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BACKGROUND: Infants with bronchiolitis are at increased risk for developing asthma. Growing evidence suggests bronchiolitis is a heterogeneous condition. OBJECTIVE: To identify biologically-distinct subgroups based on the metabolome signatures (metabotypes) in infants with severe bronchiolitis and to examine their longitudinal relationships with asthma development. METHODS: In a multi-center prospective cohort study of infants (aged

Active smoking in stable COPD subjects significantly increased eosinophil accumulation in the distal airspaces, but not in sputum or peripheral blood. Our findings support the need to investigate this cell-type as a potential driver of COPD symptomatology and progression.

Background Compositional differences in the bronchial bacterial microbiota have been associated with asthma, but it remains unclear whether the findings are attributable to asthma, to aeroallergen sensitization, or to inhaled corticosteroid treatment. Objectives We sought to compare the bronchial bacterial microbiota in adults with steroid-naive atopic asthma, subjects with atopy but no asthma, and nonatopic healthy control subjects and to determine relationships of the bronchial microbiota to phenotypic features of asthma. Methods Bacterial communities in protected bronchial brushings from 42 atopic asthmatic subjects, 21 subjects with atopy but no asthma, and 21 healthy control subjects were profiled by using 16S rRNA gene sequencing. Bacterial composition and community-level functions inferred from sequence profiles were analyzed for between-group differences. Associations with clinical and inflammatory variables were examined, including markers of type 2–related inflammation and change in airway hyperresponsiveness after 6 weeks of fluticasone treatment. Results The bronchial microbiome differed significantly among the 3 groups. Asthmatic subjects were uniquely enriched in members of the Haemophilus , Neisseria , Fusobacterium , and Porphyromonas species and the Sphingomonodaceae family and depleted in members of the Mogibacteriaceae family and Lactobacillales order. Asthma-associated differences in predicted bacterial functions included involvement of amino acid and short-chain fatty acid metabolism pathways. Subjects with type 2–high asthma harbored significantly lower bronchial bacterial burden. Distinct changes in specific microbiota members were seen after fluticasone treatment. Steroid responsiveness was linked to differences in baseline compositional and functional features of the bacterial microbiome. Conclusion Even in subjects with mild steroid-naive asthma, differences in the bronchial microbiome are associated with immunologic and clinical features of the disease. The specific differences identified suggest possible microbiome targets for future approaches to asthma treatment or prevention.

Background Asthma functional genomics studies are challenging because it is difficult to relate gene expression changes to specific disease mechanisms or pathophysiologic features. Use of simplified model systems might help to address this problem. One such model is the IL-13/Epi (IL-13–overexpressing transgenic mice with STAT6 expression limited to epithelial cells) focused transgenic mouse, which isolates the effects of a single mediator, IL-13, on a single cell type, the airway epithelial cell. These mice develop airway hyperreactivity and mucus overproduction but not airway inflammation. Objective To identify how effects of IL-13 on airway epithelial cells contribute to gene expression changes in murine asthma models and determine whether similar changes are seen in people with asthma. Methods We analyzed gene expression in ovalbumin allergic mice, IL-13–overexpressing mice, and IL-13/Epi mice with microarrays. We analyzed the expression of human orthologues of genes identified in the mouse studies in airway epithelial cells from subjects with asthma and control subjects. Results In comparison with the other 2 models, IL-13/Epi mice had a remarkably small subset of gene expression changes. Human orthologues of some genes identified as increased in the mouse models were more highly expressed in airway epithelial cells from subjects with asthma than in controls. These included calcium-activated chloride channel 1, 15-lipoxygenase, trefoil factor 2, and intelectin. Conclusion The combination of focused transgenic models, DNA microarray analyses, and translational studies provides a powerful approach for analyzing the contributions of specific mediators and cell types and for focusing attention on a limited number of genes associated with specific pathophysiologic aspects of asthma.

The study of isolated airway myocytes has provided important information relative to specific processes that regulate contraction, proliferation, and synthetic properties of airway smooth muscle (ASM). To place this information in physiological context, however, improved methods to examine airway biology in vivo are needed. Advances in genetic, biochemical, and optical methods provide unprecedented opportunities to improve our understanding of in vivo physiology and pathophysiology. This article describes 4 important methodologic advances in the study of ASM: (1) the development of transgenic mice that could be used to investigate ASM proliferation and phenotype switching during the development of hypersensitivity, and to investigate excitation-contraction coupling; (2) the use of CD38-deficient mice to confirm the role of CD38-dependent, cyclic adenosine diphosphate-ribose-mediated calcium release in airway responsiveness; (3) investigation of the role of actin filament length and p38 mitogen-activated protein kinase activity in regulating the mechanical plasticity-elasticity balance in contracted ASM; and (d) the use of bronchial biopsies to study ASM structure and phenotype in respiratory science.

