthma, but there is conflicting evidence on whether obesity is a risk factor for lung function abnormalities characteristic of asthma. We studied a cohort of 488 subjects, 47% of whom were obese. Obese and non-obese subjects with asthma had similar airflow limitation and bronchodilator responsiveness, but obese participants had increased sleep disturbance and gastroesophageal reflux disease, higher cytokine levels, and a trend towards increased exacerbations when treated with theophylline. Obese and non-obese asthmatics have similar lung function abnormalities, but comorbidities and altered responses to medications may significantly affect asthma control in obese people.
Acetates↗
Lessons from structure-function studies in asthma: myths and truths about what we teach.
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Adrenergic beta-Agonists↗
Allergic rhinitis and sinusitis in asthma: differential effects on symptoms and pulmonary function.
BACKGROUND: Allergic rhinitis and sinusitis are frequently associated with asthma. The purpose of this study was to determine the impact of self-reported allergic rhinitis and sinusitis on lower airway disease in a large cohort of participants with well-characterized asthma. METHODS: A cohort study of participants in two trials of the American Lung Association-Asthma Clinical Research Centers: 2,031 asthmatics in the Safety of Inactivated Influenza Vaccine in Asthma in Adults and Children (SIIVA) trial and 488 asthmatics in the Effectiveness of Low Dose Theophylline as Add-on Treatment in Asthma (LODO) trial. At baseline, participants reported the presence of allergic rhinitis and sinusitis, and then lung function and asthma control were measured. During the trials, participants were monitored for asthma exacerbations. RESULTS: More than 70% of participants reported either allergic rhinitis or sinusitis. Sinusitis was more common in female patients (odds ratio, 1.46 [SIIVA]), those with gastroesophageal reflux disease (odds ratio, 2.21 [SIIVA]), and those of white race (odds ratio, 1.53 [SIIVA]). Similar associations were seen for allergic rhinitis. LODO participants with allergic rhinitis and sinusitis had increased asthma symptoms and a trend toward more sleep disturbance. Participants with allergic rhinitis had higher baseline lung function than those without allergic rhinitis measured by peak flow (91.2% vs 95.8% in the SIIVA trial). Participants with sinusitis had similar lung function to those without sinusitis. Participants with and without allergic rhinitis had similar exacerbation rates. In the LODO trial only, participants with sinusitis had increased asthma exacerbations (5.68 per patient per year vs 3.72 per patient per year). CONCLUSION: Allergic rhinitis and sinusitis are associated with more severe asthmatic symptoms and, in patients with poorly controlled asthma, more exacerbations but are not associated with low lung function.
Adolescent↗
Promise and pitfalls in animal-based asthma research: building a better mousetrap.
Asthma is one of the leading chronic diseases in the world today. An essential component of the asthma research endeavor is the animal-based experimental disease system, which provides knowledge that is not attainable through study of patients alone. Animal research is especially valuable for elucidating pathophysiology, drug testing, and as an adjunct for interpreting the results of human clinical trials. However, controversies surrounding animal systems data and at the interface between animal and human studies raise questions regarding the true utility of experimental asthma research. We consider here the considerable promise and important limitations of animal-based systems and their prospects for the future study asthma.
Animal Experimentation↗
Exaggerated airway narrowing in mice treated with intratracheal cationic protein.
Airway hyperresponsiveness in mice with allergic airway inflammation can be attributed entirely to exaggerated closure of peripheral airways (Wagers S, Lundblad LK, Ekman M, Irvin CG, and Bates JHT. J Appl Physiol 96: 2019-2027, 2004). However, clinical asthma can be characterized by hyperresponsiveness of the central airways as well as the lung periphery. We, therefore, sought to establish a complementary model of hyperresponsiveness in the mouse due to excessive narrowing of the airways. We treated mice with a tracheal instillation of the cationic protein poly-l-lysine (PLL), hypothesizing that this would reduce the barrier function of the epithelium and thereby render the underlying airway smooth muscle more accessible to aerosolized methacholine. The PLL-treated animals were hypersensitive to methacholine: they exhibited an exaggerated response to submaximal doses but had a maximal response that was similar to controls. With the aid of a computational model of the mouse lung, we conclude that the methacholine responsiveness of PLL-treated mice is fundamentally different in nature to the hyperresponsiveness that we found previously in mice with allergically inflamed lungs.
