Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.5.1.19 (NOS)
 7,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molecular conjugates that target the serpin-enzyme complex receptor transfer the cDNA encoding human cystic fibrosis transmembrane conductance regulator (CFTR) to the nasal epithelium of cystic fibrosis mutant mice. These complexes effect partial correction of the chloride transport defect as assessed by in vivo nasal potential difference measurements, produce immunohistochemical staining for CFTR, and restore expression of nitric oxide synthase-2 (NOS-2), which is downregulated in the epithelium of mice and humans with cystic fibrosis. Complexes that lack the receptor ligands were ineffective, so receptor access was essential. Mice treated with receptor-targeted lacZ showed beta-galactosidase expression in epithelial cells and submucosal glands, but no electrophysiologic correction or NOS-2 expression, so simply accessing the serpin-enzyme complex receptor was not sufficient to produce the observed electrophysiologic or immunohistochemical changes. Correction of the cAMP-stimulated chloride transport was dose related at days 7 and 12 after complex administration, but, for most animals, nasal potential difference had returned to baseline by day 18. Molecular conjugates targeting the serpin-enzyme complex receptor, used to compact plasmid DNA, hold promise for gene therapy of cystic fibrosis.
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PMID:Functional evidence of CFTR gene transfer in nasal epithelium of cystic fibrosis mice in vivo following luminal application of DNA complexes targeted to the serpin-enzyme complex receptor. 1194 68

Controversy exists concerning abnormalities of the nitric oxide (NO) pathway in cystic fibrosis (CF) lung disease. Although some studies suggested that NO activity is impaired in CF, changes in NO production in young children have not been studied. We hypothesized that nitric oxide synthase (NOS II) expression is decreased in young children with CF, leading to decreased production of lower airway NO, and that decreased NOS II expression is related to airway inflammation. Accordingly, we measured lower airway exhaled NO, nitrate, and NOS II expression in airway epithelium and macrophages by bronchoscopy, bronchoalveolar lavage (BAL), and bronchial brushing in 13 children with CF, 4 adolescent patients with CF, and 14 disease control children. Lower airway NO and nitrate were not different between CF and disease controls. Immunostaining studies of NOS II expression in airway epithelial cells and macrophages were similar in CF and control patients. Within the CF group, however, expression of NOS II was inversely related to BAL neutrophil counts and IL-8, two markers of airway inflammation. We conclude that lower airway NO, nitrate levels, and NOS II expression are not different in young children with CF and disease control patients, but that NOS II expression decreases in CF as airway inflammation increases.
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PMID:NO pathway in CF and non-CF children. 1502 31

Chronic infection of the lungs with Pseudomonas aeruginosa complicates many long-term lung diseases including cystic fibrosis, bronchiectasis, chronic obstructive lung disease, and mechanical ventilation. In acute inflammatory lung diseases, increased nitric oxide synthase (NOS-2) expression leads to excess nitric oxide (NO) production, resulting in the production of reactive nitrogen intermediates, which contribute to tissue damage. In contrast, the contribution of NO to pulmonary damage in chronic Pseudomonas infection of the lung has not been directly examined and is unclear. Although NOS-2 expression is increased in this condition, NO production is not abnormally elevated. It was hypothesized that chronic infection of the airways does not cause increased NO production but, in contrast, leads to inappropriately low NO concentrations that are pro-inflammatory. A rodent model of chronic airway infection was used to examine the effects on lung damage of augmenting or inhibiting NO production after airway infection with P. aeruginosa was well established. Three days post-infection, L-arginine, which augments NO production, or L-NAME, an inhibitor of NO production, was administered in drinking water. Lung damage was assessed 12 days later. L-arginine treatment reduced tissue damage, inhibited neutrophil recruitment, and reduced the pro-inflammatory cytokine interleukin (IL)-1beta. Treatment with L-NAME caused loss of alveolar walls, greater vascular damage, and increased levels of the pro-inflammatory cytokine IL-6. Thus, in chronic airway infection, inhibition of NO production worsened lung damage, whereas augmenting NO ameliorated this damage. This is the first demonstration that augmenting endogenous NO production in chronic infective lung disease caused by P. aeruginosa is anti-inflammatory. Given that infection with this organism complicates many chronic lung diseases, most notoriously cystic fibrosis, these findings have important clinical implications.
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PMID:Anti-inflammatory effect of augmented nitric oxide production in chronic lung infection. 1653 11

Endotoxin (LPS), a Gram-negative cell wall component, has potent proinflammatory properties. Acute LPS exposure causes airway inflammation; chronic exposure causes airway hyperreactivity and remodeling. IL-10 is an important antiinflammatory cytokine, which is decreased in patients with airway disease, such as asthma and cystic fibrosis. To examine the physiologic and therapeutic role of IL-10 in acute and chronic LPS-induced airway disease. Mice were exposed to aerosolized LPS once or daily for 4 wk. Endpoints were airway inflammation, airway reactivity to methacholine, extracellular matrix protein expression, and histologic analysis. IL-10-deficient mice developed significantly enhanced airway cellularity and remodeling when compared with C57BL/6 mice after chronic LPS inhalation. However they demonstrated less airway hyperreactivity associated with higher inducible nitric oxide synthase (iNOS), endothelial NOS (eNOS), and lung lavage fluid nitrite levels. In a bone marrow transplantation model, the IL-10 antiinflammatory effect was dependent on the hematopoietic but not on the parenchymal IL-10 expression. Induced epithelial human IL-10 expression protected from the LPS effects and led to decreased collagen production. IL-10 attenuates chronic LPS-induced airway inflammation and remodeling. Physiologically, the antiinflammatory effect of IL-10 is mediated by hematopoietic cells. Therapeutically, adenovirus-driven expression of human IL-10 in airway epithelia is sufficient for its protective effect on inflammation and remodeling. The role of IL-10 on airway hyperreactivity is complex: IL-10 deficiency protects against LPS-induced hyperreactivity, and is associated with higher eNOS, iNOS, and airway nitrate levels.
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PMID:Leukocyte-derived IL-10 reduces subepithelial fibrosis associated with chronically inhaled endotoxin. 1680 36

Nitric oxide is produced by enzymes called nitric oxide synthases. It fulfills many important functions in the human body, but produced in excess amount has a proinflammatory activity. Fractional exhaled nitric oxide measurements are used in the diagnosis and monitoring of eosinophilic inflammation in the lower airways, but should not be used as an independent parameter to make a diagnosis of asthma or for the monitoring of asthma treatment. Evaluation of fractional exhaled nitric oxide concentrations is also used to determine the pathogenesis of symptoms in patients with rhinitis. In addition, they are helpful in detecting and monitoring eosinophilic inflammation in the lower respiratory tract that coexists with inflammation in the upper airways. Fractional exhaled nitric oxide concentrations may be abnormal (lowered or elevated) in other chronic diseases, such as cystic fibrosis, primary ciliary dyskinesia and inflammatory bowel diseases. Many factors, e.g. atopy, genetic polymorphisms of NOS, and the lipid profile affect the fractional exhaled nitric oxide measurement. Nasal nitric oxide measurement is useful in assessing the prevalence and severity of eosinophilic inflammation in the upper respiratory tract.
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PMID:[Usefulness of measurement of nitric oxide in exhaled air in diagnostics and treatment of allergic rhinitis and asthma in children and adolescents]. 3005