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1.
Mucosal Immunol ; 11(1): 61-70, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28488693

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease causing irreversible lung scarring and loss of pulmonary function. IPF Patients suffer from a high rate of pulmonary infections and acute exacerbations of disease that further contribute to pulmonary decline. Low expression of the inducible T-cell costimulatory molecule (ICOS) in peripheral blood mononuclear cells predicts decreased survival of IPF patients, but the mechanisms by which ICOS protects are unclear. Using a model of bleomycin-induced lung injury and fibrosis, we now demonstrate that ICOS expression enhances survival from lung injury rather than regulating fibrogenesis. Of ICOS-expressing cells, type 2 innate lymphocytes (ILC2s) are the first to respond to bleomycin-induced injury, and this expansion is ICOS dependent. Interestingly, a similar decrease in ICOS+ ILCs was found in lung tissue from IPF patients. Interleukin (IL)-5, produced primarily by ILC2s, was significantly reduced after lung injury in ICOS-/- mice, and strikingly, treatment with IL-5 protected both ICOS-/- and wild-type mice from mortality. These results imply that low ICOS expression and decreased lung ILC2s in IPF patients may contribute to poor recovery from infections and acute exacerbation and that IL-5 treatment may be a novel therapeutic strategy to overcome these defects and protect against lung injury.


Assuntos
Lesão Pulmonar Aguda/imunologia , Fibrose Pulmonar Idiopática/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Interleucina-5/metabolismo , Linfócitos/imunologia , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Bleomicina , Células Cultivadas , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Th2/imunologia
2.
J Agric Food Chem ; 65(23): 4562-4571, 2017 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-28537731

RESUMO

The harmful effect of ionic liquids (ILs) on the environment is one of the important elements of scientific research conducted around the world. This study presents the effect of ionic liquids, containing the asymmetric cations benzyltrimethylammonium chloride [BenzTMA][Cl] and benzyltriethylammonium chloride [BenzTEA][Cl], on physiological and biochemical changes in common radish plants and spring barley seedlings. The examined ILs demonstrated low toxicity to higher plants. The compound that exhibited higher phytotoxicity to these plant species was [BenzTMA][Cl], whereas the plant that was more resistant to such ILs was common radish. Both the ionic liquids, particularly at higher concentrations, led to changes in the metabolism of plants, which resulted in a decrease of chlorophyll a, chlorophyll b, total chlorophyll, and carotenoids content. The observed changes were positively correlated with increasing concentrations of the examined ILs in the soil. In the case of spring barley, a decrease in the fresh weight and an increase in the dry weight of the seedlings were also observed. The evidence of oxidative stress occurrence in spring barley was observed due to the accumulation of malondialdehyde and free proline, as well as due to an increase in the activity of catalase and peroxidase. The changes in these biomarkers indicating oxidative stress occurrence in common radish plants were much lower. An increase in the content of chloride ions was observed in both the plants.


Assuntos
Hordeum/efeitos dos fármacos , Líquidos Iônicos/farmacologia , Raphanus/efeitos dos fármacos , Poluentes do Solo/farmacologia , Carotenoides/metabolismo , Cátions/metabolismo , Clorofila/análogos & derivados , Clorofila/metabolismo , Hordeum/crescimento & desenvolvimento , Hordeum/metabolismo , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Raphanus/crescimento & desenvolvimento , Raphanus/metabolismo
3.
Clin Pharmacol Ther ; 102(5): 859-869, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28398598

