Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cystic fibrosis (CF) is an inherited disorder associated with severe inflammation and repeated bacterial infection and colonization in the lung. Airway epithelium is involved in defence against bacteria, but this system may be defective in CF. Pro-inflammatory cytokines can stimulate the expression of inducible nitric oxide synthase (iNOS), an enzyme generating nitric oxide, which functions as an important mediator in host defence mechanisms. To understand better the poor resistance to infections in the CF lung, the expression of the iNOS gene was investigated in explanted lungs from patients with cystic fibrosis (n = 13), bronchiectasis (n = 3), emphysema (n = 14), and in normal lungs (n = 8). In addition, bronchial epithelial cell lines were examined to study iNOS gene expression in vitro. Strong immunoreactivity for iNOS was seen in inflammatory cells and bronchial epithelium in all the diseased lungs, except for bronchial epithelium in CF. Quantitative analysis showed a significant reduction in the area of epithelium immunostained in CF [CF 6.8 +/- 1.6 (% +/- SEM); emphysema 18.2 +/- 2.8; normal 9.6 +/- 0.8, P < 0.01], regardless of steroid treatment. These results were supported by in situ hybridization of iNOS mRNA, which showed a pattern of gene expression in CF, emphysema, and normal lung which paralleled that of protein immunoreactivity. Stimulation with cytokines (IL-1 beta, TNF-alpha, and IFN-gamma) increased the expression of iNOS mRNA detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in cultures of normal (16HBE14o-), but not CF (CFBE41o-, with delta F508 CFTR mutation) epithelial cells. Expression of iNOS in inflammatory cells suggests that the gene is normal in CF. Absence of iNOS from bronchial epithelium may be due to low expression of the gene resulting from abnormalities in the signalling system that normally causes induction, such as cytokine receptors, second messengers or transcription factors. The resulting deficiency of the nitric oxide defence system may be relevant to the susceptibility of CF patients to pulmonary bacterial colonization.
 ...
PMID:Lack of inducible nitric oxide synthase in bronchial epithelium: a possible mechanism of susceptibility to infection in cystic fibrosis. 961 86

To provide information concerning a possible biologic role of nitric oxide (NO) in smoking-related emphysema, we performed immunohistochemical studies in lung tissue from control subjects and patients with mild and severe emphysema. We studied the presence of inducible and endothelial NO synthases (iNOS and eNOS, respectively) and determined nicotinamide diphosphate (NADPH) diaphorase activity. Patients with severe emphysema showed lower percentages of iNOS- and eNOS-positive alveolar macrophages in situ than did patients with mild emphysema. In patients with both iNOS and eNOS immunoreactivity in macrophages, the majority of the macrophages expressed either iNOS or eNOS, whereas only a minority of the macrophages showed iNOS and eNOS immunoreactivity simultaneously. Immunoreactivity for eNOS in endothelial and/or bronchiolar epithelial cells and NADPH diaphorase activity in macrophages and in endothelial, epithelial, and smooth muscle cells were similar in the three studied groups. The expression of eNOS in macrophages suggests that eNOS plays an additional role, besides iNOS, in the NO housekeeping in inflammatory processes in pulmonary tissue. We suggest that NO might have a protective role in maintenance of structural integrity of pulmonary tissue after smoke-induced damage.
 ...
PMID:Macrophages in lung tissue from patients with pulmonary emphysema express both inducible and endothelial nitric oxide synthase. 968 86

Epidemiological evidence suggests that smoking is a major cause of human lung cancer. However, the mechanism by which cigarette smoke induces the cancer remains unestablished. To evaluate the effects of cigarette smoke on the expression of inducible nitric oxide synthase (iNOS), nuclear protooncogenes and related mitogen-activated protein kinases (MAPKs) in rat lung tissue, a histopathological study of the effects of gas-phase cigarette smoke on rat lung tissue were carried out. The terminal bronchioles were found to be infiltrated predominantly by lymphocytes in the peribronchiolar region and a mild to moderate degree of emphysema was noted in the alveolar spaces. The terminal bronchioles also showed marked lipid peroxidation, dilatation, and peribronchiolar fibrosis. Immunohistochemical evaluation showed that the expression of iNOS, NF-kappa B, MAPKs (MEK1, ERK2), phosphotyrosine protein and c-fos was increased in the terminal bronchioles but protein kinase C (PKC), MEKK-1, c-jun, p38 and c-myc showed no change. These results provide evidence to suggest that exposure to cigarette smoke results in oxidant stress which leads to the stimulation of iNOS and c-fos together with the induction of protein tyrosine phosphorylation and MEK1/ERK2 which in turn may promote lung pathogenesis.
 ...
PMID:Increased expression of iNOS and c-fos via regulation of protein tyrosine phosphorylation and MEK1/ERK2 proteins in terminal bronchiole lesions in the lungs of rats exposed to cigarette smoke. 1135 18

