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Biomedical subjects

C G Irvin

Publications and source records attributed to C G Irvin.

At least 19 recordsLinked to original sources
PubMed2000

Interaction between the growing lung and asthma: role of early intervention.

Asthma is a syndrome where an imbalance exists between the forces that maintain airway patency and the forces that act to narrow, or close, airways. The child with asthma is a particular problem because of the rapid growth of the lung during growth that leaves it vulnerable. There is some evidence that asthma leads to impaired lung function in children because those children with untreated asthma show a loss of lung growth velocity. For unclear reasons, asthma is more frequent in boys. What drugs to use to treat childhood asthma is uncertain. Data show that glucocorticoids prevent the structure of the lung from fully developing. In children, the rationale for early intervention seems clear, but the exact means and criteria for initiation of the intervention are uncertain. Finally, childhood asthma raises fundamental issues and questions that are unique to the child with asthma and presents unique and many unresolved treatment dilemmas.

Asthma↗
PubMed2000

Airway-parenchyma uncoupling in nocturnal asthma.

Airway flow resistance is well known to be dependent upon lung volume. The rise in lung volume that occurs in asthma is therefore thought to be an important mechanism that defends airway patency. The purpose of the current study was to investigate the interdependence or mechanical coupling between airways and lung parenchyma during the inflammatory processes that occur in the patient with nocturnal asthma. Five patients with documented nocturnal asthma were studied in both a vertical and a horizontal body plethysmograph. Lung volume was altered with continuous negative pressure as applied to the chest wall with a poncho cuirass in different postures and during sleep. We found during the awake phase that an increase in lung volume decreased lower pulmonary resistance (Rlp); however, within 30 min of sleep onset, functional residual capacity (FRC) fell and Rlp rose more than would be expected for the fall in FRC. Restoring FRC to presleep values either at an early (half-hour) or a late (3-h) time point did not cause Rlp to significantly fall. A second phase of the study showed that the loss of Rlp dependence on lung volume was not due to the assumption of the supine posture. Indirect measurements of lung compliance were consistent with a stiffening of the lung. We conclude that with sleep there is an immediate uncoupling of the parenchyma to the airway, resulting in a loss of interdependence that persists throughout sleep and may contribute to the morbidity and mortality associated with nocturnal asthma.

Adult↗
PubMed2000

CD23 exhibits negative regulatory effects on allergic sensitization and airway hyperresponsiveness.

The effects of an anti-CD23 monoclonal antibody (B3B4) in CD23-deficient and CD23-overexpressing mice were compared in a murine model of allergic sensitization. After sensitization and challenge with OA, mice developed increased serum levels of OA-specific IgE and IgG(1) with airway eosinophilia and AHR when compared with nonsensitized animals. Anti-CD23 treatment was studied under two protocols: 10-d OA aerosol exposure and intraperitoneal sensitization followed by aerosol challenge. In both protocols anti-CD23 significantly reduced IgE and IgG(1) levels, abolished eosinophilia, and normalized AHR in BALB/c and wild-type CD23+/+ mice but not in CD23-/- mice. These changes were associated with increases in IFN-gamma and decreases in IL-4 production, suggesting that CD23 binding may affect not only IgE production but also the Th1/Th2 imbalance during the development of allergic AHR. Absence of CD23 in gene-deficient mice significantly enhanced OA-specific IgE and IgG(1) levels, airway eosinophilia, and AHR when compared with CD23+/+ wild-type littermates after sensitization and airway challenge. Sensitized and challenged CD23 transgenic mice also developed eosinophilic airway inflammation and methacholine hyperresponsiveness. However, the extent of AHR, BAL, and tissue eosinophilia in these animals showed a significant negative correlation with levels of CD23 expression on splenic T and B cells, demonstrating a limiting role of CD23 in the development of allergic AHR.

Animals↗
PubMed2000

Effects of cool, dry air stimulation on peripheral lung mechanics in asthma.

We have previously demonstrated that peripheral airway resistance (Rp) rises more in asthmatics than in nonasthmatic control subjects after segmental challenge with cool, dry air. To better understand this rise in Rp, we used a stop-flow method to measure the decay of segment pressure with time that yielded information on airway resistance (Raw), final plateau pressure (Pp), and peripheral lung compliance (Cp). After stop-flow maneuvers in all seven asthmatics and all seven normal subjects, pressure decayed smoothly without an initial sudden drop. This finding suggests that Raw was negligible and that the predominant site of flow resistance was the collateral pathways of the obstructed segment. Asthmatics had a significantly higher Pp and lower Cp at baseline than did normal subjects, but neither Pp nor Cp changed after challenge. Pp and Rp were significantly correlated. When interpreted in terms of a single-compartment nonlinear model, we concluded that Rp is predominantly determined by the resistance of the collateral airways rather than the more proximal airways. We also concluded that, compared with normal subjects, asthmatics have (1) more collateral airway narrowing and closure and lower segmental compliance, and (2) after challenge, increased collateral airway narrowing or closure without a change in compliance of the distal lung parenchyma. These results reflect the fundamental differences in peripheral lung mechanics between asthmatic and nonasthmatic subjects and in their response to directly instilled cool, dry air.