RESUMO

Changes in behavior are necessary to apply genomic discoveries to practice. We prospectively studied medication changes made by providers representing eight different medicine specialty clinics whose patients had submitted to preemptive pharmacogenomic genotyping. An institutional clinical decision support (CDS) system provided pharmacogenomic results using traffic light alerts: green = genomically favorable, yellow = genomic caution, red = high risk. The influence of pharmacogenomic alerts on prescribing behaviors was the primary endpoint. In all, 2,279 outpatient encounters were analyzed. Independent of other potential prescribing mediators, medications with high pharmacogenomic risk were changed significantly more often than prescription drugs lacking pharmacogenomic information (odds ratio (OR) = 26.2 (9.0-75.3), P < 0.0001). Medications with cautionary pharmacogenomic information were also changed more frequently (OR = 2.4 (1.7-3.5), P < 0.0001). No pharmacogenomically high-risk medications were prescribed during the entire study when physicians consulted the CDS tool. Pharmacogenomic information improved prescribing in patterns aimed at reducing patient risk, demonstrating that enhanced prescription decision-making is achievable through clinical integration of genomic medicine.


Assuntos
Sistemas de Apoio a Decisões Clínicas/normas , Prescrições de Medicamentos/normas , Sistemas de Registro de Ordens Médicas/normas , Farmacogenética/normas , Papel do Médico , Sistemas Automatizados de Assistência Junto ao Leito/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Rotulagem de Medicamentos/métodos , Rotulagem de Medicamentos/normas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética/métodos , Estudos Prospectivos , Adulto Jovem
4.
Eur Respir J ; 39(2): 344-51, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21737563

RESUMO

Hiatal hernia (HH) is associated with gastro-oesophageal reflux (GOR) and/or GOR disease and may contribute to idiopathic pulmonary fibrosis (IPF). We hypothesised that HH evaluated by computed tomography is more common in IPF than in asthma or chronic obstructive pulmonary disease (COPD), and correlates with abnormal GOR measured by pH probe testing. Rates of HH were compared in three cohorts, IPF (n=100), COPD (n=60) and asthma (n=24), and evaluated for inter-observer agreement. In IPF, symptoms and anti-reflux medications were correlated with diffusing capacity of the lung for carbon monoxide (D(L,CO)) and composite physiologic index (CPI). HH was correlated with pH probe testing in IPF patients (n=14). HH was higher in IPF (39%) than either COPD (13.3%, p=0.00009) or asthma (16.67%, p=0.0139). The HH inter-observer κ agreement was substantial in IPF (κ=0.78) and asthma (κ=0.86), and moderate in COPD (κ=0.42). In IPF, HH did not correlate with lung function, except in those on anti-reflux therapy, who had a better D(L,CO) (p<0.03) and CPI (p<0.04). HH correlated with GOR as measured by DeMeester scores (p<0.04). HH is more common in IPF than COPD or asthma. In an IPF cohort, HH correlated with higher DeMeester scores, confirming abnormal acid GOR. Presence of HH alone was not associated with decreased lung function.


Assuntos
Hérnia Hiatal/diagnóstico por imagem , Hérnia Hiatal/epidemiologia , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/epidemiologia , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Adulto , Idoso , Asma/diagnóstico por imagem , Asma/epidemiologia , Estudos de Coortes , Feminino , Refluxo Gastroesofágico/diagnóstico por imagem , Refluxo Gastroesofágico/epidemiologia , Refluxo Gastroesofágico/terapia , Humanos , Concentração de Íons de Hidrogênio , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/epidemiologia , Masculino , Manometria , Pessoa de Meia-Idade , Variações Dependentes do Observador , Prevalência , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Estudos Retrospectivos , Índice de Gravidade de Doença
5.
Int J Tuberc Lung Dis ; 6(8): 713-9, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12150484

RESUMO

SETTING: Parenchymal lung destruction accompanied by active tuberculosis is, at least in part, caused by host as well as bacillus metalloproteinases. Mycobacterium tuberculosis has been shown to stimulate MMP-9 expression in the lung of infected organisms. DESIGN: We have used quantitative zymography and computer-assisted image analysis to measure the levels of type IV collagenases in 20 serum samples of patients with active tuberculosis and in 23 serum samples of healthy volunteers. RESULTS: Mean levels of the serum MMP-9 were over three-fold higher in tuberculous samples compared with normal serum (P < 0.0001), whereas the MMP-2 levels did not differ in these two groups. The levels of MMP-9 were significantly higher in subjects with advanced disease than in those with only limited disease changes (P < 0.05). CONCLUSIONS: We suppose that the elevation of serum MMP-9 levels in patients with tuberculosis is affected by the augmentation of synthesis and/or secretion of this enzyme by inflammatory cells in response to M. tuberculosis infection. The observed association between the serum MMP-9 level and the extent of radiological change suggests that the quantification of the serum level of this enzyme may constitute a supplementary test in pulmonary tuberculosis diagnostics.


