RESUMO
Challenge of the airways of sensitized guinea pigs with aerosolized ovalbumin resulted in an early phase of microvascular protein leakage and a delayed phase of eosinophil accumulation in the airway lumen, as measured using bronchoalveolar lavage (BAL). Immunoreactive eotaxin levels rose in airway tissue and BAL fluid to a peak at 6 h falling to low levels by 12 h. Eosinophil numbers in the tissue correlated with eotaxin levels until 6 h but eosinophils persisted until the last measurement time point at 24 h. In contrast, few eosinophils appeared in BAL over the first 12 h, major trafficking through the airway epithelium occurring at 12-24 h when eotaxin levels were low. Constitutive eotaxin was present in BAL fluid. Both constitutive and allergen-induced eosinophil chemoattractant activity in BAL fluid was neutralized by an antibody to eotaxin. Allergen-induced eotaxin appeared to be mainly in airway epithelium and macrophages, as detected by immunostaining. Allergen challenge of the lung resulted in a rapid release of bone marrow eosinophils into the blood. An antibody to IL-5 suppressed bone marrow eosinophil release and lung eosinophilia, without affecting lung eotaxin levels. Thus, IL-5 and eotaxin appear to cooperate in mediating a rapid transfer of eosinophils from the bone marrow to the lung in response to allergen challenge.
Assuntos
Asma/fisiopatologia , Quimiocinas CC , Fatores Quimiotáticos de Eosinófilos/biossíntese , Citocinas/biossíntese , Eosinófilos/fisiologia , Animais , Células da Medula Óssea , Líquido da Lavagem Broncoalveolar/química , Quimiocina CCL11 , Citocinas/análise , Dexametasona/farmacologia , Feminino , Cobaias , Interleucina-5/fisiologia , Pulmão/patologia , Masculino , Albumina Sérica/análiseRESUMO
Rat spleen lymphocytes were incubated for 3 h with [14C]arachidonic acid in foetal calf serum. It was found that arachidonic acid distributed into phospholipids in the order phosphatidylcholine greater than phosphatidylethanolamine greater than phosphatidylinositol. After labelling with arachidonic acid the lymphocytes were washed, and incubated for up to 2 h with non-radioactive palmitic, oleic or linoleic acid dissolved in ethanol. The presence of ethanol or palmitic acid during a 2 h post-incubation had little effect on the amount of radioactivity found in different lipid fractions. Both oleic acid and linoleic acid, however, brought about an accumulation (up to 8-fold) of radioactivity in the diacylglycerol fraction. These fatty acids also brought about a change of radioactivity in several phospholipids, notably in phosphatidylinositol, which lost more than 50% of its counts during the 2 h incubation. Although maximum effects were seen at 2 h, diacylglycerol radioactivity was increased by 100% within 5 min after adding the fatty acids. The minimum concentration of fatty acids used (50 microM) gave an almost maximum response. The results indicate that unsaturated fatty acids may activate phosphatidylinositol phosphodiesterase in lymphocytes, as they do in brain. The possibility that a phospholipase A is activated is discussed. Possible implications for any experiments in which cells are incubated with fatty acids are pointed out.