Adult↗
PubMed2000

The invaluable pressure-volume curve.

We present a case in which the pressure-volume (P-V) curve proved invaluable in the diagnostic workup of a patient. The patient was a 43-year-old man who presented with progressive dyspnea on exertion, restrictive spirometry, exercise desaturation, and an unremarkable CT scan. Because of the unexpected finding of an unremarkable CT scan, we wanted more data assuring the presence of an indication for lung biopsy. Detailed pulmonary function tests, including a P-V curve, were administered. The P-V curve was abnormal, thus prompting a biopsy, which revealed hypersensitivity pneumonitis. In this report, we discuss the use of P-V curves and the clinical presentation of hypersensitivity pneumonitis.

Adult↗
PubMed1999

Bradykinin-induced bronchospasm in the rat in vivo: a role for nitric oxide modulation.

Bradykinin has an important role in asthma pathogenesis, but its site of action is unclear. It was previously reported by the authors that bradykinin causes a dose-dependent reduction in dynamic compliance but little change in total lung resistance. This suggested that bradykinin may have a preferential effect in the distant lung. The purpose of the current investigation was to better characterize the effects of bradykinin on pulmonary resistance in rodents and explore the role of nitric oxide release in modulating the effect of bradykinin. Airway constriction was induced in the rats by aerosol administration of bradykinin with or without treatments with the inhaled bradykinin-2 receptor antagonist, Hoe 140 or the nitric oxide synthase inhibitors N(G)-nitro-L-arginine methylester or N(G)-monomethyl-L-arginine. Total lung resistance was partitioned into tissue and airway resistance by using the alveolar capsule method. Bradykinin induced a significant increase in both resistances. Hoe 140 abolished the response to bradykinin. The nitric oxide synthase inhibitors enhanced the bronchoconstricting response. In conclusion, the bradykinin response in the rats was not only localized to conducting airways but also involved a relatively selective tissue reaction. Bradykinin-induced bronchospasm in the rat is solely due to activation of bradykinin-2 receptor. Further, it was shown that nitric oxide significantly modulates the bronchospasm caused by bradykinin, suggesting that nitric oxide is an important modulator of airways responsiveness to bradykinin.

Airway Resistance↗
PubMed1999

Development of eosinophilic airway inflammation and airway hyperresponsiveness requires interleukin-5 but not immunoglobulin E or B lymphocytes.

We previously defined a role for B cells and allergen-specific immunoglobulins in the development of allergic sensitization, airway inflammation, and airway hyperresponsiveness (AHR), using a 10-d protocol in which allergen exposure occurred exclusively via the airways, without adjuvant. In the present protocol, normal and B-cell-deficient (microMt(-/-)) mice were sensitized intraperitoneally to ovalbumin (OVA) and challenged with OVA via the airways in order to examine the requirements for AHR with this protocol. T-cell activation (antigen-specific proliferative responses and Th2-type cytokine production) and eosinophil infiltration in the peribronchial regions of the airways, with signs of eosinophil activation and degranulation, occurred in both experimental groups. In contrast to the 10-d protocol, increased in vivo airway responsiveness to methacholine and in vitro tracheal smooth-muscle responses to electrical field stimulation were observed in both normal and B-cell-deficient mice, and these responses were inhibited by anti-interleukin (IL)-5 administration before airway challenge. These data show that IL-5, but not B cells or allergen-specific IgE, are required for eosinophil airway infiltration and the development of AHR following allergen/alum sensitization and repeated airway challenge with allergen. These results emphasize that the use of different sensitization and challenge protocols can influence the requirements for development of AHR.

Allergens↗
PubMed1999

The late, but not early, asthmatic response is dependent on IL-5 and correlates with eosinophil infiltration.

Early-phase reactions (EPRs) and late-phase reactions (LPRs) are characteristic features of bronchial asthma, although the pathogenetic mechanisms responsible for each of the responses are not fully defined. A murine model of EPRs and LPRs was developed to investigate the role of IL-5 and eosinophils in development of both responses. After initial intraperitoneal sensitization and airway challenge to ovalbumin (OVA), mice were provoked by additional exposure to OVA. An EPR, characterized by a transient increase in airway responsiveness, was observed 5-30 minutes after antigen provocation. This response was followed by an LPR that reached its maximum at 6 hours after challenge and was characterized by increased airway responsiveness and significant lung eosinophilia. The EPR was blocked by cromoglycate and albuterol, whereas the LPR was abolished by cromoglycate and hydrocortisone. Before provocation with allergen, administration of anti-IL-5 antibody prevented the influx of eosinophils into the lung tissue and abolished the LPR but not EPR. These results suggest that IL-5 and eosinophils are essential for development of the LPR, but not EPR, in this model.