Assuntos
Metaloproteinase 9 da Matriz/sangue , Tuberculose Pulmonar/enzimologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Metaloproteinase 2 da Matriz/sangue , Pessoa de Meia-Idade , Índice de Gravidade de Doença
6.
J Cancer Res Clin Oncol ; 128(4): 197-204, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11935310

RESUMO

PURPOSE: Matrix metalloproteinases MMP-2 and MMP-9 are implicated in invasion and metastasis of malignant tumors. We investigated the expression and activation of MMP-2 and MMP-9 in lung cancer compared with normal lung parenchyma, and looked for a potential marker of malignancy. METHODS: Thirty-six pulmonary carcinomas and paired normal lung specimens were analyzed by gelatin zymography and computer-assisted image analysis for the expression of MMP-2 and MMP-9. RESULTS: We showed that expression of both type IV collagenases was remarkably higher in carcinoma samples than in lung parenchyma. The MMP-9 levels in lung cancer were over twofold higher than in normal lung tissues. The levels of latent and active forms of MMP-2 in lung cancer samples were, correspondingly, 3.8- and 17-fold higher than in lung parenchyma. The tumor/normal (T/N) ratios of MMP-2 were negatively correlated with the hemoglobin levels and erythrocytes number. CONCLUSIONS: A high level of the active form of MMP-2 in almost all of the carcinomas and the near lack of its activation in normal lung parenchyma shows that MMP-2 activation is associated with the malignant phenotype and may serve as a good marker of malignancy. The correlation between low hemoglobin level and T/N ratio of MMP-2 may indicate significance of MMP-2 for angiogenesis.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/biossíntese , Idoso , Feminino , Humanos , Imuno-Histoquímica , Masculino , Metaloproteinase 2 da Matriz/análise , Metaloproteinase 9 da Matriz/análise , Pessoa de Meia-Idade , Neovascularização Patológica , Fenótipo
7.
Ann Allergy Asthma Immunol ; 86(6 Suppl 1): 40-4, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11426916

RESUMO

OBJECTIVE: This article provides information on the consensus reached by the Antileukotriene Working Group on the role of leukotriene (LT) modifiers in the treatment of asthma. DATA SOURCES: Relevant and appropriate controlled clinical studies were used. Only literature in the English language was reviewed. STUDY SELECTION: Material was taken from academic/scholarly journals and appropriate reviews. RESULTS: Only limited use of LT-modifying agents has been recommended in recently published guidelines of the National Asthma Education and Prevention Program and the National Heart, Lung, and Blood Institute. Consequently, the Antileukotriene Working Group was convened to arrive at a consensus on the wider use of LT modifiers in the treatment of asthma. The group' s purpose was 2-fold: to review and disseminate information on the role of LT modifiers in clinical practice. As determined by the group, a thorough understanding of the patient's disease, patient education, and an effective patient-clinician relationship are key elements in overall patient management. CONCLUSIONS: Based on evidence from clinical trials and expert opinions of participants comprising the Antileukotriene Working Group, LT-modifying agents potentially may be used as first-line therapy, in combination regimens, and as an alternative to inhaled corticosteroids in the treatment of asthma.


