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Biomedical subjects

Sally E Wenzel

Publications and source records attributed to Sally E Wenzel.

32 records · Page 2Linked to original sources
PubMed2005

Correlation of systemic superoxide dismutase deficiency to airflow obstruction in asthma.

RATIONALE: Increased oxidative stress and decreased superoxide dismutase (SOD) activity in the asthmatic airway are correlated to airflow limitation and hyperreactivity. We hypothesized that asthmatic individuals with higher levels of oxidative stress may have greater loss of SOD activity, which would be reflected systemically in loss of circulating SOD activity and clinically by development of severe asthma and/or worsening airflow limitation. METHODS: To investigate this, serum SOD activity and proteins, the glutathione peroxidase/glutathione antioxidant system, and oxidatively modified amino acids were measured in subjects with asthma and healthy control subjects. RESULTS: SOD activity, but not Mn-SOD or Cu,Zn-SOD protein, was lower in asthmatic serum as compared with control, and activity loss was significantly related to airflow limitation. Further, serum SOD activity demonstrated an inverse correlation with circulating levels of 3-bromotyrosine, a posttranslational modification of proteins produced by the eosinophil peroxidase system of eosinophils. Exposure of purified Cu,Zn-SOD to physiologically relevant levels of eosinophil peroxidase-generated reactive brominating species, reactive nitrogen species, or tyrosyl radicals in vitro confirmed that eosinophil-derived oxidative pathways promote enzyme inactivation. CONCLUSION: These findings are consistent with greater oxidant stress in asthma leading to greater inactivation of SOD, which likely amplifies inflammation and progressive airflow obstruction.

Adult↗
PubMed2004

Interleukin-13 augments transforming growth factor-beta1-induced tissue inhibitor of metalloproteinase-1 expression in primary human airway fibroblasts.

Tissue inhibitor of metalloproteinase (TIMP)-1 is a potent inhibitor of activated matrix metalloproteinases (MMPs) such as gelatinases and collagenases. TIMP-1 is induced by transforming growth factor-beta1 (TGF-beta1), but details regarding signaling pathways remain unclear. T-helper-2 cytokines also have profibrotic properties and can interact with TGF-beta. In the present study, we examined the effects of interleukin (IL)-13 (2,500 pM) on TGF-beta1 (200 pM)-induced expression of TIMP-1 mRNA and protein in primary human airway fibroblasts obtained from 57 human subjects. IL-13 alone had no effect on TIMP-1 mRNA or protein expression. However, IL-13 synergistically augmented TGF-beta1-induced TIMP-1 mRNA and protein expression (P < 0.001 vs. TGF-beta1 alone). The upregulation of TIMP-1 by the combination of TGF-beta1 and IL-13 involved increased transcription, with little effect on mRNA stabilization. Initial exploration of the pathways leading to the synergy determined that activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway by IL-13 may have a negative effect on TIMP-1 production. The specific PI3K inhibitor LY-294002 in the presence of TGF-beta1, IL-13, or the combination of the two caused significant increases in TIMP-1 mRNA expression, while LY-294002 increased TIMP-1 protein levels in the presence of IL-13 alone. These results suggest that IL-13 augments TGF-beta1-induced profibrotic responses at both the mRNA and protein levels. Although IL-13 induced activation of PI3K-Akt, the activation did not contribute to the synergy observed with TGF-beta1 plus IL-13 in TIMP-1 expression and in fact may dampen it. The mechanisms behind the synergy remain to be determined.

1-Phosphatidylinositol 4-Kinase↗
PubMed2004

Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation.

BACKGROUND: Asthma is a heterogeneous process, yet little is understood regarding phenotypes. OBJECTIVE: To determine whether phenotypic differences exist between early-onset, severe asthma as compared with late-onset disease and whether the presence or absence of eosinophilia influences the phenotypes. METHODS: Cross-sectional analysis of integrated clinical, physiologic, and pathologic data collected from 80 subjects with severe asthma. Subjects were divided into those with asthma onset before age 12 years (n = 50) versus after age 12 (n = 30) and by the presence or absence of lung eosinophils. RESULTS: Subjects with early-onset, severe asthma had significantly more allergen sensitivity (skin test positivity, 98% vs 76%, P <.007) and more allergic symptoms (P values all <or=.02) than subjects with late-onset asthma. In contrast, subjects with late-onset asthma had lower lung function (P values =.05 to.07) than early-onset, despite a shorter (P <.0001) duration of illness. Both groups had a high degree of general asthma symptoms, but those with persistent eosinophils from either age at onset group had significantly more (multiple P values <.05). Similarly, the presence of eosinophils in either age at onset group was associated with the lowest lung function (P <or=.02). Although late-onset asthma was associated with the highest numbers of lung eosinophils (P <.007), only early-onset severe asthma was associated with a lymphocytic/mast cell inflammatory process. Finally, subjects with late-onset asthma without eosinophils had no subepithelial basement membrane thickening, suggesting a different pathologic process. CONCLUSIONS: Differentiating severe asthma by age at onset and presence or absence of eosinophils identifies phenotypes of asthma, which could benefit subsequent genetic and therapeutic studies.

