Airway Reactivity In Asthma Research Articles

Effect of Continuous Positive Airway Pressure on Airway Reactivity in Asthma. A Randomized, Sham-controlled Clinical Trial.

Studies have demonstrated that application of stress suppresses airway smooth muscle contractility. In animal models of asthma, continuous positive airway pressure (CPAP) reduced airway reactivity. Short-term studies of CPAP in patients with asthma showed reductions in airway reactivity. To evaluate whether nocturnal CPAP decreased the provocative concentration of methacholine to reduce FEV1 by 20% (PC20). One hundred ninety-four individuals with asthma were randomized (1:1:1) to use CPAP with warmed, filtered, humidified air at night at pressures either less than 1 cm H2O (sham) or at 5 cm H2O or 10 cm H2O. The primary outcome was change in PC20 after 12 weeks. Adherence to CPAP was low in all groups. Regardless, all groups had a significant improvement in PC20, with 12 weeks/baseline PC20 ratios of 2.12, 1.73, and 1.78 for the sham, 5 cm H2O, and 10 cm H2O groups, respectively, and no significant differences between the active and sham groups. Changes in FEV1 and exhaled nitric oxide were minimal in all groups. The sham group had larger improvements in most patient-reported outcomes measuring asthma symptoms and quality of life, as well as sinus symptoms, than the 5 cm H2O group. The 10 cm H2O group showed similar but less consistent improvements in scores, which were not different from improvements in the sham group. Adherence to nocturnal CPAP was low. There was no evidence to support positive pressure as being effective for reducing airway reactivity in people with well-controlled asthma. Regardless, airway reactivity was improved in all groups, which may represent an effect of participating in a study and/or an effect of warm, humid, filtered air on airway reactivity. Clinical trial registered with www.clinicaltrials.gov (NCT01629823).

Cyclic GMP-dependent protein kinase regulation of airway smooth muscle in asthma

The mechanisms regulating altered airway smooth muscle (ASM) cell tone and airway reactivity in asthma remain incompletely understood. For vascular smooth muscle (VSM), the most important endogenous relaxation pathway is the nitric oxide (NO)-guanylate cyclase-cyclic GMP-dependent protein kinase type I (PKGI) pathway in which endogenous NO from NO synthases or from exogenous nitrovasodilators activate guanylate cyclase, increasing cGMP levels, and activating PKGI. PKGI in turn targets specific VSM molecules that mediate smooth muscle relaxation. Recent evidence supports that in ASM, like in VSM, activators of guanylyl cyclases have significant cGMP-mediated relaxant and antiproliferative effects. PKGI is therefore a prime but unexplored candidate molecule to mediate ASM relaxation. Recently, we have used mice harbouring a mutation in the leucine zipper N-terminal interaction domain (LZM mice [1]) to test the hypothesis that PKGIα is a critical mediator of ASM relaxation that normally protects against airway hyperresponsivity via interactions with specific molecular targets, including ASM myosin phosphate and Rho/Rho-kinase, and that this regulatory system is perturbed in the setting of asthma. Using this knock-in mouse harboring a discrete mutation in the protein-protein interaction domain of PKGI, which disrupts NO-PKG-mediated smooth muscle relaxation by disrupting the PKGI-myosin phosphatase complex we have begun to explore the mechanism of PKGI-mediated ASM relaxation and the role of PKGI in models of asthma. Several asthma studies in LZM mice and WT littermates have now been performed and analyzed using both the acute and the chronic House Dust Mite (HDM) asthma model in WT and LZM mice. Endpoints examined include airway responsiveness to methacholine; quantification of inflammatory cell populations from Bronchoalveolar lavage (BAL); and studies of airway smooth muscle in the mice. In the LZM mice, there is a significant increase in bronchospasm noted in the airways of mutant mice in both acute and chronic asthma models. No differences between WT and LZM mice in the extent of increase in either total cells or in eosinophilia in BALF samples following HDM was noted in the either the acute or chronic models. The extent and volume of Airway SMC a-actin was also measured in the WT and LZM mice following HDM-induced asthma in the acute model. SMC labeling in the airways was quantified using immunohistochemistry and computerized morphometrics and for each measure, a significant increase in SMC number and total volume was noted in the LZM mice. Studies of PKG expression level and of SMC proliferation in the asthma models are underway. These experiments will provide better understanding of ASM relaxation at the molecular level and have the potential to identify novel gene targets for the development of new therapeutic approaches to bronchoconstriction in asthma.