Tumor necrosis factor-alpha (TNF-alpha) transgenic mice have previously been found to have characteristics consistent with emphysema and severe pulmonary hypertension. Lungs demonstrated alveolar enlargement as well as interstitial thickening due to chronic inflammation and perivascular fibrosis. In the present report, we sought to determine potential mechanisms leading to development of pulmonary hypertension in TNF-alpha transgenic mice. To determine whether sustained vasoconstriction was an important component of this pulmonary hypertension, nitric oxide was administered and hemodynamics were measured. Nitric oxide (25 ppm) failed to normalize right ventricular pressure in transgene-positive mice, suggesting that the pulmonary hypertension was not due to sustained vasoconstriction. Structural analysis of the pulmonary arteries found adventitial thickening and a trend toward medial hypertrophy in pulmonary arteries of transgene-positive mice, suggesting that vascular remodeling had occurred. Echocardiographic measurement of the percent fractional shortening of the left ventricle as a measurement of ventricular function in vivo revealed that left ventricular dysfunction was not contributing to pulmonary hypertension. We examined expression of genes known to be important in regulation of vascular tone and structure. Messenger RNA expression of vascular endothelial growth factor and its receptor flk-1 was reduced compared with transgene-negative littermates at all ages. Endothelial and inducible nitric oxide synthase mRNA levels were similar in both groups. Endothelin-1 mRNA was also decreased in TNF-alpha transgenic mice. Interestingly, female transgenic mice had decreased survival rate compared with male transgenic mice. We conclude that chronic overexpression of TNF-alpha is associated with decreased vascular endothelial growth factor and flk-1 gene expression, pulmonary vascular remodeling, and severe pulmonary hypertension, although the precise mechanism is unknown.
 ...
PMID:Pulmonary hypertension in TNF-alpha-overexpressing mice is associated with decreased VEGF gene expression. 1239 Nov 6

No currently available treatments have been shown to slow the progression of chronic obstructive pulmonary disease (COPD) or suppress the inflammation in small airways and lung parenchyma. However, several new treatments are in clinical development; some target the inflammatory process and others are directed against structural cells. A group of specific therapies are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD; these include agents directed against adhesion molecules and chemokines, as well as therapies to oppose tumour necrosis factor alpha and increase interleukin 10. Broad-range anti-inflammatory drugs are now in phase III development for COPD; they include inhibitors of phosphodiesterase 4. Other drugs that inhibit cell signalling include inhibitors of p38 mitogen-activated protein kinase, nuclear factor kappaB, and phosphoinositide-3-kinase gamma. More specific approaches are to give antioxidants, inhibitors of inducible nitric oxide synthase, and antagonists of leukotriene B4 receptor. Inhibitors of epidermal-growth-factor-receptor kinase and calcium-activated chloride channels have the potential to prevent overproduction of mucus. Therapy to inhibit fibrosis is being developed against transforming growth factor beta1 and protease-activated receptor 2. There is also a search for inhibitors of serine proteinases and matrix metalloproteinases to prevent lung destruction and the development of emphysema, as well as drugs such as retinoids that might even reverse this process. Effective delivery of drugs to the sites of disease in the peripheral lung is an important consideration, and there is a need for validated biomarkers and monitoring techniques in early clinical studies with new therapies for COPD.
 ...
PMID:Prospects for new drugs for chronic obstructive pulmonary disease. 1558 53

To explore the effects of bilirubin on alveolar macrophages (AM) and expression of iNOS and NO in them in emphysema model, the rats were pretreated with bilirubin before exposed to smoke. AM were isolated from bronchoalveolar lavage fluid (BALF) and cultured. Pathological microscopic examination of AM and immunohistochemical analysis of iNOS were performed. Nitric oxide (NO) content in the samples was determined by nitrate reductase technique. The results showed both alveoli and alveolar septum appeared normal in size and shape in normal group. AM showed kidney-shaped nucleus and were rich in Golgi complexes and primary lysosomes in the cytoplasm. The inner membrane of mitochondrion was continuous. Most cristae of the mitochondria were intact. In model group, the alveoli were expanded, ruptured and bullaes were formed. Both the population and sizes of AM increased significantly. Secondary lysosomes were rich in the cytoplasm. Deformation and pyknosis of the nucleus, swelling of the mitochondrions and rupture of the inner mitochondrial membrane could also be seen. At high magnification, most of the mitochondrial cristae were broken, or completely lost at certain points. In bilirubin group, alveoli partly expanded and the population of AM also increased, with morphological changes being slighter than that in model group. Both NO contents and expression of iNOS in model group were higher than those in normal group (P<0.05). In bilirubin group the two indice were lower than those in model group (P<0.05). Our findings suggested that high expression of iNOS and high NO content in AM accelerate the development of emphysema associated with smoking in rats. Bilirubin may exert protective effects on AM and retards the development of emphysema in rats.
 ...
PMID:Effects of bilirubin on alveolar macrophages in rats with emphysema and expression of iNOS and NO in them. 1558 89

