Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:6.2.1.7 (BAL)
1,977 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The following studies were conducted to characterize the bron-chodilatory and antiinflammatory activity of the novel, selective phosphodiesterase-IV inhibitor, CP-80,633 (2'S)5-[3-(2'-exobicyclo[2.2.1]heptyloxy-4-methoxy-phenyl]te trahydro- 2(1H)-pyrimidone, a compound in clinical development for atopic disease. In IgG1 passively sensitized guinea pigs, aerosolized ovalbumin challenge increases both pulmonary eosinophil peroxidase levels and airway obstruction. CP-80,633, administered before ovalbumin challenge, significantly attenuated both the increase in tissue eosinophil peroxidase levels (ED50 = 1.4 mg/kg, p.o.) and airway obstruction (ED50 = 0.93 +/- 0.14 mg/kg,p.o.) 10 to 30 times more potently than theophyl-line. Intraarterially administered CP-80,633 also reversed an established bronchoconstriction initiated by continuous infusion of histamine to guinea pigs (ED50 of 8.2 micrograms/kg vs. 5.6 mg/kg for theophylline). The antiinflammatory effect of CP-80,633 was also examined in atopic monkeys challenged with Ascaris suum (Ag) aerosol. CP-80,633 (1 mg/kg, qid, s.c., 1 hr before antigen challenge) significantly reduced antigen-induced increases in bronchoalveolar lavage neutrophils (72.8 +/- 15.8% inhibition) and eosinophils (61.1 +/- 5.7% inhibition) 4 hr postchallenge, but did not reduce leukocytes 24 hr postchallenge. CP-80,633 did not inhibit antigen-induced increases in BAL levels of interleukin-1 beta, -6 or -8 as measured by enzyme-linked immunosorbant assay. These results indicate that CP-80,633 possesses bronchodilatory activity in guinea pigs and some antiinflammatory effects in both guinea pigs and monkeys.
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PMID:The in vivo pharmacology of CP-80, 633, a selective inhibitor of phosphodiesterase 4. 881 22

Although neutrophil number may be increased in the airways of patients with asthma, its pathogenetic role in this disorder remains unclear. We evaluated BAL of 8 normal control subjects, 30 +/- 2 years of age, and 24 patients with mild asthma: 17 patients with allergic asthma, 24 +/- 1 years of age, and 7 patients with nonallergic asthma, 30 +/- 1 years of age. The BAL of asthmatic patients showed increased numbers of neutrophils (p < 0.01), eosinophils (p < 0.01), and ciliated epithelial cells (p < 0.05) and increased concentrations of myeloperoxidase (MPO) (p < 0.01) compared with control subjects. Positive correlations were observed between the number of BAL neutrophils and eosinophils (Rs = 0.780, p < 0.0001) and between BAL neutrophil numbers and BAL MPO levels (Rs = 0.40, p < 0.05). No correlations were found between the following: (1) BAL eosinophils or neutrophils and BAL epithelial cells (p > 0.05, each comparison); (2) BAL neutrophils or eosinophils and log Pd15 methacholine (MCh) (p > 0.05, each comparison); or (3) BAL epithelial cells or log Pd15 MCh and BAL MPO (p > 0.05, each comparison). Dividing the patient population into two groups, allergic asthmatics and nonallergic asthmatics, similar BAL neutrophil, eosinophil, and epithelial cell numbers and similar MPO levels were found (p > 0.05, each comparison). In addition, the correlations between BAL neutrophils and eosinophils showed similar significance in the two patient subgroups (p > 0.05, each comparison). These results suggest that, both in allergic and nonallergic asthma, airway recruitment and activation of neutrophils occur as does parallel eosinophil migration. However, airway neutrophils do not seem to contribute significantly to epithelial cell injury or to airway hyperresponsiveness in the steady state.
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PMID:BAL neutrophilia in asthmatic patients. A by-product of eosinophil recruitment? 891 8

