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Biomedical subjects

J V Fahy

Publications and source records attributed to J V Fahy.

At least 19 recordsLinked to original sources
PubMed2004

Effect of a single dose of the selectin inhibitor TBC1269 on early and late asthmatic responses.

BACKGROUND: Selectins participate in the initial phase of leucocyte migration from circulation to inflamed tissues and may play a role in inflammatory cellular influx into airways in asthma. In the sheep asthma model, TBC1269, a pan-selectin antagonist, reduced late allergen response by 74%. OBJECTIVE: To determine whether a single dose of TBC1269 inhibits early (EAR) and late (LAR) asthmatic responses, and whether it inhibits sputum leucocyte influx after inhalation allergen challenge in atopic asthmatic subjects treated with bronchodilators only. METHODS: Twenty-one asthmatic subjects (mean+/-SD, age=32.5+/-6.7 years, 8 males, FEV1 percent predicted=84+/-15%) with known late asthmatic response based on a screening inhalation allergen challenge were randomly assigned to receive intravenous treatment with either placebo (n=11) or TBC1269 (n=10, 30 mg/kg) infused over 15 min immediately prior to a second (post-treatment) allergen challenge at least 4 weeks after the screening challenge. After each challenge, EAR and LAR were monitored for 7 h. In addition, sputum was induced 1 day before and 1 day after each allergen challenge. RESULTS: TBC1269 did not attenuate the EAR compared with placebo (largest fall in FEV1 within 1 h of 34.1+/-13.9% vs. 31.8+/-12.2% for TBC1269 and placebo groups respectively, P=0.61) or the LAR (largest fall in FEV1 between 3 and 7 h of 39.3+/-15.3% vs. 32.6+/-13.8%, P=0.24). TBC1269 had only minor effects on allergen-induced sputum eosinophilia. CONCLUSION: We conclude that TBC1269 administered before allergen challenge as a single intravenous dose does not attenuate early or late asthmatic responses to allergen in asthmatic subjects.

Adult↗
PubMed2001

Remodeling of the airway epithelium in asthma.

Several pathologic changes occur in the airway epithelium in asthma, but the relationship between these changes and the initiation and progression of asthma remains poorly understood. One possibility is that changes in the structure and function of the epithelium induced by environmental exposure in genetically susceptible subjects represent primary pivotal events that occur early in the pathogenesis of asthma. Alternatively, these epithelial changes may occur simply as a consequence of pivotal early events in other systems, such as immune deviation in childhood to a helper T cell type 2 (Th2) subtype of CD4(+) cells. Epithelial desquamation in asthma represents a pathologic change that is frequently cited as important for the mechanisms of airway remodeling and airway hyperresponsiveness. Desquamation of the epithelium may not represent true pathology, however, but may instead be an artifact of tissue sampling and handling. Evidence is more firm for other pathologic changes in the epithelium. For example, goblet cell numbers are increased in asthma, leading to increases in stored mucins in the epithelium and in secreted mucins in sputum. The functional consequences of these changes include sputum production and airway narrowing, which lead to asthma exacerbations. Currently available data suggest that an important mechanism for goblet cell hyperplasia in asthma is the action of Th2 cytokines. Improved understanding of epithelial goblet cell abnormalities in asthma will hopefully lead to novel therapies for mucin hypersecretion, which is an important cause of morbidity and mortality.

Animals↗
PubMed2001

Allergen challenge causes inflammation but not goblet cell degranulation in asthmatic subjects.

