
Research Interests: Mechanism oriented studies of airway disease in human subjects Summary: Our research involves studies in people with airway diseases such as asthma, cystic fibrosis, and chronic bronchitis. We are involved in clinical trials of new and established treatments on the one hand and in clinical studies designed to improve understanding of mechanism of disease on the other. For clinical trials, we often collaborate with other CVRI investigators or investigators at other institutions to compare the efficacy of new and established drugs. In conducting clinical trials, we are usually interested in exploring the effects of drugs not just on measures of lung function but also on measures of airway inflammation and remodeling. For this purpose, our laboratory has developed expertise in measuring markers of inflammation and remodeling in samples of sputum or in samples of airway fluids and tissue collected during bronchoscopy. Our lab is particularly experienced in measuring gene expression using gene chips and PCR and in quantifying pathology using a rigorous method of quantitative morphology called stereology. For our research on mechanisms of airway disease, we are particularly interested in abnormalities of airway epithelial cells (the lining cells of the airway) and in abnormalities in airway mucus. Mucus abnormalities are common in lung diseases, and we are interested in finding out the specific mucus abnormalities that are characteristic of different lung diseases such as asthma and cystic fibrosis. Recently, we have begun to explore the physical properties of airway mucus - thickness, stickiness, and adhesiveness - using an instrument called a rheometer. The rheology of airway mucus has not been investigated in detail, but the research resources of the CVRI are well suited to making progress in this area. For example, in our clinical laboratories in the CVRI, we can collect induced sputum from volunteers in a carefully controlled way, and in our bench laboratories we can make careful rheological measures. These rheologic measures are allowing personnel in our lab to explore new strategies for breaking up the mucus that normally clogs airways.
Publications
Assessment of ventilation heterogeneity and particle deposition in asthmatics using combined SPECT/CT imaging and computational modeling approaches.
Cellular and molecular features of asthma mucus plugs provide clues about their formation and persistence.
Clinical and Biological Features of a Thickened Basement Membrane Zone in Asthma.
Response to the Editor Regarding: "In Office Sampling of Eosinophil Peroxidase to Diagnose Eosinophilic Chronic Rhinosinusitis".
α1-Antitrypsin Gene Variation Associates with Asthma Exacerbations and Related Health Care Utilization.
Type 1 Immune Responses Related to Viral Infection Influence Corticosteroid Response in Asthma.
Serum cAMP levels are increased in patients with asthma.
Multicohort Analysis of Bronchial Epithelial Cell Expression in Healthy Subjects and Patients with Asthma Reveals Four Clinically Distinct Clusters.
Development of an asthma health-care burden score as a measure of severity and predictor of remission in SARP III and U-BIOPRED: results from two major longitudinal asthma cohorts.
In office sampling of eosinophil peroxidase to diagnose eosinophilic chronic rhinosinusitis.
Mitochondrial DNA Copy Number Variation in Asthma Risk, Severity, and Exacerbations.
Reply to Mozaffaripour et al.: Dose Modulation, Body Mass Index, and Computed Tomography Air Trapping.
A Novel Air Trapping Segment Score Identifies Opposing Effects of Obesity and Eosinophilia on Air Trapping in Asthma.
A common polymorphism in the Intelectin-1 gene influences mucus plugging in severe asthma.
A novel DNase assay reveals low DNase activity in severe asthma.
Utility of eosinophil peroxidase as a biomarker of eosinophilic inflammation in asthma.
The Year in Perioperative Echocardiography: Selected Highlights from 2023.
Persistent mucus plugs in proximal airways are consequential for airflow limitation in asthma.
Protein-Protein interactive networks identified in bronchoalveolar lavage of severe compared to nonsevere asthma.
Mitochondrial DNA Copy Number Variation in Asthma Risk, Severity, and Exacerbations.
A novel thiol-saccharide mucolytic for the treatment of muco-obstructive lung diseases.
Genetic analyses of chr11p15.5 region identify MUC5AC-MUC5B associated with asthma-related phenotypes.
Investigations of a combination of atopic status and age of asthma onset identify asthma subphenotypes.