Assuntos
Asma/tratamento farmacológico , Antagonistas de Leucotrienos/uso terapêutico , Humanos , Cooperação do Paciente
8.
Respir Med ; 95(1): 1-4, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11207010

RESUMO

The 72 kDa matrix metalloproteinase (MMP-2) and the 92 kDa matrix metalloproteinase (MMP-9), are type IV collagenases that have been implicated as important factors in cancer invasion and metastasis formation. We have used quantitative zymography and computer-assisted image analysis to measure the levels of MMP-9 and MMP-2 in 19 samples of serum of lung cancer patients and in 23 samples of normal serum. Mean levels of MMP-9 were significantly elevated in cancer samples compared with normal sera (1.33 +/- 0.61 microU microl(-1) vs. 0.37 +/- 0.10 microU microl(-1), P<0.0001). MMP-2 levels did not differ significantly in these two groups. However, there was no significant correlation between serum MMP-9 activity and the disease stage. We found that circulation levels of MMP-9 in lung cancer patients is 3.6-fold higher than in healthy volunteers, however, we do not consider this elevation to be a direct reflection of MMP-9 over-production by tumour cells.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma de Células Pequenas/enzimologia , Neoplasias Pulmonares/enzimologia , Metaloproteinase 9 da Matriz/sangue , Adulto , Idoso , Feminino , Humanos , Masculino , Metaloproteinase 2 da Matriz/sangue , Pessoa de Meia-Idade
9.
Am J Physiol ; 270(1 Pt 1): L133-40, 1996 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-8772536

RESUMO

Cationic proteins elicit contraction of airway smooth muscle, but the mechanisms by which this occurs are not completely understood. We studied potential mechanisms by which eosinophil major basic protein (MBP) and the synthetic cationic proteins poly-L-lysine (PL) and poly-L-arginine (PA) cause contraction of isolated guinea pig tracheal smooth muscle (TSM) in vivo. Topical application of 10(-8) mol/cm2 of each protein to an isolated tracheal segment elicited TSM contraction with potency PL > MBP > PA. Pretreatment with atropine blocked the subsequent response to MBP but did not block the response to either PL or PA. Pretreatment with indomethacin blocked the subsequent response to both MBP and PL but did not block the response to PA. We demonstrate that MBP causes contraction of guinea pig TSM both through stimulation of the parasympathetic nervous system and secretion of a cyclooxygenase mediator. Neither PL nor PA, while of similar molecular weight and charge as MBP, cause TSM contraction via the parasympathetic nervous system, though some cationic proteins may act via a prostanoid mediator. Thus the cationic charge of MBP is not solely responsible for its effects on TSM in the guinea pig.


Assuntos
Proteínas Sanguíneas/farmacologia , Contração Muscular , Músculo Liso/efeitos dos fármacos , Peptídeos/farmacologia , Polilisina/farmacologia , Ribonucleases , Traqueia/efeitos dos fármacos , Acetilcolina/farmacologia , Animais , Atropina/farmacologia , Proteínas Sanguíneas/antagonistas & inibidores , Cátions/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Proteínas Granulares de Eosinófilos , Cobaias , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/fisiologia , Traqueia/fisiologia
10.
Am J Physiol ; 265(3 Pt 1): L301-7, 1993 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-8214090

