Can anti-IgE therapy prevent airway remodeling in allergic asthma?

Airway remodeling is a central feature of asthma. It is exemplified by thickening of the lamina reticularis and structural changes to the epithelium, submucosa, smooth muscle, and vasculature of the airway wall. Airway remodeling may result from persistent airway inflammation. Immunoglobulin E (IgE) is an important mediator of allergic reactions and has a central role in airway inflammation and asthma-related symptoms. Anti-IgE therapies (such as omalizumab) have the potential to block an early step in the allergic cascade and therefore have the potential to reduce airway remodeling. The reduction in free IgE levels following anti-IgE therapy leads to reductions in high-affinity IgE receptor (FcεRI) expression on mast cells, basophils, and dendritic cells. This combined effect results in attenuation of several markers of inflammation, including peripheral and bronchial tissue eosinophilia and levels of granulocyte macrophage colony-stimulating factor, interleukin (IL)-2, IL-4, IL-5, and IL-13. Considering the previously demonstrated anti-inflammatory effects of anti-IgE therapy, along with results from a small study showing continued benefit after discontinuation of long-term treatment, a larger study to assess its effect on markers of airway remodeling is underway.

Predicting worsening asthma control following the common cold.

The asthmatic response to the common cold is highly variable, and early characteristics that predict worsening of asthma control following a cold have not been identified. In this prospective multicentric cohort study of 413 adult subjects with asthma, the mini-Asthma Control Questionnaire (mini-ACQ) was used to quantify changes in asthma control and the Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) to measure cold severity. Univariate and multivariable models were used to examine demographic, physiological, serological and cold-related characteristics for their relationship to changes in asthma control following a cold. Clinically significant worsening of asthma control was observed following a cold (mean+/-SD increase in mini-ACQ score of 0.69+/-0.93). Univariate analysis demonstrated that season, centre location, cold duration and cold severity measurements were all associated with a change in asthma control. Multivariable analysis of the covariates available within the first 2 days of cold onset revealed that the day 2 and cumulative sum of day 1 and 2 WURSS-21 scores were significant predictors of the subsequent changes in asthma control. In asthmatic subjects, cold severity within the first 2 days can be used to predict subsequent changes in asthma control. This information may help clinicians prevent deterioration in asthma control following a cold.

A common cold virus, rhinovirus 16, potentiates airway inflammation after segmental antigen bronchoprovocation in allergic subjects.

Many patients with asthma have increased wheezing with colds. We hypothesized that rhinovirus colds might increase asthma by augmenting airway allergic responses (histamine release and eosinophil influx) after antigen challenge. Seven allergic rhinitis patients and five normal volunteers were infected with rhinovirus type 16 (RV16) and evaluated by segmental bronchoprovocation and bronchoalveolar lavage. Segmental challenge with saline and antigen was performed 1 mo before infection, during the acute infection, and 1 mo after infection. Lavage was performed immediately and 48 h after antigen challenge. Data were analyzed by two-way analysis of variance, and a P value of < or = 0.05 was considered to be significant. All volunteers inoculated with RV16 developed an acute respiratory infection. BAL fluid obtained from allergic rhinitis subjects during the acute viral infection, and 1 mo after infection, showed the following significant RV16-associated changes after antigen challenge: (a) an enhanced release of histamine immediately after local antigen challenge; (b) persistent histamine leak 48 h afterwards; and (c) a greater recruitment of eosinophils to the airway 48 h after challenge. These changes were not seen in non-allergic volunteers infected with RV16 and challenged with antigen, nor in allergic volunteers repetitively challenged with antigen but not infected with RV16, nor in RV16 infected allergic volunteers sham challenged with saline. We conclude that rhinovirus upper respiratory infection significantly augments immediate and late allergic responses in the airways of allergic individuals after local antigen challenge. These data suggest that one mechanism of increased asthma during a cold is an accentuation of allergic responses in the airway which may then contribute to bronchial inflammation.

Anti-leukotrienes for asthma.

The field of cysteinyl leukotriene research has moved forward considerably in the past two years. Significant recent advances have been made in three areas: genetic control of the cysteinyl leukotriene response, in which alterations in both the promoter region and in transcribed mRNA have been described; the mechanisms by which cysteinyl leukotrienes promote the development of inflammation; and extensions in the clinical arena that support broader positioning of leukotriene modifiers in the therapy of asthma and allergic diseases.