Age of Onset↗
PubMed2004

Airway eicosanoids in acute severe respiratory syncytial virus bronchiolitis.

We prospectively studied the levels of eicosanoids in intubated patients with severe bronchiolitis and compared them to electively intubated non-infected infants. LeukotrieneE(4) (LTE(4)), leukotrieneB(4) (LTB(4)), and prostaglandinE(2) (PGE(2)) levels were significantly increased (P <.01) from endotracheal (ET) aspirates of infants with bronchiolitis compared with controls, as were urinary LTE(4) levels (P <.001). We conclude that eicosanoids are increased in the tracheal aspirates and urine of children with bronchiolitis.

Acute Disease↗
PubMed2004

Transforming growth factor-beta2 induces bronchial epithelial mucin expression in asthma.

The transforming growth factor (TGF)-beta family is important for tissue repair in pathological conditions including asthma. However, little is known about the impact of either TGF-beta1 or TGF-beta2 on asthmatic airway epithelial mucin expression. We evaluated bronchial epithelial TGF-beta1 and TGF-beta2 expression and their effects on mucin expression, and the role of TGF-beta1 or TGF-beta2 in interleukin (IL)-13-induced mucin expression. Epithelial TGF-beta1, TGF-beta2, and mucin expression were evaluated in endobronchial biopsies from asthmatics and normal subjects. The effects of TGF-beta1 or TGF-beta2 on mucin MUC5AC protein and mRNA expression, and the impact of IL-13 on epithelial TGF-beta1, TGF-beta2, and MUC5AC were determined in cultured bronchial epithelial cells from endobronchial brushings of both subject groups. In biopsy tissue, epithelial TGF-beta2 expression levels were higher than TGF-beta1 in both asthmatics and normals. TGF-beta2, but not TGF-beta1, was increased in asthmatics compared with normals, and significantly correlated with mucin expression. TGF-beta2, but not TGF-beta1, increased mucin expression in cultured epithelial cells from both subject groups. IL-13 increased the release of TGF-beta2, but not TGF-beta1, from epithelial cells. A neutralizing TGF-beta2 antibody partially inhibited IL-13-induced mucin expression. These data suggest that TGF-beta2 production by asthmatic bronchial epithelial cells may increase airway mucin expression. IL-13-induced mucin expression may occur in part through TGF-beta2 up-regulation.

Adult↗
PubMed2003

Neutrophil-derived matrix metalloproteinase-9 is increased in severe asthma and poorly inhibited by glucocorticoids.

BACKGROUND: Matrix metalloproteinase (MMP)-9 levels are increased in bronchoalveolar lavage (BAL) fluid from patients with severe asthma on high doses of glucocorticoids (GCs). OBJECTIVE: We sought to identify neutrophils as the source of increased BAL fluid MMP-9 in severe asthma and to evaluate the effects of GCs on this MMP-9. METHODS: MMP-9 protein, activity, and mRNA were measured in BAL fluid and cells at baseline, and after in vitro GCs in patients with severe asthma and controls using enzyme immunoassays, zymography, Western blotting, and real-time PCR. RESULTS: The high molecular weight (HMW) form of MMP-9 was significantly increased in severe asthma (P =.02). Western blotting confirmed a heterodimer of MMP-9 and neutrophil gelatinase-associated lipocalin. The HMW MMP-9 correlated with BAL neutrophils (r =.65, P <.0001). BAL cell supernatant MMP-9 protein levels also tended to be higher in patients with severe asthma (overall, P =.09), whereas the HMW activity form was increased (P =.03). MMP-9 protein (and HMW activity) correlated with neutrophils in the cell pellet (r =.75, P <.0001). In contrast to protein and activity, BAL cell mRNA levels were marginally lower in patients with severe asthma than in control subjects (overall, P =.06). Although GCs decreased BAL cell MMP-9 protein and mRNA in vitro, the effect was significantly smaller in severe asthma (P <.01 for both). GCs decreased the pro-MMP-9 activity in patients with severe asthma and normal control subjects, while having no effects on the HMW form (P =.22). Peripheral blood neutrophil MMP-9 protein was not affected by GCs. CONCLUSIONS: BAL neutrophils contribute to BAL fluid MMP-9 protein and activity and are poorly inhibited by GCs.