In the guinea pig, interleukin-5 (IL-5) has been shown to induce airway hyperresponsiveness as well as eosinophilia, which are important symptoms in asthma. IL-5 seems to be a critical cytokine since it selectively affects eosinophil functions. The mechanism of action by which IL-5 leads to airway hyperresponsiveness may be important for our understanding of the pathogenesis of asthma. Neurogenic inflammation, which is mediated by nonadrenergic noncholinergic nerves (NANC), may play a role in the IL-5-induced effects in guinea pig airways. In this study, the role of neuropeptides in the IL-5-induced airway hyperresponsiveness and eosinophilia in the guinea pig was examined using selective neurokinin receptor antagonists. Intra-airway application of IL-5 (1 microgram, twice) induces a selective eosinophil migration (control: 12 [8-22] x 10(5) cells and IL-5: 90 [67-187] x 10(5) cells, p < 0.05) and activation (control: 6.3 +/- 0.9 ng eosinophil peroxidase [EPO]/ml bronchoalveolar lavage [BAL] fluid and IL-5: 29.3 +/- 4.9 ng EPO/ml BAL fluid, p < 0.05) and a pronounced airway hyperresponsiveness in vivo. The maximal responses to histamine are increased by 160 +/- 16% (p < 0.05) after IL-5. Treatment of guinea pigs with either the nonselective neurokinin (NK)-receptor antagonist, FK224, or the selective NK2-receptor antagonist, SR48968, results in a complete inhibition of the in vivo hyperresponsiveness found after application of IL-5. Vice versa, intra-airway administration of substance P (10 micrograms, twice) results in an airway hyperresponsiveness (increased maximal response after substance P: 166 +/- 15% [p < 0.05]) without inducing migration or activation of eosinophils. All examined NK-receptor antagonists do not influence the IL-5-induced eosinophil accumulation. In addition, no effect of the NK-receptor antagonists is observed on the IL-5-induced eosinophil activation, as determined by BAL fluid EPO levels. The release of NK2-receptor active tachykinins plays an important role in the development of IL-5-induced airway hyperresponsiveness. This feature appears to be a step following eosinophil infiltration and activation since there are no effects on eosinophil function by pretreatment of the used NK-receptor antagonists.
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PMID:Role for neurokinin-2 receptor in interleukin-5-induced airway hyperresponsiveness but not eosinophilia in guinea pigs. 927 11

Levels of cell products released by neutrophils, eosinophils and lymphocytes were measured in the bronchoalveolar lavage fluid (BALF) of 19 patients with pulmonary active Wegener's granulomatosis (WG) to assess in vivo the magnitude of cellular activation at sites of active disease. Measurements included the BAL cell profile and BALF levels of myeloperoxidase (MPO), free proteinase 3 (fPR3), complexes of PR3 and alpha1-antitrypsin (PR3/alpha1-AT), eosinophil cationic protein (ECP), peroxidase activity (PEROX), and soluble interleukin-2 receptor (sIL-2R). Six patients also underwent a repeat examination after immunosuppressive treatment. Pulmonary active WG was found to be associated with elevated MPO, PEROX, ECP, and sIL-2R levels in BALF. Only trace amounts of fPR3 were detected, the bulk of PR3 being found in PR3/alpha1-AT complexes. Clinically effective treatment depressed BAL neutrophil counts and reversed elevated levels of MPO and PEROX but had an inconsistent effect on the BAL lymphocyte count and the sIL-2R level. In conclusion, the elevated levels of extracellular MPO and PEROX at a site of active disease and the correlation between these and clinical disease activity support the view that neutrophils are indeed an important effector cell population in WG lung disease. The present data also suggest that oxidative injury is an important aspect of neutrophil-mediated lung injury, whereas it remains unresolved whether the low levels of fPR3 in the BALF adequately reflect the situation at inflammatory tissue sites.
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PMID:Activation of neutrophils, eosinophils, and lymphocytes in the lower respiratory tract in Wegener's granulomatosis. 1067 77

Alterations in the hydrophobic status of particle surfaces have been suggested to modify the toxic properties of ultrafine TiO2. We investigated the acute inflammatory responses and cell damage after intratracheal instillation of surface modified (hydrophilic and hydrophobic) fine (180 nm) and ultrafine (20-30 nm) TiO2 particles 16 h at equivalent mass (1 or 6 mg) and surface doses (100, 500, 600 and 3000 cm2) in rats. Inflammatory response and most enzyme levels were significantly related to the administered surface dose. The hydrophobic surface of the TiO2 particles, achieved by methylation, induced a lower total cell number and influx of neutrophils (PMN) compared to rats instilled with the 1 mg of the untreated, fine or ultrafine TiO2 but the outcomes were not statistically significant. No differences were observed between fine/ultrafine and hydophilic/hydrophobic TiO2 at the high dose (6 mg) or surface dose over 600 cm2. The differences in BAL cellularity at the low dose were reflected in changes in the chemokine MIP-2, but no differences were seen in levels of macrophage cytokines. Considering the large influx of PMN little cell damage was seen when studying enzyme leakage in lavage fluid, although PMNs appeared to be activated as suggested by increased myeloperoxidase (MPO) activity in the lavage fluid. We conclude that the surface area rather than the hydrophobic surface determines the acute, pulmonary inflammation induced by both fine and ultrafine TiO2.
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PMID:The surface area rather than the surface coating determines the acute inflammatory response after instillation of fine and ultrafine TiO2 in the rat. 1204 Sep 22