Assuntos
Diglicerídeos/biossíntese , Glicerídeos/biossíntese , Ácidos Linoleicos/farmacologia , Linfócitos/metabolismo , Ácidos Oleicos/farmacologia , Fosfatidilinositóis/metabolismo , Animais , Ácido Araquidônico , Ácidos Araquidônicos/metabolismo , Fenômenos Químicos , Química , Lisofosfatidilcolinas/metabolismo , Ratos , Baço/metabolismoRESUMO
Rats were fed diets devoid of (n-3) fatty acids (olive oil supplementation) or high in (n-3) fatty acids (fish oil supplementation) for a period of 10 days. In spleen lymphocytes and liver microsomes derived from animals fed fish oil diets, relatively high levels of (n-3) eicosapentaenoic (20:5), docosapentaenoic (22:5) and docosahexaenoic acids (22:6) were obtained compared to minimal levels when fed the olive oil diet. When the average lipid motional properties were examined by measuring the fluorescence anisotropy of diphenylhexatriene, no significant different was found between intact liver microsomes from animals fed the two diets. However, when lipid motion was examined in vesicles of phosphatidylcholine, isolated from the microsomes from fish oil fed animals (21.4% (n-3) fatty acids), the fluorescence anisotropy was significantly less than the corresponding phosphatidylcholine from olive oil fed animals (5.6% (n-3) fatty acids), indicating a more disordered or fluid bilayer in the presence of higher levels of (n-3) fatty acids. Phosphatidylethanolamine (n-3) fatty acids were also elevated after fish oil supplementation (41.3% of total fatty acids), compared to the level after olive oil supplementation (21.4%). The major effect of the fish oil supplementation was a replacement of (n-6) arachidonic acid by the (n-3) fatty acids and when this was 'modeled', using liposomes of synthetic lipids, 1-palmitoyl-2-arachidonyl(n-6) or docosahexaenoyl(n-3)-phosphatidylcholine, significant differences in lipid motional properties were found, with the docosahexaenoate conferring a more disordered or fluid lipid environment. Thus it appears that although lipid order/fluidity can be significantly decreased by increases in the highly unsaturated (n-3) fatty acid levels, alterations in membrane domain organization and/or phospholipid molecular species composition effectively compensated for the changes, at least as far as average lipid motional properties in the intact membranes was concerned.
Assuntos
Gorduras na Dieta/farmacologia , Ácidos Graxos/farmacologia , Lipídeos/análise , Linfócitos/análise , Microssomos Hepáticos/análise , Animais , Polarização de Fluorescência , Lipossomos/análise , Fosfolipídeos/análise , Ratos , Ratos EndogâmicosRESUMO
1, The biological effects of metabolites of leukotriene E4 (LTE4) i.e. N-acetyl LTE4 (N-AcLTE4), 20-COOH-LTE4, 20-COOH-N-AcLTE4, as well as 18-COOH-19,20-dinor-LTE4 (dinor-LTE4) and 16-COOH-17,18,19,20-tetranor-14,15-dihydro-LTE4 (tetranor-LTE4) were investigated on superfused strips of guinea-pig trachea (GPT) and lung parenchyma (GPP) in vitro. 2. The actions of LTE4 were studied in isolated, superfused strips of human lung parenchyma (HP) and bronchus (HBr), in comparison with LTD4 and histamine. Effects of N-AcLTE4, the 20-carboxy metabolites, dinor-LTE4 and tetranor-LTE4 were also investigated in HBr. 3. N-AcLTE4 (0.1-10 nmol) induced dose-related contractions of GPT and was approximately 100 times less active than LTD4 (3-100 pmol). 4. In GPP, N-AcLTE4 (0.01-3 nmol) was equiactive with LTE4 (0.01-1 nmol) and approximately one order of magnitude less active than LTD4 (1-300 pmol). Contractions caused by N-AcLTE4 and LTE4 were very similar and approximately twice as sustained as those due to LTD4. 5. LTE4 (0.1-30 nmol) contracted strips of HP and HBr and was about 2-3 orders of magnitude less active than LTD4. As in GPP, the effect of LTE4 was more protracted than that of LTD4. Actions of N-AcLTE4 were similar to those of LTE4 in HBr. 6. 20-carboxy-LTE4, 20-carboxy-N-AcLTE4, dinor-LTE4 and tetranor-LTE4, all at 0.3-30 nmol, were inactive in GPT, GPP and HBr. 7. Indomethacin (2.8 microM) potentiated the effect of N-AcLTE4 in GPT, inhibited its contraction in GPP but did not affect that due to LTE4 in either HP or HBr. FPL 55712 (1.9 microM) antagonised leukotriene-induced contractions in GPT, GPP and HBr. 8. In conclusion, the metabolism of LTD4 to LTE4 or N-AcLTE4 may represent a detoxification but not an inactivation of cysteinyl-containing leukotrienes, since both metabolites still retain considerable biological activity in guinea-pig and human airways in vitro. However, further metabolism of LTE4 and N-AcLTE4 appears to result in inactivation of leukotrienes.