Acute-Phase Proteins↗
PubMed2003

Subepithelial basement membrane immunoreactivity for matrix metalloproteinase 9: association with asthma severity, neutrophilic inflammation, and wound repair.

BACKGROUND: Asthma likely involves an active injury and repair process, including components such as neutrophils and matrix metalloproteinase 9 (MMP-9). Although MMP-9 is increased in lavage fluid and sputum in patients with asthma, controversy exists as to the role of tissue MMP-9. OBJECTIVE: The purpose of this study was to determine whether increases in submucosal cellular MMP-9, matrix MMP-9 (subepithelial basement membrane [SBM]), or both would be associated with severe asthma, neutrophilic inflammation, and wound repair. METHODS: Immunohistochemical staining and analyses of MMP-9, inflammatory cells, transforming growth factor beta, and collagen I were performed in endobronchial biopsy specimens, bronchoalveolar lavage fluid, or both from 38 patients with severe asthma and compared with results in 10 patients with mild asthma, 8 patients with moderate asthma, and 10 healthy control subjects. RESULTS: A significantly greater proportion of patients with severe asthma demonstrated MMP-9 staining of the SBM than control subjects (P =.02). Bronchoalveolar lavage MMP-9 levels were also increased in patients with severe asthma (P =.0004). The numbers of submucosal neutrophils and macrophages, but not eosinophils, were significantly higher in asthmatic individuals with MMP-9 staining of the SBM (P =.004 and P =.01, respectively). However, the presence of SBM MMP-9 was associated with a high correlation between lavage and tissue eosinophils (r = 0.58, P =.009). Although the SBM thickness did not differ between groups, higher numbers of transforming growth factor beta-positive cells were seen in subjects with SBM MMP-9 staining. Pulmonary function was significantly lower in those asthmatic subjects with SBM staining. CONCLUSIONS: These results suggest that localized tissue MMP-9 might play an important role in wound repair and cell trafficking.

Adult↗
PubMed2002

TGF-beta and IL-13 synergistically increase eotaxin-1 production in human airway fibroblasts.

Chronic diseases may involve an "innate" response followed by an adaptive immune response, of a Th1 or Th2 variety. Little is known regarding the interactions of these responses. We hypothesized that TGF-beta1 (innate response factor associated with wound repair) in combination with IL-13 (Th2 factor) might augment inflammatory processes associated with asthma. Airway fibroblasts were cultured from asthmatic subjects and normal controls. These fibroblasts were exposed to TGF-beta1 and IL-13 alone or in combination, and eotaxin-1 expression and production were evaluated. At 48 h, eotaxin-1 production was markedly increased with the combination of TGF-beta1 and IL-13 (p < 0.0001) compared with either stimulus alone. mRNA increased slightly at 1 h with IL-13 or TGF-beta1 plus IL13, peaked, and became significantly increased over IL-13 alone at 24 h. Protein was measurable from 6 h with IL-13 and TGF-beta1 plus IL-13, but greater levels were measured over time with the combination. Actinomycin ablated the increase in mRNA and protein seen with IL-13 alone and with TGF-beta1 plus IL-13. Cycloheximide blocked the increase in mRNA at 6 h in both conditions, but also blocked the increase at 24 h with TGF-beta1 plus IL-13. STAT-6 was rapidly activated with both IL-13 and the combination, without difference. Finally, eotaxin-1-positive fibroblasts were identified in severe asthma biopsies in greater numbers than in normals. These results support the concept that interactions of innate and adaptive immune systems may be important in promoting the tissue eosinophilia of asthma, particularly in those with more severe disease.

Adjuvants, Immunologic↗
PubMed2002

Respiratory outcomes in high-risk children 7 to 10 years after prophylaxis with respiratory syncytial virus immune globulin.