CCL5 is a potential bridge between type 1 and type 2 inflammation in asthma.
Low CC16 mRNA Expression Levels in Bronchial Epithelial Cells Are Associated with Asthma Severity.
Skeletal Muscle Adiposity and Lung Function Trajectory in the Severe Asthma Research Program.
Reply to Nie et al. and Bhammar et al.
Reply to Ikeda and Tomita.
The Impact of Insulin Resistance on Loss of Lung Function and Response to Treatment in Asthma.
Urinary total conjugated 3-bromotyrosine, asthma severity, and exacerbation risk.
Exploring antiviral and anti-inflammatory effects of thiol drugs in COVID-19.
DNA sequencing analysis of cystic fibrosis transmembrane conductance regulator gene identifies cystic fibrosis-associated variants in the Severe Asthma Research Program.
Mucus Plugs Persist in Asthma, and Changes in Mucus Plugs Associate with Changes in Airflow over Time.
Quantitative CT Characteristics of Cluster Phenotypes in the Severe Asthma Research Program Cohorts.
The Mucin Gene MUC5B Is Required for Normal Lung Function.
15LO1 dictates glutathione redox changes in asthmatic airway epithelium to worsen type 2 inflammation.
The Precision Interventions for Severe and/or Exacerbation-Prone (PrecISE) Asthma Network: An overview of Network organization, procedures, and interventions.
Thiol drugs decrease SARS-CoV-2 lung injury in vivo and disrupt SARS-CoV-2 spike complex binding to ACE2 in vitro.
Benefits of Airway Androgen Receptor Expression in Human Asthma.
Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium.
Mucus Plugs and Emphysema in the Pathophysiology of Airflow Obstruction and Hypoxemia in Smokers.
Mixed Sputum Granulocyte Longitudinal Impact on Lung Function in the Severe Asthma Research Program.
Responsiveness to Parenteral Corticosteroids and Lung Function Trajectory in Adults with Moderate-to-Severe Asthma.
PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment.
Quantitative CT metrics are associated with longitudinal lung function decline and future asthma exacerbations: Results from SARP-3.
Erratum: COVID-19-related Genes in Sputum Cells in Asthma: Relationship to Demographic Features and Corticosteroids.
Reply to Nannini and to Lipworth et al.
Evidence for Exacerbation-Prone Asthma and Predictive Biomarkers of Exacerbation Frequency.
The precision interventions for severe and/or exacerbation-prone asthma (PrecISE) adaptive platform trial: statistical considerations.
Genetic analyses identify GSDMB associated with asthma severity, exacerbations, and antiviral pathways.
An anti-siglec-8 antibody depletes sputum eosinophils from asthmatic subjects and inhibits lung mast cells.
COVID-19-related Genes in Sputum Cells in Asthma. Relationship to Demographic Features and Corticosteroids.
Baseline sputum eosinophil + neutrophil subgroups' clinical characteristics and longitudinal trajectories for NHLBI Severe Asthma Research Program (SARP 3) cohort.
HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma.
Severe asthma during childhood and adolescence: A longitudinal study.
Development and initial validation of the Asthma Severity Scoring System (ASSESS).
The use of hydrophobic amino acids in protecting spray dried trehalose formulations against moisture-induced changes.
Investigation of the relationship between IL-6 and type 2 biomarkers in patients with severe asthma.
Making Asthma Crystal Clear.
Clinical significance of the bronchodilator response in children with severe asthma.
Multiview Cluster Analysis Identifies Variable Corticosteroid Response Phenotypes in Severe Asthma.
Mometasone or Tiotropium in Mild Asthma with a Low Sputum Eosinophil Level.
Extracellular DNA, Neutrophil Extracellular Traps, and Inflammasome Activation in Severe Asthma.
The Cytokines of Asthma.
A Design of Experiment (DoE) approach to optimise spray drying process conditions for the production of trehalose/leucine formulations with application in pulmonary delivery.
A Transcriptomic Method to Determine Airway Immune Dysfunction in T2-High and T2-Low Asthma.
Racial disparities in asthma-related health care use in the National Heart, Lung, and Blood Institute's Severe Asthma Research Program.