Administration, Inhalation↗
PubMed1999

The pharmacology of aerosolized airway challenge.

Clinicians who perform and interpret airway challenge tests must understand the pharmacology involved. This knowledge helps one appreciate the need for certain procedures and the importance of proper technique. Methacholine and histamine are the most commonly used airway challenge agents. The authors review the pharmacology of methacholine and histamine airway challenge testing and discuss issues regarding the performance and interpretation of an airway challenge test.

Administration, Inhalation↗
PubMed1997

Development of eosinophilic airway inflammation and airway hyperresponsiveness in mast cell-deficient mice.

Mast cells are the main effector cells of immediate hypersensitivity and anaphylaxis. Their role in the development of allergen-induced airway hyperresponsiveness (AHR) is controversial and based on indirect evidence. To address these issues, mast cell-deficient mice (W/W v) and their congenic littermates were sensitized to ovalbumin (OVA) by intraperitoneal injection and subsequently challenged with OVA via the airways. Comparison of OVA-specific immunoglobulin E (IgE) levels in the serum and numbers of eosinophils in bronchoalveolar lavage fluid or lung digests showed no differences between the two groups of mice. Further, measurements of airway resistance and dynamic compliance at baseline and after inhalation of methacholine were similar. These data indicate that mast cells or IgE-mast cell activation is not required for the development of eosinophilic inflammation and AHR in mice sensitized to allergen via the intraperitoneal route and challenged via the airways.

Airway Resistance↗
PubMed1997

5-Lipoxygenase products are necessary for ovalbumin-induced airway responsiveness in mice.

To determine the role of 5-lipoxygenase products in the development of airway reactivity that follows antigen exposure, we sensitized mice by intraperitoneal injection of ovalbumin and aluminum hydroxide and serial exposure to aerosols of ovalbumin. Mice lacking a functioning 5-lipoxygenase enzyme were produced by targeted gene disruption. They and their wild-type controls had measurements of lung resistance (RL) made in response to intravenous methacholine; bronchoalveolar lavage fluid cell counts and serum immunoglobulin concentrations were also measured. Wild-type mice developed striking increases in cholinergic responsiveness; 5-lipoxygenase-deficient mice manifested minimal alterations in methacholine responsiveness (RL at the highest methacholine dose was 9.9 +/- 2.4 cmH2O.ml-1.s-1 under control conditions vs. 27.6 +/- 4.6 cmH2O.ml-1.s-1 after ovalbumin in wild-type mice; 5.9 +/- 0.9 vs. 7.01 +/- 2.2 cmH2O.ml-1.s-1 in 5-lipoxygenase-deficient mice). Ovalbumin provoked airway eosinophilia and increased immunoglobulins in wild-type mice, which were present to a significantly lesser degree in 5-lipoxygenase-deficient mice. We conclude that 5-lipoxygenase products are essential for the production of nonspecific airway reactivity in mice and suggest that 5-lipoxygenase products may be important in immunoglobulin formation.

Aerosols↗
PubMed1997

Hyperpnea-induced changes in parenchymal lung mechanics in normal subjects and in asthmatics.

The effects of hyperpnea on parenchymal lung mechanics are unknown, but they may contribute to the resultant airflow limitation commonly seen in asthma. To investigate these effects, we measured the following parameters in seven asthmatic and six normal subjects before and after 5 min of hyperpnea: specific conductance, upstream resistance, static compliance, the coefficient of retraction, lung volumes, lung hysteresis, and the ratio of maximal to partial flow rates (the M:P ratio, an indicator of the effect of deep inhalation on airflow, and a measure of relative airway and parenchymal hysteresis). In addition to a central effect on the airways, as shown by significant falls in specific conductance, hyperpnea in asthmatics, but not in normal subjects, resulted in significant increases in residual volume and pressure-volume hysteresis, suggestive of changes in parenchymal lung mechanics. The M:P ratio also increased in the asthmatics, consistent with greater increases in airway than in parenchymal hysteresis after hyperpnea. We conclude that hyperpnea has significant effects on the lung parenchyma that contribute to airflow limitation in asthmatics, and we hypothesize that these effects may be due to alterations in peripheral airway smooth muscle tone and surfactant function.

Adult↗
PubMed1997

Quality control of peak flow meters for multicenter clinical trials. The Asthma Clinical Research Network (ACRN).