BACKGROUND: An allergen challenge to the airways of sensitized mice causes eosinophilic airway inflammation and degranulation of goblet cells, which lead to airway obstruction. However, whether allergen challenge causes a similar pattern of airway inflammation and goblet cell degranulation in human beings is unknown. OBJECTIVE: The purpose of this study was to determine whether allergen challenge increases airway inflammatory cells and causes goblet cell degranulation in human subjects with asthma. METHODS: In bronchial biopsy specimens taken from 8 asthmatic subjects at 1 and 24 hours after allergen challenge, we measured eosinophil and neutrophil numbers as indicators of inflammation. We also measured goblet cell mucin stores and the amounts of secreted mucin in bronchial lavage as indicators of goblet cell degranulation. RESULTS: Airway eosinophil numbers at both 1 and 24 hours after allergen challenge were twice as high as those after diluent challenge. Changes in neutrophil numbers were smaller and statistically insignificant. Goblet cell mucin stores measured in tissue stained with alcian blue/periodic acid-Schiff did not decrease significantly from baseline to 1 hour and actually tended to increase at 24 hours. This increase was significant in the subgroup of subjects with normal stored mucin levels at baseline. Mucin-like glycoprotein concentrations in bronchial lavage did not change significantly at either time point. CONCLUSION: Although allergen challenge in asthmatic subjects increases airway eosinophil numbers as early as 1 hour after challenge, this inflammatory response does not cause goblet cell degranulation. In fact, in subjects with normal baseline mucin stores, allergen challenge increases goblet cell mucin stores.

Adult↗
PubMed2001

Relationship between airway inflammation, hyperresponsiveness, and obstruction in asthma.

BACKGROUND: Although the role of eosinophils in airway inflammation in chronic asthma has been extensively studied, a role for neutrophils has not been well characterized. Furthermore, prior studies have not systematically sought or controlled for factors that might confound the relationship between cellular markers of inflammation and physiologic measures of airway function. OBJECTIVE: The purpose of this study was to determine whether eosinophilic and neutrophilic inflammation independently contribute to abnormalities of airway function in asthma. METHODS: Multivariate analysis of data collected during screening and enrollment of 205 asthmatic adults for clinical trials was conducted to examine the relationships between cellular inflammation in induced sputum and FEV(1) and methacholine responsiveness (PC(20)) while confounding factors were controlled for. RESULTS: We found that age, sex, ethnicity, and use of inhaled corticosteroids were important confounding factors of the relationship between cellular inflammation and airway function. When these factors were controlled for, multivariate analysis showed that eosinophil percentage in induced sputum is independently associated with lower FEV(1) and lower PC(20) (P = .005 and P = .005, respectively). In the same models, increased sputum neutrophil percentage is independently associated with lower FEV(1) (P = .038) but not with PC(20) (P = .49). CONCLUSIONS: These results suggest that both eosinophilic inflammation and neutrophilic inflammation independently contribute to abnormalities of FEV(1) in asthma. Therapies directed specifically at control of neutrophilic inflammation might be useful in improving airway caliber in patients with chronic asthma.

Adult↗
PubMed2001

A novel method of gene transcript profiling in airway biopsy homogenates reveals increased expression of a Na+-K+-Cl- cotransporter (NKCC1) in asthmatic subjects.

Comprehensive and systematic analysis of airway gene expression represents a strategy for addressing the multiple, complex, and largely untested hypotheses that exist for disease mechanisms, including asthma. Here, we report a novel real-time PCR-based method specifically designed for quantification of multiple low-abundance transcripts using as little as 2.5 fg of total RNA per gene. This method of gene expression profiling has the same specificity and sensitivity as RT-PCR and a throughput level comparable to low-density DNA microarray hybridization. In this two-step method, multiplex RT-PCR is successfully combined with individual gene quantification via real-time PCR on generated cDNA product. Using this method, we measured the expression of 75 genes in bronchial biopsies from asthmatic versus healthy subjects and found expected increases in expression levels of Th2 cytokines and their receptors in asthma. Surprisingly, we also found increased gene expression of NKCC1--a Na+-K+-Cl- cotransporter. Using immunohistochemical method, we confirmed increased protein expression for NKCC1 in the asthmatic subject with restricted localization to goblet cells. These data validate the new transcriptional profiling method and implicate NKCC1 in the pathophysiology of mucus hypersecretion in asthma. Potential applications for this method include transcriptional profiling in limited numbers of laser captured cells and validation of DNA microarray data in clinical specimens.

Adult↗
PubMed2001

Relationship of epidermal growth factor receptors to goblet cell production in human bronchi.