The lipid mediator PAF plays an important role in the phagocytosis of particles, including bacteria, and consequent production of pro-inflammatory cytokines, such as TNF-alpha and IL-8. Using a PAF receptor antagonist (UK-74,505) and PAF receptor knock-out mice, we have investigated the relevance of PAF for the inflammatory changes and lethality after pulmonary infection with the gram-negative bacteria Klebsiella pneumoniae in mice. At an inoculum of 3 x 10(6) bacteria, there was marked pulmonary (bronchoalveolar lavage and lung) neutrophilia that started early (2.5 h after infection) and peaked at 48 h. All animals were dead by day 4 of infection. The chemokine KC and the pro-inflammatory cytokine TNF-alpha increased rapidly and persisted for 48 h in the lungs. Pretreatment with UK-74,505 (30 mg kg(-1) per day, p.o.) had no significant effects on the number of infiltrating neutrophils in BAL fluid or lung tissue, as assessed by histology and measuring myeloperoxidase, or on the concentrations of KC. In contrast, concentrations of TNF-alpha and the number of bacteria inside neutrophils were significantly diminished. In order to support a role for the PAF during K. pneumoniae infection, experiments were also carried out in PAFR-deficient mice. In the latter animals, lethality occurred earlier than in wild-type controls. This was associated with greater number of bacteria in lung tissue and diminished percentage of neutrophils containing bacteria in their cytoplasm. Our results suggest that PAF, acting on its receptor, plays a protective role during infection with K. pneumoniae in mice.
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PMID:Role of the platelet-activating factor (PAF) receptor during pulmonary infection with gram negative bacteria. 1238 75

(1) We have studied whether curcumin prevents amiodarone-induced lung fibrosis in rats. Intratracheal instillation of amiodarone (6.25 mg kg(-1) on days 0 and 2, and then killed on day 3, day 5, week 1, week 3 and week 5 after amiodarone administration) induced increases in total protein and lactate dehydrogenase (LDH) activity on days 3 and 5 in bronchoalveolar lavage fluid (BALF). Total cell counts, alveolar macrophages, neutrophils and eosinophils recovered by BAL, and lung myeloperoxidase (MPO) activity were significantly higher in amiodarone rats. (2) Tumor necrosis factor-alpha (TNF-alpha) release after lipopolysaccharide (LPS) stimulation and superoxide anion generation after phorbol myristate acetate (PMA) stimulation were higher in the alveolar macrophages of amiodarone rats at 3 and 5 weeks postamiodarone instillation than in controls. Amiodarone also induced increases in transforming growth factor-beta1 (TGF-beta1) expression, collagen deposition, type I collagen expression and c-Jun protein in lungs. (3) Curcumin (200 mg kg(-1) body weight after first amiodarone instillation and daily thereafter for 5 weeks)-treated amiodarone rats had reduced levels of protein, LDH activity, total cell numbers and differential cell counts in BALF. LPS-stimulated TNF-alpha release and PMA-stimulated superoxide generation were significantly suppressed by curcumin. Furthermore, curcumin inhibited the increases in lung MPO activity, TGF-beta1 expression, lung hydroxyproline content, expression of type I collagen and c-Jun protein in amiodarone rats. Our results have important implications for the treatment of amiodarone-induced lung fibrosis.
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PMID:Protective effects of curcumin against amiodarone-induced pulmonary fibrosis in rats. 1289 Jul 14

