Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.37 (neutrophil elastase)
 4,078 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over the years, there has emerged a considerable body of evidence supporting the importance of antimicrobial therapy in exacerbations of chronic bronchitis. The following lines of evidence suggest that most acute exacerbations are caused by bacterial infection: (1) the individual with chronic bronchitis is susceptible to bacterial infection as a consequence of local damage from prolonged cigarette smoking; (2) subtle defects in the local immune system can be shown, including impaired particle transport, defective immunoglobulin A production, chronic mucous impaction, and defective neutrophil phagocytosis; (3) acute bronchitic exacerbations are associated with a proliferation of pathogenic bacteria in the lower respiratory tract, based on quantitative culture data obtained by bronchoscopy with a protected specimen brush; (4) viral respiratory infections, which were once linked to over 50% of purulent exacerbations, probably account for only a minority of bronchitic exacerbations; (5) some "culture negative" exacerbations may be caused by bacteria susceptible to antibiotics such as Mycoplasma pneumoniae or Chlamydia pneumoniae. There are also secondary effects of bacteria that are potentially amenable to antibiotic therapy. Bacteria that colonize the respiratory tract of chronic bronchitics cause direct damage to the respiratory epithelium. Lipooligosaccharide, a major component of the outer membrane of Haemophilus influenzae, is an endotoxin-like mediator of respiratory cell damage. The host inflammatory response to bacterial proliferation is ineffective and may be potentially harmful; the enzyme neutrophil elastase is released by the host during phagocytosis of bacteria and may lead to progressive airway damage. In addition, bacterial superinfections may complicate viral exacerbations of chronic bronchitis. Clinical trials examining the efficacy of antibiotic therapy in mild to moderate exacerbations of chronic bronchitis have yielded conflicting results, caused in part to fundamental differences in study design. The major double-blinded and placebo-controlled studies suggest a trend in favor of antimicrobial therapy, although the effect is modest. For the individual patient, the risks of antimicrobial therapy are small compared with the potential benefits of returning to work earlier and avoiding the rare case of respiratory decompensation.
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PMID:Pro: antibiotics for chronic bronchitis with exacerbations. 793 21

Acute exacerbations of asthma are frequently caused by viral infections, but the inflammatory mechanisms in virus-induced asthma are poorly understood. The aim of the present study was to determine whether viral infection in acute asthma was associated with increased sputum neutrophil degranulation and increased cellular lysis and whether these changes are related to clinical severity. Adults (n=49) presenting to the emergency department with acute asthma were examined for infection by means of sputum direct-fluorescence antigen detection, sputum culture, and sputum polymerase chain reaction for Mycoplasma, Chlamydia and Legionella pneumophila, and all common respiratory viruses. Subjects infected with one of these agents were classed as having an infective exacerbation. Spirometry and sputum induction were performed on presentation and 4-5 weeks later. Thirty-seven subjects (76%) had virus infection and acute asthma. Those with virus infection had increased sputum neutrophils (p<0.05) and increased neutrophil elastase (p<0.05), this was related to increased elevated sputum lactate dehydrogenase (LDH). Subjects with noninfective asthma had an increase in the proportion of sputum eosinophils. Both groups had elevated sputum eosinophil cationic protein (ECP) concentrations. Higher levels of sputum LDH and ECP were associated with a longer hospital stay. Virus infection and acute asthma is associated with neutrophilic inflammation, cell lysis and more severe clinical disease.
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PMID:Neutrophil degranulation and cell lysis is associated with clinical severity in virus-induced asthma. 1185 95

For 50 years, macrolide antibiotics have been used to treat community acquired pneumonia and atypical infections such as Chlamydia pneumonia and Mycoplasma. In the late 1960s it was noted that when the 14-member ring macrolide antibiotic troleandomycin was given to asthma patients who required large doses of systemic corticosteroids, they could often reduce their steroid dose or even stop steroids completely without exacerbation of their asthma. Because of this experience, Prof. S. Kodoh and colleagues first used erythromycin as an immunomodulatory agent to treat diffuse panbronchiolitis (DPB). DPB is a cystic fibrosis (CF)-like condition seen predominantly in young, nonsmoking adults in Japan and Korea. The introduction of erythromycin profoundly improved survival, and in many of these very ill patients the illness disappeared. Since then, research has focused attention on many non-antibacterial, disease modifying effects of this class of compounds. These include downregulation of proinflammatory cytokines via an effect on nuclear transcription factors, reduction in adhesion molecule expression, suppression of inducible nitric oxide synthase (iNOS), reduced neutrophil chemotaxis and degranulation, inhibition of neutrophil elastase, cytoprotection against bioactive phospholipids, improvement in the rheological properties of mucus, reduction in bronchial hyperreactivity, and, perhaps, modulation of neutrophil death by apoptosis pathways, and in the end, airway remodeling. Additionally, they have unconventional effects on microorganisms, including inhibiting Pseudomonas aeruginosa twitching motility and thus biofilm formation. There are small case series and three large randomized controlled trials that have established unequivocal evidence of benefit in CF. There is less evidence for an immunomodulatory effect in bronchiectasis. Future work is likely to focus on the development of macrolides with disease-specific modes of action.
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PMID:Macrolides as biological response modifiers in cystic fibrosis and bronchiectasis. 1608 89