Assuntos
SRS-A/análogos & derivados , Animais , Biotransformação , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Cromonas/farmacologia , Cobaias , Humanos , Técnicas In Vitro , Indometacina/farmacologia , Leucotrieno E4 , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Oxirredução , SRS-A/antagonistas & inibidores , SRS-A/metabolismo , SRS-A/farmacologia , Traqueia/efeitos dos fármacos , Traqueia/metabolismoRESUMO
1. The effect of rapamycin (0.001 to 5 mg kg-1) on the increased leukocyte counts in bronchoalveolar lavage (BAL) fluid and hyperreactivity of isolated bronchial strips to histamine and acetylcholine (ACh) was studied following the intravenous injection of Sephadex beads to guinea-pigs. 2. The intramuscular (i.m.) injection of rapamycin (0.012 to 5 mg kg-1) dose-dependently inhibited the increase in leukocyte counts in BAL fluid. Rapamycin (5 mg kg-1) reduced the numbers of eosinophils neutrophils, macrophages and lymphocytes in BAL fluid by 64, 55, 19 and 50% respectively. In addition, rapamycin (0.012 to 5 mg kg-1) significantly inhibited the Sephadex-induced hyperreactivity of bronchial tissue to both histamine and ACh. 3. At a dose of 0.001 mg kg-1, rapamycin did not significantly reduce leukocyte infiltration or bronchial hyperreactivity. 4. Cyclosporin (5 mg kg-1) significantly reduced both lymphocyte and eosinophil numbers in BAL fluid of Sephadex-injected guinea-pigs whereas dexamethasone (1 mg kg-1) significantly reduced lymphocyte numbers. Neither drug affected the bronchial hyperreactivity to histamine and ACh. 5. It is concluded that the new immunosuppressive drug, rapamycin, is a potent inhibitor of leukocyte migration and bronchial hyperreactivity observed following the intravenous injection of Sephadex beads to guinea-pigs. Rapamycin also appears to be more effective than cyclosporin or dexamethasone in reducing leukocyte counts and bronchial hyperreactivity in this model. 6. Our results suggest that inflammatory mechanisms which are inhibited by rapamycin may be important in the induction of Sephadex-induced hyperreactivity.
Assuntos
Hiper-Reatividade Brônquica/prevenção & controle , Imunossupressores/farmacologia , Leucócitos/efeitos dos fármacos , Polienos/farmacologia , Acetilcolina/farmacologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Movimento Celular/efeitos dos fármacos , Ciclosporina/farmacologia , Dexametasona/farmacologia , Dextranos , Feminino , Cobaias , Histamina/farmacologia , Contagem de Leucócitos/efeitos dos fármacos , Masculino , SirolimoRESUMO
1. The effect of vasoactive intestinal peptide (VIP) was studied on the contractile response of guinea-pig lung parenchymal strips (GPP) induced by bronchoconstrictor agonists, such as leukotriene D4 (LTD4), histamine and acetylcholine (ACh). This effect of VIP was compared with helodermin, a peptide that is structurally related to VIP, and galanin, another neuropeptide that is thought to co-exist with VIP. 2. VIP (10 nM) induced a potent and reversible inhibition of the contractions of GPP induced by LTD4 (1-30 pmol) but did not affect those due to ACh (1-100 nmol) or histamine (1-30 nmol). A ten fold higher concentration of VIP (100 nM) did not further inhibit LTD4-induced responses or reduce those induced by histamine or ACh. 3. Helodermin (10 nM) had a similar inhibitory effect on contractions of GPP induced by LTD4 (3-30 pmol) but did not affect contractions induced by histamine (1-10 nmol). 4. Indomethacin (2.8 microM) and salbutamol (10 nM) significantly reduced responses elicited by LTD4 and histamine but not those due to ACh. A ten fold higher concentration of salbutamol (100 nM) further inhibited the contractions due to LTD4 and histamine and at this concentration responses induced by ACh were inhibited. 5. VIP (10 nM) and helodermin (10 nM) significantly reduced the LTD4-induced release of thromboxane A2 (TXA2), measured as TxB2 by radioimmunoassay, from GPP. The smaller release of TxA2 induced by histamine was not significantly reduced in the presence of VIP. 6. In comparative studies, galanin (10-100 nM) did not affect contractions of GPP induced by either LTD4, histamine or ACh. In contrast to VIP and helodermin, both at 0.1-3 nmol, which induced doserelated relaxations of guinea-pig trachea, galanin was inactive on this preparation in doses of up to 3 nmol.7. In conclusion, our results show that contractions of GPP induced by LTD4 are more sensitive to inhibition by VIP and helodermin than are contractions due to histamine or ACh. This inhibition appears to be associated with the different contribution of released TxA2 to contractions evoked by the agonists. VIP and helodermin inhibit the cyclo-oxygenase-dependent component of the LTD4-induced response, as in the case of indomethacin.