To determine the relationship of epidermal growth factor receptor (EGFR) expression to mucin synthesis in human airways, we examined EGFR and MUC5AC expression at both gene and protein levels using in situ hybridization and immunohistochemical analysis in human bronchi. Bronchial mucosal biopsy specimens were obtained from 12 asthmatic subjects and 11 healthy subjects. In asthmatic airways, EGFR mRNA was expressed in the airway epithelium. EGFR immunoreactivity staining patterns varied among the asthmatic airways: staining was positive mainly in goblet cells, in basal cells, or in both. In contrast, healthy airways showed little expression of EGFR mRNA; EGFR immunoreactivity was observed mainly in goblet cells. In parallel to EGFR expression, MUC5AC mRNA expression was greater in asthmatic airways; mucous glycoconjugates that stained positively with Alcian blue/PAS were also increased in asthmatic airways. Ciliated cells were negative for EGFR and MUC5AC both in asthmatic and in healthy subjects at both mRNA and protein levels. There was a significant positive correlation between EGFR immunoreactivity and the area of MUC5AC-positive staining in both asthmatics and healthy subjects. These findings suggest a sequence of events by which EGFR activation is involved in mucin expression in asthmatic airway epithelium.

Adult↗
PubMed2001

Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression.

Excessive airway mucus is an important cause of morbidity and mortality in asthma, but the relationship between accumulation of mucus and goblet cell size, number, and function is incompletely understood. To address these questions, stored mucin in the epithelium and goblet cell size and number were measured morphometrically, and mucin gene expression was measured by polymerase chain reaction and immunohistochemistry in endobronchial biopsies from 13 subjects with mild and moderate asthma and from 12 healthy control subjects. Secreted mucin was measured in induced sputum. We found that stored mucin in the airway epithelium was three times higher than normal in the subjects with asthma (p < 0.005). Goblet cell size was similar in both groups, but goblet cell number was significantly higher in the subjects with asthma (93,043 +/- 15,824 versus 41,959 +/- 9,230/mm3, p < 0.05). In mild asthma (FEV1 > or = 80% pred, n = 7), the level of stored mucin was as high as in moderate asthma (FEV1 < 80% pred, n = 6), but the level of secreted mucin was significantly lower (28.4 +/- 6.3 versus 73.5 +/- 47.5 microg/ml, p < 0.05). Secreted mucin was inversely correlated with stored mucin for the whole asthma group (rs = -0.78, p = 0.007). MUC5AC was the predominant mucin gene expressed in healthy subjects and subjects with asthma, and MUC5AC protein was increased in the subjects with asthma. We conclude that even mild asthma is associated with goblet cell hyperplasia and increased stored mucin in the airway epithelium, whereas moderate asthma is associated with increased stored mucin and secreted mucin. These findings suggest that acute degranulation of hyperplastic goblet cells may represent a mechanism for asthma exacerbations in mild and moderate asthma and that chronic degranulation of goblet cells may contribute to chronic airway narrowing in moderate asthma.

Adult↗
PubMed2001

Safety and reproducibility of sputum induction in asthmatic subjects in a multicenter study.

The safety of sputum induction and the reproducibility of measurements in induced sputum in multicenter studies is unknown. We examined the safety of sputum induction in a two-visit, six-center study in 79 subjects with moderate to severe asthma (mean +/- SD FEV(1) 71 +/- 12% predicted, 67% taking inhaled corticosteroids). In addition, we compared the reproducibility of markers of inflammation in induced sputum with the reproducibility of the FEV(1) and the methacholine PC(20). The FEV(1) decreased > or = 20% from the postbronchodilator baseline in 14% of all subjects and in 25% of subjects whose initial prebronchodilator baseline was 40 to 60% of predicted. All subjects responded promptly to additional albuterol treatment, and no subject developed refractory bronchoconstriction requiring treatment other than reversal of bronchospasm in the study laboratory. The reproducibility of measurements of the eosinophil percentage, eosinophil cationic protein, tryptase, and methacholine PC(20) were similar (concordance correlation coefficients of 0.74, 0.81, 0.79, and 0.74, respectively), without any significant among-center effect. We conclude that sputum induction can be performed safely in subjects with moderate to severe asthma in multicenter clinical trials when carried out under carefully monitored conditions. Importantly, we demonstrate that measurement of markers of inflammation in induced sputum is as reproducible as methacholine PC(20) and should prove useful in the assessment of airway inflammation in multicenter clinical trials.