Autopsy and Imaging Studies of Mucus in Asthma. Lessons Learned about Disease Mechanisms and the Role of Mucus in Airflow Obstruction.
Purpose of the Conference: The 2018 Transatlantic Conference on Lung Diseases.
Neutrophil cytoplasts induce TH17 differentiation and skew inflammation toward neutrophilia in severe asthma.
Pruning of the Pulmonary Vasculature in Asthma. The Severe Asthma Research Program (SARP) Cohort.
Effects of endogenous sex hormones on lung function and symptom control in adolescents with asthma.
Refractory airway type 2 inflammation in a large subgroup of asthmatic patients treated with inhaled corticosteroids.
Cadherin-26 (CDH26) regulates airway epithelial cell cytoskeletal structure and polarity.
Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction.
IFN-stimulated Gene Expression, Type 2 Inflammation, and Endoplasmic Reticulum Stress in Asthma.
Purpose of the Conference: The 2017 Transatlantic Conference on Lung Diseases.
Corticosteroid and long-acting ß-agonist therapy reduces epithelial goblet cell metaplasia.
After asthma: redefining airways diseases.
Baseline Features of the Severe Asthma Research Program (SARP III) Cohort: Differences with Age.
Asthma and corticosteroids: time for a more precise approach to treatment.
Effects of Age and Disease Severity on Systemic Corticosteroid Responses in Asthma.
Natural killer cell-mediated inflammation resolution is disabled in severe asthma.
Inflammatory and Comorbid Features of Patients with Severe Asthma and Frequent Exacerbations.
Purpose of the Conference: 2016 Transatlantic Airway Conference.
Abnormalities in MUC5AC and MUC5B Protein in Airway Mucus in Asthma.
Measuring Airway Mucin 2 in Patients with Severe Chronic Obstructive Pulmonary Disease with Bacterial Colonization.
Association Between Insomnia and Asthma Burden in the Severe Asthma Research Program (SARP) III.
Metabolic consequences of obesity as an "outside in" mechanism of disease severity in asthma.
Alternative splicing of interleukin-33 and type 2 inflammation in asthma.
Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts.
Cross-Talk between Epithelial Cells and Type 2 Immune Signaling. The Role of IL-25.
Claudin-18 deficiency is associated with airway epithelial barrier dysfunction and asthma.
FleA Expression in Aspergillus fumigatus Is Recognized by Fucosylated Structures on Mucins and Macrophages to Prevent Lung Infection.
Mast cells in asthma: biomarker and therapeutic target.
Asthma Was Talking, But We Weren't Listening. Missed or Ignored Signals That Have Slowed Treatment Progress.
Future Research Directions in Asthma. An NHLBI Working Group Report.
Purpose of the Conference: 2015 Transatlantic Airway Conference.
The Role of Type 2 Inflammation in the Pathogenesis of Asthma Exacerbations.
Oxidation increases mucin polymer cross-links to stiffen airway mucus gels.
Type 2 inflammation in asthma--present in most, absent in many.
Twenty-Ninth Transatlantic Airway Conference. Innate and adaptive immune responses in airway disease. Purpose of the conference.
Accumulation of BDCA1⁺ dendritic cells in interstitial fibrotic lung diseases and Th2-high asthma.
Intelectin-1 is a prominent protein constituent of pathologic mucus associated with eosinophilic airway inflammation in asthma.
Asthma and the flu: a tricky two-step.
Asthma: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases.
Chair's summary: Mechanisms of relevance to clinical heterogeneity of asthma and chronic obstructive pulmonary disease.
Purpose of the conference.
Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma.
Type 2 immune responses in obese individuals with asthma.
A qPCR-based metric of Th2 airway inflammation in asthma.
An integrated nano-scale approach to profile miRNAs in limited clinical samples.
P2X7-regulated protection from exacerbations and loss of control is independent of asthma maintenance therapy.
Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction.
Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients.
Network analysis identifies a putative role for the PPAR and type 1 interferon pathways in glucocorticoid actions in asthmatics.
Asthma outcomes: biomarkers.