Short palate, lung, and nasal epithelium clone 1 (SPLUNC1) protein is highly expressed in normal airways, but is dramatically decreased in allergic and cigarette smoke exposure settings. We have previously demonstrated SPLUNC1 in vitro antibacterial property against Mycoplasma pneumoniae (Mp). However, its in vivo biological functions remain unclear. The objectives of this study were to determine the in vivo functions of SPLUNC1 following bacterial (eg, Mp) infection, and to examine the underlying mechanisms. We generated SPLUNC1-deficient mice and utilized transgenic mice overexpressing human SPLUNC1 exclusively within the airway epithelium. These mice were infected with Mp and, twenty-four hours post infection, their host defense responses were compared to littermate controls. Mp levels and inflammatory cells increased in the lungs of SPLUNC1(-/-) mice as compared to wild type controls. SPLUNC1 deficiency was shown to contribute to impaired neutrophil activation. In contrast, mice overexpressing hSPLUNC1 exclusively in airway epithelial cells demonstrated lower Mp levels. Furthermore, neutrophil elastase activity was significantly increased in mice overexpressing hSPLUNC1. Lastly, we demonstrated that SPLUNC1 enhanced Mp-induced human neutrophil elastase (HNE) activity, and HNE directly inhibited the growth of Mp. Our findings demonstrate a critical in vivo role of SPLUNC1 in host defense against bacterial infection, and likely provide a novel therapeutic approach to restore impaired lung innate immune responses to bacteria in patients with chronic lung diseases.
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PMID:SPLUNC1 promotes lung innate defense against Mycoplasma pneumoniae infection in mice. 2151 30

Hepatocyte growth factor (HGF) promotes lung epithelial repair after injury. Because prior studies established that human neutrophil proteases inactivate HGF in vitro, we predicted that HGF levels decrease in lungs infiltrated with neutrophils and that injury is less severe in lungs lacking HGF-inactivating proteases. After establishing that mouse neutrophil elastase cleaves mouse HGF in vitro, we tested our predictions in vivo by examining lung pathology and HGF in mice infected with Mycoplasma pulmonis, which causes neutrophilic tracheobronchitis and pneumonia. Unexpectedly, pneumonia severity was similar in wild type and dipeptidylpeptidase I-deficient (Dppi-/-) mice lacking neutrophil serine protease activity. To assess how this finding related to our prediction that Dppi-activated proteases regulate HGF levels, we measured HGF in serum, bronchoalveolar lavage fluid, and lung tissue from Dppi(+/+) and Dppi(-/-) mice. Contrary to prediction, HGF levels were higher in lavage fluid from infected mice. However, serum and tissue concentrations were not different in infected and uninfected mice, and HGF lung transcript levels did not change. Increased HGF correlated with increased albumin in lavage fluid from infected mice, and immunostaining failed to detect increased lung tissue expression of HGF in infected mice. These findings are consistent with trans-alveolar flux rather than local production as the source of increased HGF in lavage fluid. However, levels of intact HGF from infected mice, normalized for albumin concentration, were two-fold higher in Dppi(-/-) versus Dppi(+/+) lavage fluid, suggesting regulation by Dppi-activated proteases. Consistent with the presence of active HGF, increased expression of activated receptor c-Met was observed in infected tissues. These data suggest that HGF entering alveoli from the bloodstream during pneumonia compensates for destruction by Dppi-activated inflammatory proteases to allow HGF to contribute to epithelial repair.
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PMID:Regulation of hepatocyte growth factor in mice with pneumonia by peptidases and trans-alveolar flux. 2593 94