Aged↗
PubMed2001

The utility of peak flow, symptom scores, and beta-agonist use as outcome measures in asthma clinical research.

STUDY OBJECTIVES: Several methods of utilizing peak expiratory flow (PEF) and other markers of disease activity have been suggested as useful in the management of asthma. It remains unclear, however, as to which surrogate markers of disease status are discriminative indicators of treatment failure, suitable for use in clinical trials. DESIGN: We analyzed the operating characteristics of 66 surrogate markers of treatment failure using a receiver operating characteristic (ROC) curve analysis. PARTICIPANTS: Information regarding FEV(1), symptoms, beta(2)-agonist use, and PEF was available from 313 subjects previously enrolled in two Asthma Clinical Research Network trials, in which 71 treatment failures occurred (defined by a 20% fall in FEV(1) from baseline). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: None of the measures had an acceptable ability to discriminate subjects with a > or % fall in FEV(1) from those without, regardless of the duration of the period of analysis or the criteria for test positivity employed. Areas under the ROC curves generated ranged from 0.51 to 0.79, but none were statistically superior. Sensitivity and specificity combinations were generally poor at all cutoff values; true-positive rates could not be raised without unacceptably elevating false-positive rates concurrently. CONCLUSIONS: Studies that seek to detect treatment failure defined by a significant fall in FEV(1) should not use such individual surrogate measures to estimate disease severity.

Adolescent↗
PubMed2000

Reducing IgE levels as a strategy for the treatment of asthma.

IgE secretion by B lymphocytes defines the allergic state and nearly all asthmatics have higher than normal IgE levels in serum following adjustment for age and sex. It is thought that allergic mechanisms may be responsible for the increasing prevalence of asthma. In particular, in utero changes may encourage T cells to differentiate into Th2 subtypes. Th2 cells produce cytokines such as IL-4 and IL-5, which can act indirectly via B cells, mast cells and eosinophils to mediate the asthma phenotype. Alternatively, IL-4 and IL-13 may act directly on the airway. Th2 lymphocyte inflammation in asthma predisposes subjects to B cell and IgE-mediated airway inflammation. IgE binds to receptors on the surface of a variety of effector cells causing them to release a variety of mediators that promote airway hyperresponsiveness, mucus secretion and increased vascular permeability. Several strategies for decreasing IgE have been developed as a possible treatment for asthma. For example, anti-IgE monoclonal antibodies such as rhuMAb-E25 and CGP 56901 block binding of IgE to its high-affinity receptor and have been shown to reduce IgE levels in humans without causing anaphylaxis. IgE levels must be nearly completely suppressed. Recent clinical studies in subjects with asthma have shown that rhuMAb-E25 attenuates both the early and late phase responses to inhaled allergen, and reduces the associated increase in eosinophils in induced sputum. rhuMAb-E25 is well tolerated and has shown promising results in improving symptoms and lung function in patients with moderate to severe asthma. Other strategies for decreasing IgE levels include interferon gamma, IL-4 antibodies, IL-4 receptor antibodies and soluble IL-4 receptors.

Antibodies, Anti-Idiotypic↗
PubMed2000

Airway inflammation and remodeling in asthma.

An important advance in our understanding of the pathophysiology of asthma has been the discovery that airway inflammation is not confined to severe asthma but also characterizes mild and moderate asthma. Inflammation in asthma may be the result of a peculiar type of lymphocytic inflammation whereby Th2 lymphocytes secrete cytokines that orchestrate cellular inflammation and promote airway hyperresponsiveness. The term "airway remodeling" in asthma refers to structural changes that occur in conjunction with, or because of, chronic airway inflammation. Airway remodeling results in alterations in the airway epithelium, lamina propria, and submucosa, leading to thickening of the airway wall. The consequences of airway remodeling in asthma may include incompletely reversible airway narrowing, bronchial hyperresponsivenesss, airway edema, and mucus hypersecretion. Airway remodeling in asthma thus may predispose persons with asthma to asthma exacerbations and even death from airway obstruction caused by smooth muscle contraction, airway edema, and mucus plugging. Although much has been learned in the past 25 years about the pathophysiology of airway inflammation and airway remodeling in asthma, important questions remain about the relation between airway inflammation and remodeling, the natural history of airway remodeling, and the effects of current asthma treatments on remodeled airways.