270 Physiologic specificity of emotions and their impact on airway reactivity in asthma

270 Physiologic specificity of emotions and their impact on airway reactivity in asthma

Inflammation and airway reactivity in asthma

The increased airway reactivity characteristic of asthma may be due to contraction of airway smooth muscle, mucus hypersecretion, edema and thickening of airway walls, and the pressure of serum proteins and inflammatory cells and their products in the airways. Increased airway reactivity in asthma correlates with airway epithelial damage and is clearly related to airway inflammation, a process that most likely involves a complex interaction among mast cells, lymphocytes, eosinophils, and macrophages. Thus, although symptomatic treatment of airway narrowing is best accomplished with bronchial smooth muscle relaxants, treatment of the basic pathophysiologic defect should attempt to reduce airway inflammation. Bronchodilators (inhaled β-agonists and, occasionally, theophylline), which do not decrease airway reactivity, are often used to treat the symptoms of patients with mild or episodic asthma; inhaled corticosteroids, which do decrease airway inflammation and reactivity, are used to treat patients with more severe symptoms. Methotrexate and cromolyn sodium may also be used, although their role in treating the underlying pathophysiology remains controversial. Identification of new agents that are as effective as corticosteroids but that do not produce their side effects would represent a major therapeutic advance for patients with asthma.

Advances in outpatient antimicrobial therapy: Loracarbef

O ur understanding of the structure-activity relationships of antibiotics has increased dramatically since penicillin became available almost 50 years ago. This knowledge has enabled investigators to develop new agents with a variety of improvements compared with early antibiotics, including a wider spectrum of antibacterial activity, greater chemical stability, greater oral absorption with less effect on gastrointestinal flora, fewer side effects, more convenient dosing schedules, and fewer drug interactions. The progressive development of the fl-lactam antibiotics has included side chain modifications in their chemical structures, such as those that resulted in penicillinase-resistant penicillins, and nuclear ring alterations that have led to new classes of antibiotics, such as the cephalosporins. A recent addition to the/3-1actam antibiotics is the oral agent loracarbef, which represents a new carbacephem class. The carbacephems are similar in structure to the cephalosporins except that a methylene group in the tetrahydropyridine ring of the carbacephem nucleus has replaced the sulfur atom in the dihydrothiazine ring of the cephalosporin nucleus. This change renders the carbacephem nucleus more chemically stable than the corresponding cephalosporin nucleus. On June 13-15, 1991, an investigators' meeting was held in San Francisco, California, to discuss the preclinical and clinical data on loracarbef. The safety and efficacy results of clinical trials that compared loracarbef with oral antibiotics currently in use for a variety of bacterial infections--including acute bronchitis, acute exacerbations of chronic bronchitis, pneumonia, sinusitis, pharyngitis and tonsillitis, skin infections, pyelonephritis, and urinary tract infections--were reported at the meeting. Also included in the program was a clinical forum on pathogenesis of and therapy for common lung disorders. The focus of the clinical forum was the underlying mechanisms of respiratory dysfunction, including inflammation and airway reactivity in asthma, fibrosis in acute lung injury, and the effects of neutrophils on the lung, as well as new treatments in cystic fibrosis, such as aerosolization of therapeutic agents and somatic gene therapy. The articles in this supplement are based on the presentations and discussions at this meeting. Preclinical data on loracarbef indicate that this compound has broad in vitro activity against common pathogens (including fl-lactamase-producing organisms) and that it is well absorbed and clinically stable. In singleor double-blind, randomized clinical trials involving more than 9,000 patients, it was compared with other antibiotics for its ability to resolve a number of bacterial infections, including acute bronchitis, acute exacerbations of chronic bronchitis, pneumonia, sinusitis, pharyngitis and tonsillitis, otitis media, skin infections, urinary tract infections, and pyelonephritis. A data base of this size, which is unprecedented in comparative antibiotic trials, allows more reliable conclusions to be drawn concerning the safety and activity of the drugs studied. It also allows the analysis of special subpopulations, such as elderly and pediatric patients, both of whom frequently experience adverse effects from antibiotics. The results of these clinical trials indicate that the efficacy of loracarbef is comparable to that of the comparison agents and that it has a favorable safety profile, even in pediatric and geriatric patients. Most adverse events that occurred in the loracarbef-treated patients were mild and transient; diarrhea was the most common adverse reaction, but it was reported less frequently in the loracarbef patients than in those who received the comparison agents. The safety, efficacy, broadspectrum activity, and stability of loracarbef suggest that it is reasonable to consider this compound as an option when empirical therapy is indicated for a variety of common bacterial infections. The extensive clinical information provided in this supplement should enable the practicing physician to utilize loracarbef effectively in appropriate patients.