Increased nitric oxide production by airway cells of sensitized and challenged IL-10 knockout mice.

The anti-inflammatory cytokine interleukin (IL)-10 suppresses inducible nitric oxide synthase (iNOS); therefore, NO production should increase in the absence of IL-10. Production of NO (as nitrite) by bronchoalveolar lavage cells of IL-10 knockout ((-/-)) mice was assessed after ovalbumin sensitization and airway challenge (S/C) and was compared with the IL-10-sufficient, wild-type (WT) C57Bl6. Eosinophil recruitment occurred in S/C WT and IL-10(-/-) mice, suggesting allergic airway inflammation. Alveolar macrophages (per g mouse) were unchanged (approximately 3x10(4) cells) with the exception of a doubling in the S/C IL-10(-/-) mice (approximately 6x10(4) cells, P<0.05). NO production (per million cells) was doubled in cells from S/C IL-10(-/-) (15.3 microM) mice compared with WT (7.6 microM, P<0.05). Inhibition of iNOS by L-N(5)-(1-iminoethyl)-ornithine reduced NO production in all S/C mice, confirming that the increase was a result of up-regulation of iNOS. We conclude that IL-10 is a critical cytokine regulating iNOS in murine airway cells and that its absence can lead to up-regulation of iNOS and development of allergic airway inflammation.

Variable tracheal stenosis related to body position.

We demonstrated a variable extrathoracic tracheal stenosis which developed after technically adequate tracheostomy and was worsened by changes in body position. When the patient's arms were above his head, minimal airway diameter was reduced 31 percent, and maximal inspiratory flow rate 37 percent below values measured with arms down, but expiratory flow rates were preserved. Tracheostomy may disrupt the integrity of tracheal support and allow airway collapse under circumstances of increased extratracheal or decreased intratracheal pressure.

Current outpatient management of asthma shows poor compliance with International Consensus Guidelines.

STUDY OBJECTIVE: This study aimed to establish whether the outpatient management of patients presenting with an asthma exacerbation to the emergency department (ED) was in compliance with the 1992 guidelines of the "International Consensus Report on the Diagnosis and Management of Asthma." DESIGN: Prospective, observational study using a researcher-administered questionnaire. SETTING: University tertiary referral ED. PATIENTS: Convenience sample of asthmatics (aged 18 to 54 years) presenting for asthma treatment between July 1, 1997, and June 30, 1998. RESULTS: Eighty-five asthmatic patients were enrolled. Of these, 34 patients (40%) smoked, 53 patients (62%) were undertreated with medication when compared to the consensus guidelines, and 74 patients (87%) had no written "plan of action." During an asthma attack, 9 patients (11%) did not use a bronchodilator as first-line action and 76 patients (89%) did not commence or increase the use of an inhaled steroid. Forty-nine patients (58%) did not know that bronchospasm occurred in asthma, and 53 patients (62%) did not know that bronchial swelling occurred. Twenty-six patients (31%) thought short-acting bronchodilator drugs were asthma preventers. Sixty-two patients (73%) could not adequately define peak expiratory flow (PF), 41 patients (48%) did not own a PF meter, and only 8 patients (9%) determined their PF daily. Fifty-three patients (62%) were reviewed by a physician once a year or less, and 18 patients (21%) noted family and friends as their only source of asthma education. CONCLUSIONS: The outpatient management of most asthma patients presenting to the ED did not comply with the consensus guidelines, and asthma knowledge was poor.

The role of eosinophils in the pathophysiology of asthma.

From current information, a number of conclusions can be drawn. Antigen activation of the allergic reaction in the airways is associated with an immediate rise in mast cell derived mediators, including histamine and tryptase. Associated with antigen activation of the allergic reaction is recruitment of eosinophils to the airways. This can best be seen in the airway lavage 48 hours after challenge with antigen. An increased presence of eosinophils suggests that they are an important contributor to the late allergic reaction and may be one of the major constituents in the development of bronchial inflammation. Although many factors participate in the late allergic inflammatory response, eosinophil-derived proteins are known to cause airway injury. Regulation of eosinophils in this process is not clearly established; however, our findings of increased IL-5 in relationship to the presence of eosinophils and their granular proteins suggests that this cytokine may be an important modulator of eosinophil function and activation following allergen challenge. However, much remains unknown in understanding bronchial inflammation and the eosinophil's role in the process. In conclusion, the eosinophil is a major cellular participant in late phase allergic airway disease. Its presence and known functions suggest that the eosinophil is a significant cellular factor in the development of allergic airways disease in asthma. Further advances in this area will follow continued studies, particularly those which involve biopsy and correlation with airway physiology.