Administration, Inhalation↗
Nitrogen dioxide enhances allergic airway inflammation and hyperresponsiveness in the mouse.
In addition to being an air pollutant, NO2 is a potent inflammatory oxidant generated endogenously by myeloperoxidase and eosinophil peroxidase. In these studies, we sought to determine the effects of NO2 exposure on mice with ongoing allergic airway disease pathology. Mice were sensitized and challenged with the antigen ovalbumin (OVA) to generate airway inflammation and subsequently exposed to 5 or 25 ppm NO2 for 3 days or 5 days followed by a 20-day recovery period. Whereas 5 ppm NO2 elicited no pathological changes, inhalation of 25 ppm NO2 alone induced acute lung injury, which peaked after 3 days and was characterized by increases in protein, LDH, and neutrophils recovered by BAL, as well as lesions within terminal bronchioles. Importantly, 25 ppm NO2 was also sufficient to cause AHR in mice, a cardinal feature of asthma. The inflammatory changes were ameliorated after 5 days of inhalation and completely resolved after 20 days of recovery after the 5-day inhalation. In contrast, in mice immunized and challenged with OVA, inhalation of 25 ppm NO2 caused a marked augmentation of eosinophilic inflammation and terminal bronchiolar lesions, which extended significantly into the alveoli. Moreover, 20 days postcessation of the 5-day 25 ppm NO2 inhalation regimen, eosinophilic and neutrophilic inflammation, pulmonary lesions, and AHR were still present in mice immunized and challenged with OVA. Collectively, these observations suggest an important role for NO2 in airway pathologies associated with asthma, both in modulation of degree and duration of inflammatory response, as well as in induction of AHR.
Animals↗
Airway hyperresponsiveness induced by cationic proteins in vivo: site of action.
Major basic protein and other native cationic proteins increase airway hyperresponsiveness when administered to the luminal surface of the airways in vitro. To determine whether the same applies in vivo, we assessed airway responsiveness in rats challenged with both aerosolized and intravenously infused methacholine. We partitioned total lung resistance into its airway and tissue components using the alveolar capsule technique. Neither poly-l-lysine nor major basic protein altered baseline mechanics or its dependence on positive end-expiratory pressures ranging from 1 to 13 cmH(2)O. When methacholine was administered to the lungs as an aerosol, both cationic proteins increased responsiveness as measured by airway resistance, tissue resistance, and tissue elastance. However, responsiveness of all three parameters was unchanged when the methacholine was infused. Together, these findings suggest that cationic proteins alter airway responsiveness in vivo by an effect that is apparently limited to the bronchial epithelium.
Aerosols↗
Tumor necrosis factor-alpha overexpression in lung disease: a single cause behind a complex phenotype.
RATIONALE: Tumor necrosis factor alpha (TNF-alpha) has been implicated as a key cytokine in many inflammatory lung diseases. These effects are currently unclear, because a transgenic mouse overexpressing TNF-alpha in the lung has been shown in separate studies to produce elements of both emphysema and pulmonary fibrosis. OBJECTIVES: We sought to elucidate the phenotypic effects of TNF-alpha overexpression in a mouse model. MEASUREMENTS: We established the phenotype by measuring lung impedance and thoracic gas volume, and using micro-computed tomography and histology. MAIN RESULTS: We found that airways resistance in this mouse was not different to control mice, but that lung tissue dampening, elastance, and hysteresivity were significantly elevated. Major heterogeneous abnormalities of the parenchyma were also apparent in histologic sections and in micro-computed tomography images of the lung. These changes included airspace enlargement, loss of small airspaces, increased collagen, and thickened pleural septa. We also found significant increases in lung and chest cavity volumes in the TNF-alpha-overexpressing mice. CONCLUSIONS: We conclude that TNF-alpha overexpression causes pathologic changes consistent with both emphysema and pulmonary fibrosis combined with a general lung inflammation, and consequently does not model any single human disease. Our study thus confirms the pleiotropic effects of TNF-alpha, which has been implicated in multiple inflammatory disorders, and underscores the necessity of using a wide range of investigative techniques to link gene expression and phenotype in animal models of disease.
Animals↗
Early intervention of therapy in asthma.