RESUMO

We studied the biochemical indexes and corresponding induction of airway smooth muscle contraction and hyperresponsiveness in guinea pig trachealis in situ caused by cultured eosinophils derived from mononuclear cell fractions of human umbilical cord blood. A method was developed that permitted isolation of large numbers of cells (approximately 2.6 x 10(6)/ml cord blood) having morphological and immunohistological characteristics of human peripheral blood eosinophils. After activation with 10(-6) M formyl-Met-Leu-Phe + 5 micrograms/ml cytochalasin B (fMLP + B), in situ application to the epithelial surface of 6 x 10(6) cord-derived eosinophils (CDE)/surface area (cm2) caused 1.46 +/- 0.24 g/cm maximal active tracheal tension in guinea pig tracheal smooth muscle (P < 0.005 vs. zero baseline). Muscarinic responsiveness also was augmented in situ in trachealis preparations treated with activated 3-wk CDE. Contraction caused by 3 x 10(-7) mol/kg iv methacholine (MCh) was 0.94 +/- 0.18 g/cm at baseline vs. 1.80 +/- 0.24 g/cm after activated CDE (P = 0.02). Control (sham-activated) 3-wk CDE caused neither significant contraction [0.41 +/- 0.16 g/cm active tension (AT); P < 0.05 vs. fMLP+B] nor augmented muscarinic responsiveness. Cells cultured for 5 wk contained fewer granules than 3-wk CDE and also caused less direct contraction of trachealis (0.73 +/- 0.14 g/cm AT) after activation (P < 0.01 vs. 3-wk CDE). Both contraction and muscarinic augmentation were blocked in 3-wk CDE after blockade of leukotriene C4 (LTC4) synthesis by pretreatment with the 5-lipoxygenase inhibitor, A63162 (50 microM). Treatment with A63162 had no effect on the stimulated release of eosinophil peroxidase.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Células Sanguíneas/fisiologia , Eosinófilos/fisiologia , Sangue Fetal , Traqueia/fisiologia , Animais , Células Cultivadas , Eosinófilos/enzimologia , Cobaias , Humanos , Leucotrieno C4/farmacologia , Inibidores de Lipoxigenase , Masculino , Cloreto de Metacolina/farmacologia , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Peroxidase/metabolismo , Traqueia/efeitos dos fármacos
11.
Am Rev Respir Dis ; 147(6 Pt 1): 1477-82, 1993 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8503558

RESUMO

We studied the modulatory effect of airway epithelium on guinea pig tracheal smooth muscle (TSM) contraction. Isometric force was measured in vivo before and after removal of the tracheal epithelium. In parallel studies, TSM contraction was also measured isometrically in epithelium-intact and epithelium-denuded TSM strips in vitro. Epithelial removal in vivo did not alter the contractile response of TSM to acetylcholine (ACh) or serotonin. In nine guinea pigs, active tension (AT) caused by 3 x 10(-7) mol/kg of intravenous ACh was 0.74 +/- 0.14 g force per longitudinal length of the segment (g/cm) in the presence of epithelium versus 0.89 +/- 0.16 g/cm after removal of airway epithelium (confirmed histologically) (p NS). The threshold response to ACh was also unchanged (-8.0 +/- 0.3 log mol/kg control versus -8.3 +/- 0.3 log mol/kg after epithelial removal, p NS). In six guinea pigs, the AT caused by 3 x 10(-8) mol/kg of intravenous serotonin was 1.92 +/- 0.63 g/cm with an intact epithelium versus 2.15 +/- 0.70 g/cm after epithelial removal in vivo (p NS). Epithelial removal in vitro increased the sensitivity of TSM contraction to ACh when the data were expressed as the percentage maximal response to ACh. The concentration of ACh causing 50% of the maximal response (EC50) was -5.74 +/- 0.25 log M in eight epithelium-intact TSM strips versus -6.37 +/- 0.16 log M after epithelial removal in controls (n = 8) (p = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Acetilcolina/farmacologia , Músculo Liso/efeitos dos fármacos , Serotonina/farmacologia , Animais , Relação Dose-Resposta a Droga , Estimulação Elétrica , Epitélio/efeitos dos fármacos , Epitélio/fisiologia , Cobaias , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Tono Muscular/efeitos dos fármacos , Músculo Liso/fisiologia , Traqueia/efeitos dos fármacos , Traqueia/fisiologia
12.
Am J Physiol ; 264(5 Pt 1): L475-81, 1993 May.
Artigo em Inglês | MEDLINE | ID: mdl-8498524