A large subgroup of mild-to-moderate asthma is persistently noneosinophilic.
A protective role for periostin and TGF-β in IgE-mediated allergy and airway hyperresponsiveness.
The airway epithelium as a regulator of Th2 responses in asthma.
The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose.
Hexaphenylbenzene as a rigid template for the straightforward syntheses of "star-shaped" glycodendrimers.
Gene expression patterns of Th2 inflammation and intercellular communication in asthmatic airways.
Airway mucus function and dysfunction.
Negative methacholine challenge tests in subjects who report physician-diagnosed asthma.
A trial of clarithromycin for the treatment of suboptimally controlled asthma.
Tiotropium bromide step-up therapy for adults with uncontrolled asthma.
The H antigen at epithelial surfaces is associated with susceptibility to asthma exacerbation.
Roles of epithelial cell-derived periostin in TGF-beta activation, collagen production, and collagen gel elasticity in asthma.
Accumulation of intraepithelial mast cells with a unique protease phenotype in T(H)2-high asthma.
Identifying clinical phenotypes of asthma: steps in the right direction.
Safety and efficacy of an inhaled epidermal growth factor receptor inhibitor (BIBW 2948 BS) in chronic obstructive pulmonary disease.
Effect of beta2-adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial.
Distinct roles of FOXA2 and FOXA3 in allergic airway disease and asthma.
T-helper type 2-driven inflammation defines major subphenotypes of asthma.
Differential enzymatic activity of common haplotypic versions of the human acidic Mammalian chitinase protein.
Ex vivo sputum analysis reveals impairment of protease-dependent mucus degradation by plasma proteins in acute asthma.
Eosinophilic and neutrophilic inflammation in asthma: insights from clinical studies.
Acute exacerbations of asthma: epidemiology, biology and the exacerbation-prone phenotype.
Chitotriosidase is the primary active chitinase in the human lung and is modulated by genotype and smoking habit.
Predicting worsening asthma control following the common cold.
Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids.
Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma.
The Predicting Response to Inhaled Corticosteroid Efficacy (PRICE) trial.
Epithelial mucin stores are increased in the large airways of smokers with airflow obstruction.
Combination therapy with a long-acting beta-agonist and a leukotriene antagonist in moderate asthma.
Characterizing mucous cell remodeling in cystic fibrosis: relationship to neutrophils.
Anti-IgE: lessons learned from effects on airway inflammation and asthma exacerbation.
Effects of multiday exposure to ozone on airway inflammation as determined using sputum induction.
beta-Adrenergic receptor polymorphisms and response to salmeterol.
Dissecting asthma using focused transgenic modeling and functional genomics.
Daily versus as-needed corticosteroids for mild persistent asthma.
Sputum eosinophil counts predict asthma control after discontinuation of inhaled corticosteroids.
Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial.
Adenosine up-regulation of the mucin gene, MUC2, in asthma.
Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma.
Hyperplasia of smooth muscle in mild to moderate asthma without changes in cell size or gene expression.
Effect of a single dose of the selectin inhibitor TBC1269 on early and late asthmatic responses.
Applying stereology to measure thickness of the basement membrane zone in bronchial biopsy specimens.
Effects of individual self-management education on clinical, biological, and adherence outcomes in asthma.
The role of mucus in fatal asthma.
Standardised methodology of sputum induction and processing.
Airway remodeling in asthma.
Systemic effect comparisons of six inhaled corticosteroid preparations.
A role for neutrophils in asthma?
Significant variability in response to inhaled corticosteroids for persistent asthma.
Practical management of acute asthma in adults.
Quality control within the Asthma Clinical Research Network.
Epithelial desquamation in asthma.
Remodeling of the airway epithelium in asthma.
Allergen challenge causes inflammation but not goblet cell degranulation in asthmatic subjects.
Relationship between airway inflammation, hyperresponsiveness, and obstruction in asthma.
Safety and reproducibility of sputum induction in asthmatic subjects in a multicenter study.
"Reactive airways disease". A lazy term of uncertain meaning that should be abandoned.
Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression.