Although long-acting bronchodilators have been an important advance for the management of chronic obstructive pulmonary disease (COPD), these drugs do not deal with the underlying inflammatory process. No currently available treatments reduce the progression of COPD or suppress the inflammation in small airways and lung parenchyma. Several new treatments that target the inflammatory process are now in clinical development. Some therapies, such as chemokine antagonists, are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD, whereas others target inflammatory cytokines such as tumour necrosis factor-alpha. Broad spectrum anti-inflammatory drugs are now in phase III development for COPD, and include phosphodiesterase-4 inhibitors. Other drugs that inhibit cell signalling include inhibitors of p38 mitogen-activated protein kinase, nuclear factor-kappaB and phosphoinositide-3 kinase-gamma. More specific approaches are to give antioxidants, inhibitors of inducible nitric oxide synthase and leukotriene B(4) antagonists. Other treatments have the potential to combat mucus hypersecretion, and there is also a search for serine proteinase and matrix metalloproteinase inhibitors to prevent lung destruction and the development of emphysema. More research is needed to understand the cellular and molecular mechanisms of chronic obstructive pulmonary disease and to develop biomarkers and monitoring techniques to aid the development of new therapies.
 ...
PMID:COPD: current therapeutic interventions and future approaches. 1592 66

No currently available treatments reduce the progression of COPD or suppress the inflammation in small airways and lung parenchyma. However, several new treatments that target the inflammatory process are in clinical development. A group of specific therapies are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD; these include adhesion molecule and chemokine-directed therapy, as well as therapies to combat tumour necrosis factor-alpha and augment interleukin-10. Broad spectrum anti-inflammatory drugs are now in phase III development for COPD, and include phosphodiesterase-4 inhibitors. Other drugs that inhibit cell signalling include inhibitors of p38 mitogen-activated protein kinase, nuclear factor-kappaB and phosphoinositide-3 kinase-gamma. More specific approaches are to give antioxidants, inhibitors of inducible nitric oxide synthase, and leukotriene B4 receptor antagonists. Epidermal growth factor receptor kinase inhibitors and calcium-activated chloride channel inhibitors have potential to combat mucus overproduction. Therapy to inhibit fibrosis is being developed against transforming growth factor-beta1 and protease activated receptor-2. There is also a search for serine proteinase and matrix metalloproteinase inhibitors to prevent lung destruction and the development of emphysema, as well as drugs such as retinoids that may even reverse this process. Effective delivery of drugs to the sites of disease in the peripheral lung is an important consideration, and there is the need for validated biomarkers and monitoring techniques in early clinical studies with new therapies for COPD.
 ...
PMID:Emerging targets for COPD therapy. 1730 23

Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a key transcription factor that plays a central role in cellular defense against oxidative and electrophilic insults by timely induction of antioxidative and phase-2 detoxifying enzymes and related stress-response proteins. The 5'-flanking regions of genes encoding these cytoprotective proteins contain a specific consensus sequence termed antioxidant response element (ARE) to which Nrf2 binds. Recent studies have demonstrated that Nrf2-ARE signaling is also involved in attenuating inflammation-associated pathogenesis, such as autoimmune diseases, rheumatoid arthritis, asthma, emphysema, gastritis, colitis and atherosclerosis. Thus, disruption or loss of Nrf2 signaling causes enhanced susceptibility not only to oxidative and electrophilic stresses but also to inflammatory tissue injuries. During the early-phase of inflammation-mediated tissue damage, activation of Nrf2-ARE might inhibit the production or expression of pro-inflammatory mediators including cytokines, chemokines, cell adhesion molecules, matrix metalloproteinases, cyclooxygenase-2 and inducible nitric oxide synthase. It is likely that the cytoprotective function of genes targeted by Nrf2 may cooperatively regulate the innate immune response and also repress the induction of pro-inflammatory genes. This review highlights the protective role of Nrf2 in inflammation-mediated disorders with special focus on the inflammatory signaling modulated by this redox-regulated transcription factor.
 ...
PMID:A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. 1979 17

The initiation and evolution of the receptor concept and its application in pharmacology can be traced back to Paul Ehrlich's original experiments. Since several decades the receptor concept is in the foreground of cell biology and pharmacology. We present here a short reminder of Ehrlich's concepts on receptor action, its evolution and modifications as a result of increasing life expectancy of human societies. Results obtained by several teams on the age-dependent modifications of receptor function are reviewed with special emphasis on the age-dependent loss of receptors and of uncoupling of receptors from their intracellular transmission pathway. As a special example we summarize our results on the elastin receptor and its age-dependent modifications. These modifications result in the loss of the physiologically helpful functions mediated by this receptor, such as vasodilation by coupling with the inducible nitric oxide synthase (iNOS)-inhibition of cellular cholesterol synthesis and modulation of free radical production by inhibition of the guanine nucleotide binding protein (Gi protein)-mediated transmission pathway. Only the harmful effects such as free radical release and up-regulation of elastase production remain in "old" cells. The age-dependent modifications of receptor function play an important role in the increasing frequency and severity of age-related diseases such as athero-arteriosclerosis and emphysema as well as the loss of hormone- and drug actions. These processes and their inhibition or correction represent a new challenge for cellular pharmacology.
 ...
PMID:Receptors and aging: dedicated to the memory of Paul Ehrlich for the 100th anniversary of his Nobel Prize. 2000 83


1 2 3 Next >>