RESUMO

We studied the relationship between mode of activation of isolated human eosinophils and in situ responsiveness in isolated tracheal smooth muscle (TSM) of guinea pigs. Human peripheral blood eosinophils were activated with either 10(-7) M phorbol myristate acetate (PMA) or 10(-6) M formyl-methionyl-leucyl-phenylalanine (fMLP) + 5 micrograms/ml cytochalasin B (CYB), and activation was confirmed by measurement of eosinophil peroxidase (EPO) secretion by kinetic assay. EPO secretion was similar after activation with fMLP+CYB (10.2 +/- 3.2% of total eosinophil content) and PMA (10.0 +/- 2.8% of total content; P = NS). Topical application of 6 x 10(6) eosinophils/cm2 activated with fMLP+CYB to the TSM segment caused 0.51 +/- 0.14 g/cm active tension (AT) in five preparations (P < 0.03 vs. baseline); cells activated with PMA caused no contractile response (0.04 +/- 0.03 g/cm AT, P = NS vs. baseline). Both PMA- and fMLP+CYB-activated cells caused augmentation of muscarinic responsiveness of guinea pig trachealis. The dose of intravenous acetylcholine required to cause a threshold response (ED0.3) was -7.3 +/- 0.1 log mol/kg at baseline vs. -8.7 +/- 0.5 log mol/kg after treatment with fMLP+CYB-activated eosinophils (P = 0.05) and -6.9 +/- 0.1 log mol/kg at baseline vs. -7.5 +/- 0.1 log mol/kg after PMA-activated cells (P < 0.01). Both AT and augmented muscarinic responsiveness were blocked by pretreating the eosinophils with 200 microM A-63162, an inhibitor of 5-lipoxygenase, before activation with fMLP+CYB. We demonstrate that eosinophils activated comparably (as assessed by EPO secretion) cause augmented muscarinic responsiveness and/or direct contraction of guinea pig TSM through secretion of a product of the 5-lipoxygenase pathway.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Eosinófilos/fisiologia , Contração Muscular , Músculo Liso/fisiologia , Traqueia/fisiologia , Acetamidas/farmacologia , Acetilcolina/farmacologia , Animais , Citocalasina B/farmacologia , Eosinófilos/efeitos dos fármacos , Eritropoetina/sangue , Eritropoetina/metabolismo , Cobaias , Humanos , Técnicas In Vitro , Cinética , Inibidores de Lipoxigenase/farmacologia , Masculino , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Éteres Fenílicos , Acetato de Tetradecanoilforbol/farmacologia
13.
J Clin Invest ; 91(5): 2118-25, 1993 May.
Artigo em Inglês | MEDLINE | ID: mdl-8387540

RESUMO

The unique granular proteins of eosinophils may have a pathogenetic role in asthma and in the defense against parasitic infestations. However, the mechanisms regulating eosinophil degranulation are largely unknown. We examined the hypothesis that release of these proteins is regulated by endogenous activation of phospholipase A2. Human eosinophils (HE) were isolated from the peripheral blood of 42 subjects either by Percoll density separation or by negative-selection immunomagnetic fractionation. Eosinophil activation was initiated in vitro with 10(-6) M FMLP and 5 micrograms/ml cytochalasin B and was assessed by measurement of eosinophil peroxidase (EPO), leukotriene C4 (LTC4) and superoxide radical (.O2-) secretion. Treatment of HE with 100 microM mepacrine before activation blocked EPO release (2.0 +/- 0.2 vs 10.2 +/- 2.1% cell content for activated HE, P < 0.004, n = 9), .O2- generation (2.6 +/- 0.9 vs 44.2 +/- 10.8 nmol/ml per 10(6) HE, P < 0.002, n = 5), and LTC4 secretion (68.2 +/- 32.2 vs 1,125.2 +/- 526.8 pg/ml per 10(6) HE, P < 0.04, n = 8). Pretreatment of HE with 100 microM 4-bromophenacyl bromide before activation similarly blocked EPO release, .O2- generation and LTC4 secretion. Addition of AA to HE after treatment with 100 microM mepacrine and before subsequent activation reversed the inhibition of both EPO (10.4 +/- 2.2% with 1 microM AA vs 2.0 +/- 0.2% for mepacrine, n = 5, P < 0.02) and LTC4 secretion (695.1 +/- 412.9 with 10 microM AA vs 68.2 +/- 32.2 pg/ml per 10(6) HE for mepacrine, n = 8, P < 0.04), but did not reverse inhibition of .O2- generation by mepacrine. We demonstrate that secretion of preformed cytotoxic proteins and .O2- by eosinophils is regulated endogenously by phospholipase A2.