Assuntos
Acetilcolina/farmacologia , Histamina/farmacologia , Pulmão/efeitos dos fármacos , Peptídeos/farmacologia , SRS-A/farmacologia , Peptídeo Intestinal Vasoativo/farmacologia , Acetilcolina/antagonistas & inibidores , Albuterol/farmacologia , Animais , Galanina , Cobaias , Antagonistas dos Receptores Histamínicos/farmacologia , Técnicas In Vitro , Indometacina/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Endoperóxidos Sintéticos de Prostaglandinas/farmacologia , Radioimunoensaio , SRS-A/antagonistas & inibidores , Tromboxano B2/análise , Tromboxano B2/metabolismo , Traqueia/efeitos dos fármacosRESUMO
The effect of pituitary adenylate cyclase activating peptide (PACAP 1-27) was examined on epithelium-intact and -denuded guinea-pig tracheal strips (GPT) and compared to vasoactive intestinal peptide (VIP) and salbutamol. PACAP (10(-11)-10(-8) moles) induced dose-dependent relaxations of the basal tone of both epithelium-intact and -denuded GPT. PACAP was approximately three times less potent than either VIP or salbutamol in relaxing epithelium-intact GPT. The relaxant effects of both peptides and salbutamol were markedly attenuated following removal of the epithelial layer. L-NAME (10(-4) M), a nitric oxide synthase inhibitor, did not affect the responses induced by either PACAP or VIP demonstrating that the relaxant effect is independent of nitric oxide synthesis. Phosphoramidon (5 x 10(-6) M) potentiated the relaxant responses of epithelium-intact GPT to both PACAP and VIP but did not affect the responses of epithelium-denuded GPT. PACAP and VIP also induced relaxations of the guinea-pig upper bronchus. In addition, PACAP (10(-6) M), as well as VIP, significantly inhibited the release of TxB2 induced by LTD4 (10(-7) M) from chopped guinea-pig lung suggesting that this newly isolated peptide, which has 68% homology with VIP, may possess anti-inflammatory action in the lung.
Assuntos
Agonistas Adrenérgicos beta/farmacologia , Albuterol/farmacologia , Músculo Liso/efeitos dos fármacos , Neuropeptídeos/farmacologia , Peptídeo Intestinal Vasoativo/farmacologia , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Brônquios/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Epitélio/efeitos dos fármacos , Cobaias , Técnicas In Vitro , Leucotrieno D4/farmacologia , Relaxamento Muscular/efeitos dos fármacos , Tono Muscular/efeitos dos fármacos , NG-Nitroarginina Metil Éster , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase , Tromboxano B2/metabolismo , Traqueia/efeitos dos fármacosRESUMO
Vasoactive intestinal peptide (VIP, 10 nM) inhibited the release of cyclo-oxygenase products, detected by both bioassay and radioimmunoassay, induced by leukotriene (LT) D4 (3-30 pmol) and bradykinin (BK, 3-30 nmol) from guinea-pig isolated perfused lung. Helodermin (10 nM), a peptide that is structurally related to VIP, and salbutamol (10 nM), a beta 2-adrenoceptor agonist, evoked a similar inhibitory effect on LTD4-induced release of cyclo-oxygenase products. The generation of TxB2 and 6-keto-PGF1 alpha following stimulation with exogenously administered arachidonic acid (30-300 nmol) was not significantly attenuated in the presence of either VIP, helodermin or salbutamol. These results show that VIP, helodermin and salbutamol are potent inhibitors of the release of cyclo-oxygenase products induced by agonists known to activate endogenous arachidonic acid metabolism in guinea-pig lung. Since the metabolism of exogenously administered arachidonic acid was not inhibited these results suggest that the inhibitory effect may be exerted on events preceding the mobilisation of arachidonic acid and may involve cyclic AMP.