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. (J Allergy Clin Immunol 2001;108:784-90.)

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 FEV1 and methacholine responsiveness (PC20) 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 FEV1 and lower PC20 (P = .005 and P = .005, respectively). In the same models, increased sputum neutrophil percentage is independently associated with lower FEV1 (P = .038) but not with PC20 (P = .49). Conclusions: These results suggest that both eosinophilic inflammation and neutrophilic inflammation independently contribute to abnormalities of FEV1 in asthma. Therapies directed specifically at control of neutrophilic inflammation might be useful in improving airway caliber in patients with chronic asthma. (J Allergy Clin Immunol 2001;108:753-8.)

Background The 3-gene signature of periostin, chloride channel accessory 1 (CLCA1) , and Serpin β2 (SERPINB2) in airway epithelial brushings is used to classify asthma into T H 2-high and T H 2-low endotypes. Little is known about the utility of gene profiling in sputum as a molecular phenotyping method. Objective We sought to determine whether gene profiling in sputum cells can identify T H 2-high and T H 2-low subtypes of asthma. Methods In induced sputum cell pellets from 37 asthmatic patients and 15 healthy control subjects, PCR was used to profile gene expression of the epithelial cell signature of IL-13 activation (periostin, CLCA1 , and SERPINB2 ), T H 2 genes ( IL4 , IL5 , and IL13 ), and other genes associated with airway T H 2 inflammation. Results Gene expression levels of CLCA1 and periostin, but not SerpinB2, were significantly higher than normal in sputum cells from asthmatic subjects. Expression levels of IL-4, IL-5, and IL-13 were also significantly increased in asthmatic patients and highly correlated within individual subjects. By combining the expression levels of IL-4, IL-5, and IL-13 in a single quantitative metric ("T H 2 gene mean"), 26 (70%) of the 37 asthmatic patients had T H 2-high asthma, which was characterized by more severe measures of asthma and increased blood and sputum eosinophilia. T H 2 gene mean values tended to be stable when initial values were very high or very low but fluctuated above or below the T H 2-high cutoff when initial values were intermediate. Conclusion IL-4, IL-5, and IL-13 transcripts are easily detected in sputum cells from asthmatic patients, and their expression levels can be used to classify asthma into T H 2-high and T H 2-low endotypes.

BackgroundEosinophilic airway inflammation is heterogeneous in asthmatic patients. We recently described a distinct subtype of asthma defined by the expression of genes inducible by T(H)2 cytokines in bronchial epithelium. This gene signature, which includes periostin, is present in approximately half of asthmatic patients and correlates with eosinophilic airway inflammation. However, identification of this subtype depends on invasive airway sampling, and hence noninvasive biomarkers of this phenotype are desirable.ObjectiveWe sought to identify systemic biomarkers of eosinophilic airway inflammation in asthmatic patients.MethodsWe measured fraction of exhaled nitric oxide (Feno), peripheral blood eosinophil, periostin, YKL-40, and IgE levels and compared these biomarkers with airway eosinophilia in asthmatic patients.ResultsWe collected sputum, performed bronchoscopy, and matched peripheral blood samples from 67 asthmatic patients who remained symptomatic despite maximal inhaled corticosteroid treatment (mean FEV(1), 60% of predicted value; mean Asthma Control Questionnaire [ACQ] score, 2.7). Serum periostin levels are significantly increased in asthmatic patients with evidence of eosinophilic airway inflammation relative to those with minimal eosinophilic airway inflammation. Alogistic regression model, including sex, age, body mass index, IgE levels, blood eosinophil numbers, Feno levels, and serum periostin levels, in 59 patients with severe asthma showed that, of these indices, the serum periostin level was the single best predictor of airway eosinophilia (P= .007).ConclusionPeriostin is a systemic biomarker of airway eosinophilia in asthmatic patients and has potential utility inpatient selection for emerging asthma therapeutics targetingT(H)2 inflammation.