Assuntos
Eosinófilos/fisiologia , Fosfolipases A/sangue , Acetofenonas/farmacologia , Ácido Araquidônico/farmacologia , Separação Celular/métodos , Centrifugação com Gradiente de Concentração/métodos , Citocalasina B/farmacologia , Relação Dose-Resposta a Droga , Peroxidase de Eosinófilo , Eosinófilos/efeitos dos fármacos , Eosinófilos/enzimologia , Homeostase , Técnicas In Vitro , Cinética , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Peroxidases/sangue , Fosfolipases A2 , Quinacrina/farmacologia , SRS-A/sangue , Superóxidos/sangue
14.
Am Rev Respir Dis ; 145(6): 1463-8, 1992 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-1596019

RESUMO

We examined the effect of phospholipase A2 (PLA2; Naja naja) on isometric tracheal smooth muscle force generation in guinea pig trachealis in situ. Direct application of PLA2 to the surface of the trachea caused dose-related contraction of tracheal smooth muscle. In seven guinea pigs, a dose/density of 100 micrograms/cm2 PLA2 caused active tension (AT) that began immediately and was maximum (1.32 +/- 0.13 g/cm) at 5 min (p less than 0.01 versus baseline tension). PLA2 also augmented the contractile response to intravenously administered acetylcholine (ACh); AT caused by 3 x 10(-7) mol/kg ACh was 0.98 +/- 0.13 g/cm after PLA2 versus 0.64 +/- 0.09 g/cm in control animals (p = 0.003). PLA2 inactivated with bromophenacyl bromide (BPB) prior to topical application neither caused contraction (-0.18 +/- 0.18 g/cm AT, p = NS versus baseline tension) nor altered muscarinic responsiveness to 3 x 10(-7) mol/kg ACh. Contraction caused by 100 micrograms/cm2 PLA2 was greater after epithelium removal (2.73 +/- 0.40 g/cm AT versus 1.32 +/- 0.13 g/cm AT in epithelium-intact animals, p less than 0.005). However, epithelium removal (confirmed histologically) attenuated completely augmentation of muscarinic contraction caused by PLA2. Augmentation of muscarinic contraction also was blocked with 15 mg/kg 3-amino-1-(3-trifluoromethylphenyl)-2-pyrazoline hydrochloride (BW 755c), an inhibitor of eicosanoid synthesis, administered intravenously 30 min prior to topical application of 100 micrograms/cm2 PLA2. In contrast, contraction of tracheal smooth muscle caused by PLA2 was not affected significantly by blockade of eicosanoid synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Fosfolipases A/farmacologia , 4,5-Di-Hidro-1-(3-(Trifluormetil)Fenil)-1H-Pirazol-3-Amina/farmacologia , Acetofenonas/farmacologia , Acetilcolina/farmacologia , Animais , Hiper-Reatividade Brônquica/fisiopatologia , Relação Dose-Resposta a Droga , Eicosanoides/metabolismo , Cobaias , Masculino , Músculo Liso/fisiologia , Fosfolipases A/antagonistas & inibidores , Fosfolipases A2 , Receptores Muscarínicos/fisiologia , Traqueia/efeitos dos fármacos , Traqueia/fisiologia
15.
Am J Physiol ; 260(4 Pt 1): L260-7, 1991 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-2018147