Relationship of epidermal growth factor receptors to goblet cell production in human bronchi.
Effect of polymorphism of the beta(2)-adrenergic receptor on response to regular use of albuterol in asthma.
Histopathology of fatal asthma: drowning in mucus.
Use of biological markers of airway inflammation to detect the efficacy of nurse-delivered asthma education.
Epithelial desquamation in asthma: artifact or pathology?
Targeting cytokines in asthma therapy: round one.
The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma.
Predictors of late asthmatic response. Logistic regression and classification tree analyses.
Reducing IgE levels as a strategy for the treatment of asthma.
Cytotoxic prenylxanthones from Garcinia bracteata.
Increased neutrophil numbers and IL-8 levels in airway secretions in acute severe asthma: Clinical and biologic significance.
Airway inflammation and remodeling in asthma.
Low- and high-dose fluticasone propionate in asthma; effects during and after treatment.
Allergen-induced IL-9 directly stimulates mucin transcription in respiratory epithelial cells.
Effect of aerosolized anti-IgE (E25) on airway responses to inhaled allergen in asthmatic subjects.
Fractional analysis of sequential induced sputum samples during sputum induction: evidence that different lung compartments are sampled at different time points.
The effect of methacholine challenge on the cellular composition of induced sputum.
Neutrophil elastase and elastase-rich cystic fibrosis sputum degranulate human eosinophils in vitro.
A safe, simple, standardized method should be used for sputum induction for research purposes.
Effect of low-dose beclomethasone dipropionate on asthma control and airway inflammation.
Targeting IgE with monoclonal antibodies: the future is now.
Methods for sputum induction and analysis of induced sputum: a method for assessing airway inflammation in asthma.
An evaluation of colchicine as an alternative to inhaled corticosteriods in moderate asthma. National Heart, Lung, and Blood Institute's Asthma Clinical Research Network.
Safety of one method of sputum induction in asthmatic subjects.
The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects.
Similar RANTES levels in healthy and asthmatic airways by immunoassay and in situ hybridization.
Comparison of two methods of collecting induced sputum in asthmatic subjects.
Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. Asthma Clinical Research Network.
High-resolution computed tomography of airway changes after induced bronchoconstriction and bronchodilation in asthmatic volunteers.
Controversies involving inhaled beta-agonists and inhaled corticosteroids in the treatment of asthma.
Basic mechanisms of asthma.
Effect of an NK1 receptor antagonist (CP-99,994) on hypertonic saline-induced bronchoconstriction and cough in male asthmatic subjects.
Analysis of induced sputum after air and ozone exposures in healthy subjects.
Comparison of samples collected by sputum induction and bronchoscopy from asthmatic and healthy subjects.
Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation.
Cystic fibrosis sputum induces a secretory response from airway gland serous cells that can be prevented by neutrophil protease inhibitors.
Analysis of induced sputum to examine the effects of prednisone on airway inflammation in asthmatic subjects.
Analysis of cellular and biochemical constituents of induced sputum after allergen challenge: a method for studying allergic airway inflammation.
Use of mucin antibodies and cDNA probes to quantify hypersecretion in vivo in human airways.
Cellular and biochemical analysis of induced sputum from asthmatic and from healthy subjects.
Disappearance of eosinophils from bronchoalveolar lavage fluid after patient education and high-dose inhaled corticosteroids: a case report.
Lack of effect of prophylactic aerosolized pentamidine on the detection of Pneumocystis carinii in induced sputum or bronchoalveolar lavage specimens.
Markers of mucus secretion and DNA levels in induced sputum from asthmatic and from healthy subjects.
Mucus hypersecretion in bronchiectasis. The role of neutrophil proteases.
Effect of aerosolized pentamidine prophylaxis on the clinical severity and diagnosis of Pneumocystis carinii pneumonia.
Toxoplasma gondii pneumonitis in patients infected with the human immunodeficiency virus.
Aminoglycoside induced ototoxicity in patients with cystic fibrosis.
A chest radiograph scoring system in adult cystic fibrosis: correlation with pulmonary function.
Bacteraemia and fungaemia in adults with cystic fibrosis.
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