Airway Obstruction↗
PubMed2000

Increased neutrophil numbers and IL-8 levels in airway secretions in acute severe asthma: Clinical and biologic significance.

The inflammatory events in the airways at the time of acute respiratory failure from acute severe asthma are poorly understood. To determine the patterns of cellular inflammation in the airways in acute severe asthma, we analyzed tracheal aspirates collected within 12 h of intubation from patients intubated emergently for acute severe asthma (n = 10) and from patients intubated electively for nonpulmonary surgery (n = 14). The number of neutrophils in tracheal aspirates from asthma patients was 10 times higher than normal (4.2 [0.6 to 335.0] [median, range] versus 0.4 [0.009 to 9.4] x 10(6)/ml, p = 0.001), and there was a strong trend for a positive relationship between neutrophil number and duration of intubation (r(s) = 0.64, p = 0.06). Although eosinophil numbers were also significantly higher than normal (0.5 [0.0 to 23.3] versus 0.0 [0.0 to 0.1] x 10(6)/ml, p = 0.003), the numbers of eosinophils were 8-fold less than neutrophils, and there was no significant correlation between eosinophil number and duration of intubation (r(s) = 0.4, p = 0.26). Interleukin-8 (IL-8), a chemoattraction for neutrophils, was 19 times higher than normal in tracheal aspirates from asthmatic patients (75.0 [9.0 to 168.0] versus 4.0 [0.08 to 24.0] ng/ml, p < 0. 05) and correlated significantly with the neutrophil number (r(s) = 0.77, p = 0.03). Furthermore, the IL-8 levels correlated positively with the duration of mechanical ventilation (r(s) = 0.74, p = 0.03). Surprisingly, the number of neutrophils increased significantly during the period of intubation in the asthmatic subjects, possibly because of intravenous corticosteroid treatment. We conclude that neutrophils are the dominant inflammatory leukocyte characterizing airway inflammation in acute severe asthma that requires mechanical ventilation, and that IL-8 is an important mediator of this neutrophilia.

Adult↗
PubMed2000

Predictors of late asthmatic response. Logistic regression and classification tree analyses.

To identify predictors of the late asthmatic response (LAR), we reviewed data from 60 asthmatic subjects who had undergone allergen challenge over the past 5 yr (33 females, age 31.4 +/- 6.7 yr [mean +/- SD], FEV(1) 90% +/- 14% predicted). Variables considered likely predictors of LAR included baseline FEV(1), PC(20) methacholine (PC(20)), sputum eosinophil percent, and the decrease in FEV(1) within 20 min of allergen challenge. A LAR (FEV(1) >/= 15% fall between 3 and 7 h after challenge) was documented in 57% of subjects. A variety of logistic regression methods revealed a significant inverse association between LAR and PC(20) (odds ratio [OR] = 0.14 [95% CI = 0.03-0.66]) and a positive association between LAR and the decrease in FEV(1) at 20 min (OR = 1.18 [1.04 -1.33]). Classification tree analysis revealed that a threshold of 0.25 mg/ml for PC(20) was most predictive of LAR; LAR developed in 87% of those with PC(20) </= 0.25 mg/ml (n = 23) and in 38% of those with PC(20) > 0.25 mg/ml (n = 37). Notably, in subjects with PC(20) > 0.25 mg/ml, the incidence of LAR increased from 38% to 57% if the allergen-induced decline in FEV(1) at 20 min was >/= 27%. Surprisingly, baseline FEV(1) and percent eosinophils in induced sputum were not significantly associated with LAR. We conclude that a threshold value of 0.25 mg/ml for PC(20) methacholine is a good predictor of LAR. Measuring the PC(20) methacholine may be useful as a screening method to improve the efficiency of identifying asthmatic subjects with a LAR.

Asthma↗