PURPOSE OF REVIEW: In addition to the acute manifestations of asthma, researchers now understand that asthma is a chronic inflammatory disease of the airways. Knowing the critical time to intervene in asthma is of utmost importance to clinicians and patients alike. This article reviews recent evidence that early intervention improves long-term outcomes in asthma. RECENT FINDINGS: The recent published literature demonstrates that early in the course of asthma, changes in structure occur, and that even in very young children, measurable abnormalities of lung function have already occurred. Large studies of inhaled corticosteroids given early in the progression of asthma show, at best, only modest effects on long-term lung function. Though a study on inhaled corticosteroids in very young children is ongoing, there is little evidence to suggest that any other commonly used medications have important effects on underlying lung function. Recent studies have also highlighted the lack of clear understanding of the relation between inflammation and remodeling, and parallel the disappointing results from studies of inhaled corticosteroids on lung function. SUMMARY: Current anti-inflammatory medications have modest effects on preventing loss of lung function in asthma. Although inhaled corticosteroids are highly efficacious in controlling the overt clinical manifestations of the disease, their effects on lung function are small. The standard paradigm of inflammation leading to remodeling and remodeling to loss of lung function may be overly simplistic. In the future, novel pharmacologic targets and careful timing of treatments must occur to intervene effectively with remodeling and/or decline in lung function in asthma.
Anti-Asthmatic Agents↗
Knowledge and use of office spirometry for the detection of chronic obstructive pulmonary disease by primary care physicians.
BACKGROUND: The importance of office spirometry has been strongly advocated in the pulmonary community, but whether its importance is recognized and accepted by primary care physicians is less well established. METHODS: To assess primary care physicians' knowledge and use of office spirometry for the detection of chronic obstructive pulmonary disease, we conducted a brief mail survey on the local practice of office spirometry, barriers to performing office spirometry, and general knowledge about spirometry. We also provided 60-min educational workshops to assess whether such an approach would increase spirometry testing or perceptions about spirometry. RESULTS: Twenty-nine of 57 (51%) primary care offices responded to the survey. Of these, 66% owned their own spirometer. The most common reasons for not performing spirometry were uncertainty about the impact of the test (41%), physician and staff unfamiliarity (38%), and lack of training (34%). Twenty-one respondents participated in the workshops. In the 3 months following the workshops, the number of spirometry tests increased by 59% (p = 0.004). After the workshops, the proportion of clinics that reported reasons for not performing the test decreased by 13% (p = 0.01), but important barriers to performing office spirometry were still present, including physician and staff unfamiliarity (22%), uncertain interpretation of results (22%), time (22%), and reimbursement (22%). CONCLUSIONS: The general knowledge and use of office spirometry in the primary care community is poor, but can be improved, at least in the short-term, by a simple educational workshop.
Clinical Competence↗
NF-kappa B activation in airways modulates allergic inflammation but not hyperresponsiveness.
Airways display robust NF-kappaB activation and represent targets for anti-inflammatory asthma therapies, but the functional importance of NF-kappaB activation in airway epithelium remains enigmatic. Therefore, transgenic mice were created in which NF-kappaB activation is repressed specifically in airways (CC10-IkappaBalpha(SR) mice). In response to inhaled Ag, transgenic mice demonstrated significantly ameliorated inflammation, reduced levels of chemokines, T cell cytokines, mucus cell metaplasia, and circulating IgE compared with littermate controls. Despite these findings, Ag-driven airways hyperresponsiveness was not attenuated in CC10-IkappaBalpha(SR) mice. This study clearly demonstrates that airway epithelial NF-kappaB activation orchestrates Ag-induced inflammation and subsequent adaptive immune responses, but does not contribute to airways hyperresponsiveness, the cardinal feature that underlies asthma.
Allergens↗
Defining a link with asthma in mice congenitally deficient in eosinophils.
Eosinophils are often dominant inflammatory cells present in the lungs of asthma patients. Nonetheless, the role of these leukocytes remains poorly understood. We have created a transgenic line of mice (PHIL) that are specifically devoid of eosinophils, but otherwise have a full complement of hematopoietically derived cells. Allergen challenge of PHIL mice demonstrated that eosinophils were required for pulmonary mucus accumulation and the airway hyperresponsiveness associated with asthma. The development of an eosinophil-less mouse now permits an unambiguous assessment of a number of human diseases that have been linked to this granulocyte, including allergic diseases, parasite infections, and tumorigenesis.
Allergens↗
Oscillation mechanics of the human lung periphery in asthma.