PURPOSE: Respiratory syncytial virus infections have been implicated in the development of asthma. We evaluated the long-term effects of respiratory syncytial virus immune globulin, an effective prophylactic agent for the prevention of these infections in children, on respiratory and allergic outcomes in children at high risk of chronic airway disease. SUBJECTS AND METHODS: Thirteen children at high risk of respiratory disease (mean [+/-SD] age, 8.6 +/- 1.1 years) were evaluated using pulmonary function and allergy skin testing 7 to 10 years after they had received prophylaxis with respiratory syncytial virus immune globulin. For comparison, 26 high-risk control children (mean age, 8.5 +/- 0.9 years) were also evaluated. Health outcomes data were collected from all subjects. The children were matched for age and gestational age. There were more boys, and a lesser frequency of a lower respiratory tract infection with respiratory syncytial virus (P <0.001) in the group that had been treated prophylactically than in the controls. The ratio of the forced expiratory volume in 1 second to forced vital capacity was significantly better in children who had received immune globulin (median, 0.88; interquartile range, 0.81 to 0.91) than in the controls (median, 0.76; interquartile range, 0.67 to 0.86; P = 0.02). Children were also less atopic (2 of 13) in the respiratory syncytial virus immune globulin group than in the control group (13 of 26, P <0.04) and were less likely to have missed school (P = 0.006) or have had an asthma attack (P = 0.03). CONCLUSION: The results suggest that prophylaxis of respiratory syncytial virus infections in infancy may have long-term effects on respiratory and immunologic parameters relevant to the development of asthma. Larger-scale studies are needed.

Bronchial Provocation Tests↗
PubMed2002

Interleukin-15 inhibits spontaneous apoptosis in human eosinophils via autocrine production of granulocyte macrophage-colony stimulating factor and nuclear factor-kappaB activation.

Prolonged eosinophil survival, i.e., reduced apoptosis, is implicated in the pathogenesis of chronic allergic inflammation. Here we demonstrate that interleukin (IL)-15, in the presence or absence of tumor necrosis factor (TNF)-alpha, reduces spontaneous apoptosis in freshly isolated human eosinophils. The prosurvival effect of IL-15 was abrogated by neutralizing antibody to granulocyte macrophage-colony stimulating factor (GM-CSF), although GM-CSF was not detected in conditioned media by ELISA. Additionally, the effect of IL-15 on spontaneous eosinophil apoptosis appeared to require nuclear factor-kappaB (NF-kappaB) activation based on evidence for NF-kappaB nuclear translocation and abrogation of the effect by the NF-kappaB inhibitor, Bay 11- 7082. Finally, the data demonstrate that IL-15 expression is higher in the submucosa of endobronchial tissues from subjects with moderate to severe asthma when compared with control subjects. Thus, our results suggest that IL-15, either alone or in combination with TNF-alpha, may perpetuate allergic inflammation by reduction of spontaneous eosinophil apoptosis through autocrine production of GM-CSF and NF-kappaB activation.

Adolescent↗
PubMedDate not supplied

The role of leukotrienes in asthma.

Leukotrienes (LT), both the cysteinyl LTs, LTC(4), LTD(4) and LTE(4), as well as LTB(4) have been implicated in the clinical course, physiologic changes, and pathogenesis of asthma. The cysteinyl LTs are potent bronchoconstrictors, which have additional effects on blood vessels, mucociliary clearance and eosinophilic inflammation. In addition, the cysteinyl LTs are formed from cells commonly associated with asthma, including eosinophils and mast cells. LTB(4), whose role is less well defined in asthma, is a potent chemoattractant (and cell activator) for both neutrophils and eosinophils. In the last 5 years, drugs have been developed which block the actions or formation of these mediators. Clinical and physiologic studies have demonstrated that they are modest short-acting bronchodilators, with sustained improvement in FEV(1) occurring in double-blind, placebo-controlled clinical trials for up to 6 months. These drugs have demonstrated efficacy in preventing bronchoconstriction caused by LTs, allergen, exercise and other agents. Additionally, there are multiple published studies which have demonstrated improvement in asthma symptoms, beta agonist use and, importantly, exacerbations of asthma in both adults and children. Comparison studies with inhaled corticosteroids (ICS) suggest that ICS are superior to leukotriene modifying drugs in moderate persistent asthma. However, several published studies now suggest that leukotriene modifying drugs are effective when added to ongoing therapy with ICS, either to improve current symptoms or to decrease the dose of ICS required to maintain control. While an anti-inflammatory effect is suggested, longer-term, earlier intervention, studies are needed to determine whether these compounds will have any effect on the natural history of the disease.

Adrenal Cortex Hormones↗