Current prospective of aldose reductase inhibition in the therapy of allergic airway inflammation in asthma.

The prevalence of asthma and costs of its care have been continuously increasing, but novel therapeutic options to treat this inflammatory disease have not been brought to the US market. Current therapies such as inhaled steroids, long-acting beta-agonist bronchodilators, antihistamines and immunomodulators may control the symptoms of allergic asthma but fail to modify the underlying disease. Excessive use of steroids and other immunosuppresents alter the patient's quality of life, produce undesirable toxicities, and increase the risk of other pathologies such as diabetes. Hence novel therapeutic options to manage asthma are desirable. In the present review, we have discussed the role of the polyol pathway enzyme aldose reductase (AR) in the amplification of allergic airway inflammation. Recent studies have indicated that AR inhibition prevents the NF-κB-dependent generation of pro-inflammatory cytokines and chemokines in mouse models of allergic airway inflammation indicating the potential use of AR inhibition as a novel tool to control allergic responses. Since orally available AR inhibitors have already undergone phase III clinical trials for diabetic neuropathy and appear to have a manageable side effects profile, they could be readily developed as potential new drugs for the treatment of asthma and related complications.

Summary of clinical trials with zafirlukast.

Zafirlukast is an orally active and selective cysteinyl leukotriene (cysLT) receptor antagonist. In humans, zafirlukast antagonized the effects of exogenously administered LTD4 and cysLTs released endogenously in response to physical and chemical stimuli. Zafirlukast antagonized LTD4-induced bronchoconstriction, with effects still evident 12 h after drug administration. In clinical models of asthma, zafirlukast inhibited bronchospasm after allergen or exercise challenge in patients with asthma. In multicenter trials in patients with chronic, stable asthma, zafirlukast reduced asthma symptoms, decreased as-needed beta-agonist use, and improved pulmonary function without increasing the number of adverse events. Zafirlukast also exhibited evidence of an anti-inflammatory effect in the lung in preliminary studies involving segmental antigen challenge. The results from these clinical trials demonstrate that zafirlukast is effective and safe for the prophylactic treatment of asthma.

Asthma entities.

Asthma is a syndrome characterized by variable airflow limitation, airway hyperresponsiveness and airway inflammation. Considering asthma in aggregate, it is clear that a number of distinct mechanisms underlie the development of this disorder. In some patients, the mechanistic distinctions can be clearly drawn, and important therapeutic insights can be gained. In other patients, several mechanisms may coexist, or it may be impossible to separate them with current methods and technology. To distinguish subsets of asthma is more than an academic exercise. For both clinicians and asthma researchers, it is valuable to distinguish asthma subtypes as clearly as possible. Clinicians strive to prescribe the most effective, most safe, and most cost effective therapy possible, and understanding asthma subsets and their underlying mechanistic differences can substantively facilitate achieving that objective. Asthma research is often limited by significant, and sometimes dramatic intersubject variability. It is likely that at least some of that variability may arise from the (unrecognized) mechanistic heterogeneity of asthma. Better definition and selection of more homogeneous subsets of asthma may then lead to greater statistical power, and more definitive conclusions from asthma investigations.

Enhanced reactive oxygen species metabolism of air space cells in hypersensitivity pneumonitis.