To more precisely measure the mechanical properties of the lung periphery in asthma, we have developed a forced oscillation technique that applies a broad-band flow signal through a wedged bronchoscope. We interpreted the data from four healthy and eight mildly asthmatic subjects in terms of an anatomically accurate computer model of the wedged segment. There was substantial overlap in impedance between the two groups, with resistance (R) showing minimal frequency dependence and elastance (E) showing positive and negative frequency dependence across subjects. After direct instillation of methacholine, R rose in both groups, but compared with healthy subjects, the asthmatic subjects displayed upward, parallel shifts in their dose-response curves. The baseline frequency-response patterns of E were enhanced after methacholine. Frequency dependencies of R and E were well reproduced in two normal subjects by a computational model that employed rigid airways connected to constant-phase tissue units but were better reproduced in the other two normal and three asthmatic subjects when the model employed heterogeneous, peripheral airway narrowing and compliant airways. To capture the frequency dependencies of R and E in the remaining five asthmatic subjects, the model was modified by increasing airway wall stiffness. These results indicate that the lung periphery of mildly asthmatic subjects is not well distinguished from that of healthy subjects by measurement of mechanical impedance at baseline, but group differences are seen after challenge with methacholine. Modeling of the response suggests that variable contributions of airway narrowing and wall compliance are operative in determining overall mechanical impedance of the lung periphery in humans with asthma, likely reflecting the functional consequences of airway inflammation and remodeling.
Adult↗
Unrestrained plethysmography is an unreliable measure of airway responsiveness in BALB/c and C57BL/6 mice.
There has been significant utilization of the technique described by Hamelmann et al. (Am J Respir Crit Care Med 156: 766-775, 1997) in which a parameter, enhanced pause (Penh), related to airways responsiveness is noninvasively measured by unrestrained plethysmography (UP). Investigating this technique, we sought to answer these questions: 1). How do changes in Penh compare with changes in traditional plethysmographic and lung mechanical parameters? 2). How do UP parameters perform in two different mouse strains? Awake immunized and control BALB/c (n = 16) and C57BL/6 (n = 14) mice were placed in the UP chamber and exposed to doses of aerosolized methacholine while the following parameters were measured at each concentration: inspiratory time (Ti), expiratory time (Te), total time (Ttot), Ti/Ttot, peak inspiratory pressure, peak expiratory pressure, Pause, Penh, tidal volume (Vt), Vt/Ti, Vt/Te, and Vt/Ttot. The next day, lung resistance (Rl) and compliance (Cl) were invasively measured in the same animals. For the BALB/c, the parameters with the highest magnitude of correlation coefficient vs. Rl are (in order) 1). Cl, 2). Pause and Penh, 3). parameters of breathing frequency (Te, Ttot, Ti), and 4). parameters related to Vt (inspiratory pressure, expiratory pressure). Flow parameters (Vt/Ttot, Vt/Te, Vt/Ti) and duty cycle parameters (Ti/Ttot) had insignificant correlations. This ordering is significantly different in C57BL/6 mice, in which the parameters with the largest correlations are 1). Cl, 2). parameters of breathing frequency, and 3). flow parameters. Pause, Penh, Vt, and duty cycle parameters had insignificant correlations. These data show that Penh is problematic in the sense that it is strain specific; it behaves very differently in BALB/c and C57BL/6 mice. We suggest that UP parameters largely originate as part of reflex control of breathing processes, rather than in the lung mechanics and conclude that it is inappropriate to use UP parameters in general, and Penh specifically, as substitute variables for invasive mechanical indexes such as Rl.
Airway Resistance↗
Inhibition of NFAT specifically in T cells prevents allergic pulmonary inflammation.
NFAT is a family of transcription factors important in the regulation of cytokine genes and is widely expressed in different lymphoid and nonlymphoid tissues. Consequently, the role of NFAT in CD4+ T cells during an in vivo immune response is not completely clear. In this study, we use transgenic mice expressing a dominant negative NFAT mutant exclusively in T cells to address the role of NFAT in T cells during a Th2 immune response in a model of allergic airway inflammation. We have observed that inhibition of NFAT in T cells results in a reduction of Ag-specific Th2 Ab levels and IL-4 production by CD4+ T cells. The accumulation of eosinophils in the bronchoalveolar lavage is delayed in dominant negative NFAT-transgenic mice. These mice are also more resistant to the development of lung pathology in response to allergen exposure. We, therefore, conclude that activation of NFAT in CD4+ T cells is required for the development of a Th2 immune response in vivo and allergic airway inflammation.
Animals↗