Lymphocyte proliferation to antigen E: Demonstration of the restriction of antigen E-specific T cells to ragweed-allergic donors

Allergic sensitivity to ragweed is common among atopic individuals in North America and can be associated with symptoms of seasonal hay fever and increased airway reactivity in asthma. This sensitivity is mediated by IgE antibody to ragweed antigens that in turn is presumed to be the product of B-lymphocytes regulated by various T cell subsets. Proliferation in vitro by lymphocytes obtained from individuals allergic to ragweed and cultured in the presence of ragweed antigen E (AgE) has been repeatedly described, but a comprehensive study of this proliferation has questioned the specificity of this response. We have examined this question and found that in the first week of culture, the specific lymphocyte proliferation to AgE may be obscured by high background and mitogen-like proliferation. However, by carrying the cells for a longer period of time in culture and providing a second in vitro boost with AgE, specific proliferation could be clearly documented. Lymphocytes from atopic ragweed-allergic donors proliferated at levels 20 to 50 times beyond background in the presence of AgE. Cells from nonragweed-allergic donors (either nonatopic or atopic) did not do so. The AgE-responsive cells could be expanded in culture and demonstrated to be T cells. Moreover, AgE-responsive T cells could only be cloned from AgE-allergic donors and, after expansion and subcloning, demonstrated to respond to AgE but not partially purified dust mite antigen. In contrast, a clone of T cells from a dust mite-sensitive individual proliferated in response to the dust mite antigen but not AgE.

Enhanced IgE-dependent basophil histamine release and airway reactivity in asthma.

IgE-dependent basophil histamine release does not necessarily correlate with the amount of cell-bound IgE, thus it has been suggested that basophil "releasability" is an important, but yet undefined, factor in this secretory process. Because mast cell, and possibly basophilic leukocyte, mediator release contributes to airway reactivity, any enhancement of this secretory process would favor asthma provocation. To evaluate IgE-dependent basophil histamine releasability in asthma, suspensions of leukocytes were isolated from patients with an allergic and nonallergic component to their airway disease and stimulated with concanavalin A (Con A) (0.03 to 10.0 micrograms/ml) and anti-IgE (10 to 1,000 ng/ml). Basophil histamine release to Con A and anti-IgE was significantly greater in both allergic and nonallergic asthmatic patients when compared with normal subjects. In contrast, basophil histamine release to the calcium ionophore A23187 was similar in leukocytes from normal subjects and asthmatic patients, suggesting the observed abnormality in secretion may be limited to an IgE-dependent process. To further determine if basophil histamine releasability in asthma correlated to measures of airway reactivity, bronchial provocation with histamine was performed. An inverse correlation was found between the provocative dose of inhaled histamine required to produce a 20% decrease, PD20, in the FEV1 and the leukocyte histamine release to Con A (p less than 0.05) and anti-IgE (p less than 0.05). Thus, we have new evidence that enhanced IgE-dependent release of leukocyte histamine correlates with airway reactivity in asthma. The mechanism of basophil releasability and its relationship to the pathogenesis of airway reactivity in asthma have yet to be established.

Pupillary responses and airway reactivity in asthma

Pupillary responses to phenylephrine and carbachol and airway reactivity were determined in 19 drug-free persons with mild allergic asthma, 21 nonatopic control subjects, and six asymptomatic atopic control subjects. The concentration of phenylephrine required to dilate the pupil 1 mm, obtained by interpolation on the dose-response curve, was taken as a measure of α-adrenergic sensitivity. This concentration was significantly lower for subjects with asthma than for atopic or nonatopic control subjects (1.11± 0.68% [mean ± SD], 1.86 ± 0.81%, and 1.52 ± 0.67%, respectively; p < 0.05 by analysis of variance). The concentration of carbachol required for pupillary constriction of 1 mm, obtained by interpolation on the dose-response curve, was taken as ameasure of cholinergic sensitivity. This value was significantly lower for subjects with asthma than for atopic or nonatopic control subjects (0.23 ± 0.12%, 0.41 ± 0.14%, and 0.35 ± 0.19%, respectively; p < 0.05 by analysis of variance). Pupillary α-adrenergic and cholinergic sensitivity were significantly correlated (Spearman's rank correlation coefficient, R s = 0.42, p < 0.05). Both α-adrenergic and cholinergic sensitivity of the pupils correlated with airway reactivity expressed as concentration of methacholine causing a 20% fall in FEV, (R s = 0.35%, p < 0.05, and R s = p < 0.05, respectively). The autonomic aberrations cannot be attributed to drug use or significantly abnormal pulmonary mechanics. Autonomic abnormalities are associated with allergic asthma and may contribute to the airway reactivity characteristic of the disease.

The Influence of Resting Airway Calibre on Non-Specific and Specific Airway Reactivity in Asthma

The Influence of Resting Airway Calibre on Non-Specific and Specific Airway Reactivity in Asthma