Reactive oxygen species (ROS) are produced by phagocytic cells as part of host defense mechanisms, but these same products released by air space cells have been shown to contribute to pulmonary inflammation in interstitial lung diseases and likely represent a general mechanism of lung injury. However, the possible contribution of these compounds to lung inflammation in hypersensitivity pneumonitis (HP) has yet to be reported. We performed 11 bronchoalveolar lavage (BAL) studies in six patients with HP and compared the results with results from studies in 21 healthy normal volunteers. In patients with HP, spontaneous and stimulated measures of ROS metabolism by air space cells were significantly higher than those seen in normal volunteers. When alveolar macrophages were purified by depleting neutrophils and eosinophils on density gradients of Percoll (specific gravity 1.075 gm/ml), ROS metabolism remained elevated when compared with that in cells obtained from healthy controls, confirming that alveolar macrophage ROS metabolism is enhanced in patients with HP. Further, we found significant elevations in BAL total protein, lymphocytes, eosinophils, and neutrophils in patients with HP when they were compared with normal volunteers, with an increased proportion of BAL T lymphocytes expressing CD8 and natural killer surface antigens, consistent with previous work. Lavage samples from patients with HP with clinically active disease had higher proportions of BAL eosinophils and concentrations of total protein, lower forced expiratory volume in 1 second, lower forced vital capacity, and lower arterial oxygen tensions, and higher indices of ROS metabolism than samples from patients with HP with inactive disease. HP is associated with evidence of air space inflammation, to which alveolar macrophage-derived ROS may contribute.

Heterogeneity in cell recovery and superoxide production in buoyant, density-defined subpopulations of human alveolar macrophages from healthy volunteers and sarcoidosis patients.

Reactive oxygen species (ROS) are ubiquitous compounds produced by phagocytes with important roles in both host defense and pulmonary inflammation. Enhanced ROS metabolism by alveolar macrophages (AM) has been previously demonstrated in various interstitial lung diseases including sarcoidosis. We studied 17 healthy, nonsmoking volunteers and 10 patients with sarcoidosis by bronchoalveolar lavage, and separated AM on discontinuous Percoll gradients to determine patterns of airspace cell recovery and the corresponding ROS metabolism of density-defined AM subpopulations. AM subpopulations were largely purified from contaminating granulocytes, thereby allowing more accurate estimation of ROS metabolism by AM. In bronchoalveolar lavage material from sarcoidosis patients, increased recovery of cells of high (1.075 gm/ml) density was found, which contrasted with the pattern seen in the volunteers in whom cells of lowest density (1.045 gm/ml) predominated. In addition, dense cells from sarcoidosis patients exhibited enhanced stimulated ROS metabolism compared with cells of similar density obtained from the volunteers or with sarcoid cells of lower density. At least three mechanisms may contribute to increased lung oxidative burden in sarcoidosis. The combination of increased bronchoalveolar lavage cell counts, increased cell recovery at high density, and increased cell function produced substantial increases in the total oxidative burden imposed on the lungs of sarcoidosis patients by airspace cells. We conclude that AM metabolism of ROS is dependent on the density and, by implication, the maturity of the cells and that regulation of AM ROS metabolism differs markedly between sarcoidosis patients and healthy volunteers.

Exercise-induced asthma is not associated with mast cell activation or airway inflammation.

Exercise-induced asthma (EIA) may affect up to 90% of patients with asthma. Hyperpnea associated with exercise leads to increased airway water and heat loss, which contributes to the development of EIA. Measurement of circulating mediators has suggested that mast cells may participate in the development of EIA via release of histamine and neutrophil chemotactic factor. To evaluate further the contribution of pulmonary mast cell-mediator release in the pathogenesis of EIA and to determine whether EIA is associated with enhancement of airway inflammation, we studied 11 subjects with mild stable asthma (FEV1, 93% +/- 3% predicted; mean +/- SEM) with significant EIA (after exercise fall in FEV1, 41% +/- 5%). Bronchoalveolar lavage (BAL) was performed immediately (less than 1 hour) after exercise challenge (EC) and repeated 24 hours later (exercise studies). On another occasion, paired BALs were done 24 hours apart (control studies). A minimum of 2 weeks separated the exercise and control pairs. No changes were observed in BAL cell counts, differentials, or reactive oxygen species metabolism after EC. Neither BAL histamine nor BAL tryptase levels increased, either shortly (less than 1 hour) or 24 hours after EC. We conclude that EC in subjects with asthma is not associated with cellular influx to airspace and that mechanisms other than histamine release by pulmonary mast cells may be responsible for EIA.

Enhanced reactive oxygen species metabolism of airspace cells and airway inflammation follow antigen challenge in human asthma.