Although peak expiratory flow (PEF) measurements are recommended for monitoring and assessing treatment of asthmatic patients, and widely employed to assess outcome in clinical trials and epidemiologic studies, information about performance of peak flow meters (PFM) under field conditions is lacking. We describe a simple testing system consisting of a testing chamber, a spirometer, and a calibration syringe to evaluate the relative accuracy or median relative bias (MRB), precision, or inter-quartile range (IQR) of the mini-Wright PFM. The relative accuracy ranged from -4.4 to 13.2% (mean, 4.1%) and the precision from 0.06 to 11.5% (mean, 1.2%). Durability of this PFM was assessed during a 26-wk clinical trial in 255 asthmatic subjects at five centers. Seventy-one PFM (19.9%) were identified as having failed to meet acceptance criteria, predominantly because of loss of relative accuracy, by the clinics at follow-up visits (n = 36), and by the Data Coordinating Center on retrospective review of quality control measurements submitted by the clinics (n = 35). This study indicates that a simple device can be used to evaluate the relative accuracy and precision of a given PFM and to ensure the quality of PEF measurements during a clinical trial. To the extent that one can extrapolate these data to other devices, our findings indicate that the failure rate of PFM over time can be high, indicating that quality control of a PFM over time is absolutely essential in clinical trials as well as in routine clinical care.

Asthma↗
PubMed1997

Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography.

To study the mechanisms and kinetics underlying the development of increased airway responsiveness (AR) after allergic sensitization, animal models have been invaluable. Using barometric whole-body plethysmography and increases in enhanced pause (Penh) as an index of airway obstruction, we measured responses to inhaled methacholine in conscious, unrestrained mice after sensitization and airway challenge with ovalbumin (OVA). Sensitized and challenged animals had significantly increased AR to aerosolized methacholine compared with control animals. AR measured as Penh was associated with increased IgE production and eosinophil lung infiltration. In a separate approach we confirmed the involvement of the lower airways in the response to aerosolized methacholine using tracheotomized mice. Increases in Penh values after methacholine challenge were also correlated with increased intrapleural pressure, measured via an esophageal tube. Lastly, mice demonstrating AR using a noninvasive technique also demonstrated increased pulmonary resistance responses to aerosolized methacholine when measured using an invasive technique the following day in the same animals. The increases in Penh values were inhibited by pretreatment of the mice with a beta 2-agonist. These data indicate that measurement of AR to inhaled methacholine by barometric whole-body plethysmography is a valid indicator of airway hyperresponsiveness after allergic sensitization in mice. The measurement of AR in unrestrained, conscious animals provides new opportunities to evaluate the mechanisms and kinetics underlying the development and maintenance of airway hyperresponsiveness and to assess various therapeutic interventions.

Airway Resistance↗
PubMed1997

Methacholine challenge testing: safety of low starting FEV1. Asthma Clinical Research Network (ACRN).

STUDY OBJECTIVE: The lower limit for the baseline value to initiate methacholine bronchial hyperresponsiveness testing has not been well established. Recommendations have varied from > 1 L to above 80% of predicted. The objective was to determine if an FEV1 < 60% predicted was acceptable. DESIGN: Retrospective analysis of challenges in 88 patients with a baseline FEV1 of < 60% predicted (mean=45.8%; range, 22 to 59%. SETTING: Academic institutions. RESULTS: There were only four individuals whose FEV1 did not return to > 90% of baseline following one poststudy beta2-agonist treatment. All four responded to a second treatment. There were no adverse sequelae following challenge in any individual. Neither age (up to 79 years) nor gender influenced outcome. CONCLUSIONS: In chronic moderate to severe asthma, it appears that bronchial hyperresponsiveness testing can be safely performed even in those patients with a low baseline FEV1.

Adrenergic beta-Agonists↗
PubMed1997

Office spirometry: equipment selection and training of staff in the private practice setting.

Spirometry is a basic pulmonary function test that is widely used for the detection of airflow limitation. Its use will continue to grow in the medical office setting because it is useful for both diagnostic and monitoring purposes. Additionally, the assessment of airflow reversibility is a quick, safe, and useful adjunct to baseline spirometry. Many manufacturers offer various models and types of spirometers. Before purchasing, determine the needs and characteristics of the office and its staff, and then choose an appropriate device. There is no "holy grail" for selecting what instrument is best for a specific office. Rather, it requires time and effort to make a good choice. Carefully assess the instrument before purchase and, ideally, compare several instruments. Once an instrument is purchased and it arrives, carefully validate it before reporting results. Proper training of the technicians who perform the testing is perhaps the most important factor in obtaining good spirometric testing. After adequate training, it is also important to have continued competency assessments, periodic inservices, and careful review of test results. The ATS and American Association for Respiratory Care (AARC) published extensive guidelines on the performance of spirometry. These recommendations should be followed to ensure quality and reduce interlaboratory variability. Patients should be properly prepared, the instrumentation properly calibrated, and the test conducted so that there is a good start, adequate exhalation time, satisfactory end-of-test, and good reproducibility between trials.

Age Factors↗