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1.  The H Antigen at Epithelial Surfaces Is Associated with Susceptibility to Asthma Exacerbation 
Rationale: Acute asthma exacerbations, precipitated by viral infections, are a significant cause of morbidity, but not all patients with asthma are equally susceptible.
Objectives: To explore susceptibility factors for asthma exacerbations, we considered a role for histoblood group antigens because they are implicated in mechanisms of gastrointestinal viral infection, specifically the O-secretor mucin glycan phenotype. We investigated if this phenotype is associated with susceptibility to asthma exacerbation.
Methods: We performed two consecutive case-control studies in subjects with asthma who were either prone or resistant to asthma exacerbations. Exacerbation-prone cases had frequent use of prednisone for an asthma exacerbation and frequent asthma-related healthcare utilization, whereas exacerbation-resistant control subjects had rarely reported asthma exacerbations. The frequency of different mucin glycan phenotypes, defined by the presence or absence of H (O), A, B, or AB antigens, was compared in cases and control subjects.
Measurements and Main Results: In an initial study consisting of 49 subjects with asthma (23 cases and 26 control subjects), we found that having the O-secretor phenotype was associated with a 5.8-fold increase in the odds of being a case (95% confidence interval, 1.7–21.0; P = 0.006). In a replication study consisting of 204 subjects with asthma (101 cases and 103 control subjects), we found that having the O-secretor phenotype was associated with a 2.3-fold increased odds of being a case (95% confidence interval, 1.2–4.4; P = 0.02).
Conclusions: The O-secretor mucin glycan phenotype is associated with susceptibility to asthma exacerbation.
Clinical trial registered at (NCT00201266).
PMCID: PMC3040389  PMID: 20732988
asthma; mucins; fucosylation; H antigen; blood groups
2.  Accumulation of intraepithelial mast cells with a unique protease phenotype in TH2-high asthma 
Previously, we found that mast cell tryptases and carboxypeptidase A3 (CPA3) are differentially expressed in the airway epithelium in asthmatic subjects. We also found that asthmatic subjects can be divided into 2 subgroups (“TH2 high” and “TH2 low” asthma) based on epithelial cell gene signatures for the activity of TH2 cytokines.
We sought to characterize intraepithelial mast cells (IEMCs) in asthma.
We performed gene expression profiling in epithelial brushings and stereology-based quantification of mast cell numbers in endobronchial biopsy specimens from healthy control and asthmatic subjects before and after treatment with inhaled corticosteroids (ICSs). We also performed gene expression and protein quantification studies in cultured airway epithelial cells and mast cells.
By means of unsupervised clustering, mast cell gene expression in the airway epithelium related closely to the expression of IL-13 signature genes. The levels of expression of mast cell genes correlate positively with lung function improvements with ICSs. IEMC density was 2-fold higher than normal in subjects with TH2-high asthma compared with that seen in subjects with TH2-low asthma or healthy control subjects (P = .015 for both comparisons), and these cells were characterized by expression of tryptases and CPA3 but not chymase. IL-13 induced expression of stem cell factor in cultured airway epithelial cells, and mast cells exposed to conditioned media from IL-13–activated epithelial cells showed downregulation of chymase but no change in tryptase or CPA3 expression.
IEMC numbers are increased in subjects with TH2-high asthma, have an unusual protease phenotype (tryptase and CPA3 high and chymase low), and predict responsiveness to ICSs. IL-13–stimulated production of stem cell factor by epithelial cells potentially explains mast cell accumulation in TH2-high asthmatic epithelium.
PMCID: PMC2918406  PMID: 20451039
Asthma; mast cells; tryptase; chymase; carboxypeptidase A3; stem cell factor
3.  Ex Vivo Sputum Analysis Reveals Impairment of Protease-dependent Mucus Degradation by Plasma Proteins in Acute Asthma 
Rationale: Airway mucus plugs, composed of mucin glycoproteins mixed with plasma proteins, are an important cause of airway obstruction in acute severe asthma, and they are poorly treated with current therapies.
Objectives: To investigate mechanisms of airway mucus clearance in health and in acute severe asthma.
Methods: We collected airway mucus from patients with asthma and nonasthmatic control subjects, using sputum induction or tracheal aspiration. We used rheological methods complemented by centrifugation-based mucin size profiling and immunoblotting to characterize the physical properties of the mucus gel, the size profiles of mucins, and the degradation products of albumin in airway mucus.
Measurements and Main Results: Repeated ex vivo measures of size and entanglement of mucin polymers in airway mucus from nonasthmatic control subjects showed that the mucus gel is normally degraded by proteases and that albumin inhibits this degradation. In airway mucus collected from patients with asthma at various time points during acute asthma exacerbation, protease-driven mucus degradation was inhibited at the height of exacerbation but was restored during recovery. In immunoblots of human serum albumin digested by neutrophil elastase and in immunoblots of airway mucus, we found that albumin was a substrate of neutrophil elastase and that products of albumin degradation were abundant in airway mucus during acute asthma exacerbation.
Conclusions: Rheological methods complemented by centrifugation-based mucin size profiling of airway mucins in health and acute asthma reveal that mucin degradation is inhibited in acute asthma, and that an excess of plasma proteins present in acute asthma inhibits the degradation of mucins in a protease-dependent manner. These findings identify a novel mechanism whereby plasma exudation may impair airway mucus clearance.
PMCID: PMC2724713  PMID: 19423716
airway mucus; rheology; neutrophil elastase; plasma; asthma exacerbation
4.  Inhibition of c-Jun N-Terminal Kinase 2 Expression Suppresses Growth and Induces Apoptosis of Human Tumor Cells in a p53-Dependent Manner 
Molecular and Cellular Biology  2000;20(5):1713-1722.
c-Jun N-terminal kinase (JNK) plays a critical role in coordinating the cellular response to stress and has been implicated in regulating cell growth and transformation. To investigate the growth-regulatory functions of JNK1 and JNK2, we used specific antisense oligonucleotides (AS) to inhibit their expression. A survey of several human tumor cell lines revealed that JNKAS treatment markedly inhibited the growth of cells with mutant p53 status but not that of cells with normal p53 function. To further examine the influence of p53 on cell sensitivity to JNKAS treatment, we compared the responsiveness of RKO, MCF-7, and HCT116 cells with normal p53 function to that of RKO E6, MCF-7 E6, and HCT116 p53−/−, which were rendered p53 deficient by different methods. Inhibition of JNK2 (and to a lesser extent JNK1) expression dramatically reduced the growth of p53-deficient cells but not that of their normal counterparts. JNK2AS-induced growth inhibition was correlated with significant apoptosis. JNK2AS treatment induced the expression of the cyclin-dependent kinase inhibitor p21Cip1/Waf1 in parental MCF-7, RKO, and HCT116 cells but not in the p53-deficient derivatives. That p21Cip1/Waf1 expression contributes to the survival of JNK2AS-treated cells was supported by additional experiments demonstrating that p21Cip1/Waf1 deficiency in HCT116 cells also results in heightened sensitivity to JNKAS treatment. Our results indicate that perturbation of JNK2 expression adversely affects the growth of otherwise nonstressed cells. p53 and its downstream effector p21Cip1/Waf1 are important in counteracting these detrimental effects and promoting cell survival.
PMCID: PMC85354  PMID: 10669748

Results 1-4 (4)