Airflow limitation and airway inflammation follow antigen bronchoprovocation in sensitized individuals. Inflammation likely results from the interplay of several previously demonstrated factors, but the participation and persistence of enhanced reactive oxygen species (ROS) metabolism of airspace cells after antigen challenge have received more limited attention. We studied nine subjects with mild asthma by bronchoalveolar lavage before and 48 (one subject) to 72 (eight subjects) hours after antigen bronchoprovocation and compared airspace cell numbers and types, cell function, and bronchoalveolar lavage fluid protein, albumin, and immunoglobulins. Mild, but significant, airflow limitation persisted at the time of the second lavage. Eosinophil influx was a notable component of the increased airspace cells in postchallenge lavages. Airspace cells demonstrated significantly enhanced ROS metabolism, and total protein, albumin, and IgM levels were higher in postchallenge lavage specimens. Antigen bronchial challenge produces airspace inflammation, which may develop, in part, as a consequence of enhanced ROS metabolism of airspace cells.

Bronchoalveolar lavage in stable asthmatics does not cause pulmonary inflammation.

Bronchoalveolar lavage (BAL) has become an important tool for evaluating changes in airway cells and fluid in asthma, and it may give insights into mechanisms of bronchial inflammation. Many factors contribute to airway inflammation in asthma including, possibly, airway instrumentation. To establish whether BAL leads to diffuse airway inflammation in stable asthmatics, we performed paired BAL studies (24 h apart) in eight subjects with mild asthma whose prebronchoscopy spirometric results were similar on both days. Airflow limitation did not occur in any subject after bronchoscopy. We observed no significant changes in BAL volume return, cell differential, lymphocyte subsets, reactive oxygen species metabolism by air-space cells, or BAL total protein. There was a slight increase in second-day BAL total cell return. We conclude that bronchoscopy and BAL in stable asthmatics with mild disease is not associated with evidence of diffuse airway inflammation.

Modulation of human peripheral blood monocyte superoxide release by interferon-gamma and lipopolysaccharide.

Reactive oxygen species (ROS) have generated increasing interest for their possible role in a wide variety of diseases. Interferon-gamma (IFN-gamma), a potent immunoregulatory lymphokine, is likely involved in control of ROS metabolism. In this study, the superoxide release of cultured human peripheral blood monocytes (PBM) after exposure to IFN-gamma and lipopolysaccharide (LPS) was examined. Compared with controls, adherent monocytes cultured with 80 units of IFN-gamma for 48 hours demonstrated fourfold increased spontaneous and twofold increased PMA stimulated release of superoxide anion. In addition, the enhanced superoxide release was both dose and time dependent. Further experiments showed that bacterial LPS in concentrations as low as 4 ng/mL markedly reduced monocyte superoxide release and abrogated the enhancing effects of IFN-gamma.

Enhanced production of oxygen radicals in asthma.

Oxygen radicals have been implicated in a variety of disease processes including asthma. In this study we investigated the production of superoxide by airspace cells in 56 patients with asthma as compared with 49 normal controls. We found that with patients with asthma with a forced expiratory vital capacity in the 1st second (FEV1) of less than 80% (n = 13) had higher spontaneous superoxide (SO) production when compared with normal subjects (3.6 +/- 1.0 versus 1.9 +/- 0.2 nmol/5 x 10(5) cells/hour, p < 0.01), whereas those with FEV1 > 80% (n = 40) were similar to normal subjects in superoxide generation (2.1 +/- 0.3 nmol/5 x 10(5) cells/hour). Airspace cells from patients with mild asthma and those with moderate asthma had higher phorbol myristate acetate (PMA)-stimulated SO production when compared with those from normal subjects (8.9 +/- 0.7, 11.1 +/- 2.4, and 6.5 +/- 0.4 nmol/5 x 10(5) cells/hour respectively, p < 0.005, r = -0.35, both comparisons). However, PMA-stimulated SO production was similar in both asthmatic subgroups. Finally, spontaneous generation of SO inversely correlated with FEV1% prediction (r = 0.35, p < 0.01) in the asthma group. We conclude that worsening of airway obstruction in asthma is associated with increased spontaneous generation of SO by airspace leukocytes.