RESUMO

We examined the mechanism of constriction and muscarinic augmentation of contraction of airway smooth muscle caused by platelet-activating factor (PAF) in airways from 55 Sprague-Dawley rats perfused through the isolated bronchial circulation (BC) and pulmonary circulation (PC) and isometrically in tissue perfusion chambers. Dose-response curves were generated cumulatively by infusing 10(-10) to 10(-7) mol PAF dissolved in Krebs-Henseleit solution buffer containing 4% bovine serum albumin into the BC or PC. The efficacy of PAF in central airways (BC) was approximately twofold greater in increasing lung resistance (RL) than for more peripheral airways perfused by the PC (P less than 0.05). Tachyphylaxis was demonstrated in both BC and PC for preparations in which a second PAF dose-response curve was generated. Bolus injection of 10(-6) mol of the PAF antagonist, CV-6209, plus 10(-7) mol PAF caused 81% reversal of the maximal BC response. The same dose of CV-6209 reversed the response to PAF in the PC by 99.2%. Initial administration of 10(-6) mol CV-6209 with PAF prevented completely contraction elicited by PAF in the BC and PC. Concentration-response studies also were generated isometrically in tissue perfusion chambers from 64 tracheal smooth muscle strips. Maximal contraction elicited by 10(-6) M PAF was blocked completely with 10(-6) M CV-6209. In separate studies, addition of 10(-6) mol CV-6209 to the BC perfusate caused 93% blockade of the RL response to PAF and 100% inhibition when administered in the PC. Prior administration of PAF caused two- to fourfold augmentation of the contractile response to acetylcholine (ACh) within the same preparation; in the presence of CV-6209, the response to ACh was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Pulmão/fisiologia , Fator de Ativação de Plaquetas/farmacologia , Circulação Pulmonar/efeitos dos fármacos , Acetilcolina/farmacologia , Animais , Sangue , Brônquios/irrigação sanguínea , Brônquios/efeitos dos fármacos , Brônquios/fisiologia , Relação Dose-Resposta a Droga , Técnicas In Vitro , Pulmão/efeitos dos fármacos , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Perfusão , Fator de Ativação de Plaquetas/antagonistas & inibidores , Compostos de Piridínio/farmacologia , Ratos , Ratos Endogâmicos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Taquifilaxia
16.
J Appl Physiol (1985) ; 66(6): 2788-98, 1989 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-2745342

RESUMO

We assessed the longitudinal distribution of intra-airway heat and water exchanges and their effects on airway wall temperature by directly measuring respiratory fluctuations in airstream temperature and humidity, as well as airway wall temperature, at multiple sites along the airways of endotracheally intubated dogs. By comparing these axial thermal and water profiles, we have demonstrated that increasing minute ventilation of cold or warm dry air leads to 1) further penetration of unconditioned air into the lung, 2) a shift of the principal site of total respiratory heat loss from the trachea to the bronchi, and 3) alteration of the relative contributions of conductive and evaporative heat losses to local total (conductive plus evaporative) heat loss. These changes were not accurately reflected in global measurements of respiratory heat and water exchange made at the free end of the endotracheal tube. Raising the temperature of inspired dry air from frigid to near body temperature principally altered the mechanism of airway cooling but did not influence airway mucosal temperature substantially. When local heat loss was increased from both trachea and bronchi (by increasing minute ventilation), only the tracheal mucosal temperature fell appreciably (up to 4.0 degrees C), even though the rise in heat loss from the bronchi about doubled that in the trachea. Thus it appears that the bronchi are better able to resist changes in airway wall temperature than is the trachea. These data indicate that the sites, magnitudes, and mechanisms of respiratory heat loss vary appreciably with breathing pattern and inspired gas temperature and that these changes cannot be predicted from measurements made at the mouth. In addition, they demonstrate that local heat (and presumably, water) sources that replenish mucosal heat and water lost to the airstream are important in determining the degree of local airway cooling (and presumably, drying).


Assuntos
Regulação da Temperatura Corporal , Água Corporal/metabolismo , Fenômenos Fisiológicos Respiratórios , Animais , Cães , Masculino , Sistema Respiratório/metabolismo
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