In addition to being an air pollutant, NO2 is a potent inflammatory oxidant generated endogenously by myeloperoxidase and eosinophil peroxidase. In these studies, we sought to determine the effects of NO2 exposure on mice with ongoing allergic airway disease pathology. Mice were sensitized and challenged with the antigen ovalbumin (OVA) to generate airway inflammation and subsequently exposed to 5 or 25 ppm NO2 for 3 days or 5 days followed by a 20-day recovery period. Whereas 5 ppm NO2 elicited no pathological changes, inhalation of 25 ppm NO2 alone induced acute lung injury, which peaked after 3 days and was characterized by increases in protein, LDH, and neutrophils recovered by BAL, as well as lesions within terminal bronchioles. Importantly, 25 ppm NO2 was also sufficient to cause AHR in mice, a cardinal feature of asthma. The inflammatory changes were ameliorated after 5 days of inhalation and completely resolved after 20 days of recovery after the 5-day inhalation. In contrast, in mice immunized and challenged with OVA, inhalation of 25 ppm NO2 caused a marked augmentation of eosinophilic inflammation and terminal bronchiolar lesions, which extended significantly into the alveoli. Moreover, 20 days postcessation of the 5-day 25 ppm NO2 inhalation regimen, eosinophilic and neutrophilic inflammation, pulmonary lesions, and AHR were still present in mice immunized and challenged with OVA. Collectively, these observations suggest an important role for NO2 in airway pathologies associated with asthma, both in modulation of degree and duration of inflammatory response, as well as in induction of AHR.
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PMID:Nitrogen dioxide enhances allergic airway inflammation and hyperresponsiveness in the mouse. 1608 73

Glutamate (Glu) N-methyl-D-aspartate (NMDA) receptor is present in the lungs, and NMDA receptor antagonist MK-801 attenuates oxidant lung injury. We hypothesized that Glu excitotoxicity may participate in the pathogenesis of hyperoxia-induced lung injury. To determine possible pulmonary protective effects, we administered 0.05 ml/kg MK-801 or saline intraperitoneally daily to neonatal rats exposed to more than 95% oxygen in air. After 7 days, MK-801 decreased the hyperoxia-associated elevation of wet-to-dry lung weight, total leukocyte and neutrophil counts, total protein and lactate dehydroase in BAL fluid, total myeloperoxidase activity, and lung pathological injury. MK-801 inhibited hyperoxia-associated increments in reactive oxygen species production and NF-kappaB production. Hence, NMDA receptor antagonist MK-801 ameliorates hyperoxia-induced lung injury in neonatal rats, and is associated with decreased reactive oxygen species and NF-kappaB. We conclude that Glu may play an important role in hyperoxia-induced lung injury by activation of NMDA receptor.
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PMID:Role of N-methyl-D-aspartate receptor in hyperoxia-induced lung injury. 1616 26

To investigate the protective effect of genistein on endotoxin-induced acute lung injury in rats, and explore the underlying mechanisms, 32 male Sprague-Dawley rats were randomly divided into 4 experimental groups: saline control, genistein alone, lipopolysaccaride alone, and genistein pretreatment. Each treatment group consisted of eight animals. Animals were observed for 6 h after LPS challenge, and the wet/dry (W/D) weight ratio of the lung and bronchoalveolar lavage fluid (BALF) protein content were used as a measure of lung injury. Neutrophil recruitment and activation were evaluated by BALF cellularity and myeloperoxidase (MPO) activity. RT-PCR analysis was performed in lung tissue to assess gene expression of ICAM-1. The histopathological changes were also observed using the HE staining of lung tissue. Our results showed that lung injury parameters, including the wet/dry weight ratio and protein content in BALF, were significantly higher in the LPS alone group than in the saline control group (P < 0.01). In the LPS alone group, a larger number of neutrophils and greater MPO activity in cell-free BAL and lung homogenates were observed when compared with the saline control group (P < 0.01). There was a significant increase in lung ICAM-1 mRNA in response to LPS challenge (P < 0.01, group 1 versus group S). Genistein pretreatment significantly attenuated LPS-induced changes in these indices. LPS caused extensive lung damage, which was also lessened after genistein pretreatment. All above-mentioned parameters in the genistein alone group were not significantly different from those of the saline control group. It is concluded that genistein pretreatment attenuated LPS-induced lung injury in rats. This beneficial effect of genistein may involves, in part, an inhibition of neutrophilic recruitment and activity, possibly through an inhibition of lung ICAM-1 expression.
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PMID:Protective effect of genistein on lipopolysaccharide-induced acute lung injury in rats. 1619 2


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