Assuntos
Bradicinina/farmacologia , Pulmão/efeitos dos fármacos , Peptídeos/farmacologia , Prostaglandina-Endoperóxido Sintases/fisiologia , SRS-A/farmacologia , Peptídeo Intestinal Vasoativo/farmacologia , Albuterol/farmacologia , Animais , AMP Cíclico/fisiologia , Cobaias , Peptídeos e Proteínas de Sinalização Intercelular , Pulmão/metabolismo , Masculino , Perfusão , Prostaglandinas/metabolismo , Tromboxano B2/metabolismo , Peçonhas/farmacologiaRESUMO
Platelet-activating factor (PAF, 10-1000 pmol) induced dose-dependent relaxations of the basal tone of superfused strips of epithelium-intact guinea-pig trachea. Indomethacin (1.4 microM) completely inhibited and WEB 2086 (1 and 10 nM) effectively antagonised these relaxations. Following epithelial removal PAF evoked a single contraction. These results show that the PAF-induced relaxations of guinea-pig trachea are dependent on an intact epithelial layer and are mediated by a cyclo-oxygenase product.
Assuntos
Azepinas/farmacologia , Músculo Liso/efeitos dos fármacos , Fator de Ativação de Plaquetas/antagonistas & inibidores , Triazóis/farmacologia , Albuterol/farmacologia , Animais , Epitélio/fisiologia , Cobaias , Técnicas In Vitro , Indometacina/farmacologia , Masculino , Relaxamento Muscular/efeitos dos fármacos , Fator de Ativação de Plaquetas/análogos & derivados , Fator de Ativação de Plaquetas/farmacologia , Traqueia/efeitos dos fármacosRESUMO
The influence of inflammatory cells on airway reactivity was investigated on arachidonic acid-induced relaxations of guinea-pig trachea and on arachidonic acid metabolism in guinea-pig tracheal epithelial cells. The presence of either eosinophils or neutrophils (1.0 x 10(7) cells/ml), from bronchoalveolar lavage, decreased the tracheal relaxations induced by arachidonic acid (1.0-30 microM). The basal synthesis of prostaglandin E2 was increased in epithelial cells (from 176 +/- 36 to 7920 +/- 898 pg/ml), eosinophils (from 360 +/- 56 to 2693 +/- 686 pg/ml) and neutrophils (from 352 +/- 81 to 4400 +/- 272 pg/ml) following incubation with arachidonic acid (10 microM). The co-incubation of either eosinophils or neutrophils with epithelial cells, in the presence of arachidonic acid, decreased the synthesis of prostaglandin E2 (2600 +/- 686 and 4400 +/- 272 pg/ml respectively) but increased the synthesis of thromboxane B2 (from 60 +/- 6 to 11634 +/- 840 and 9282 +/- 485 pg/ml respectively). Similarly, when major basic protein-treated (100 micrograms/ml) epithelial cells were incubated with arachidonic acid, the prostaglandin E2 synthesis decreased (75%) but thromboxane B2 synthesis was unaffected. The results suggest that eosinophils and neutrophils may impair arachidonic acid metabolism in guinea-pig epithelium in favor of production of bronchoconstrictor prostanoids.
Assuntos
Ácido Araquidônico/farmacologia , Eosinófilos/fisiologia , Músculo Liso/efeitos dos fármacos , Neutrófilos/fisiologia , Traqueia/efeitos dos fármacos , Animais , Líquido da Lavagem Broncoalveolar/citologia , Dinoprostona/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Eosinofilia/patologia , Feminino , Cobaias , Técnicas In Vitro , Masculino , Relaxamento Muscular/efeitos dos fármacos , Tromboxano B2/metabolismoRESUMO
Rabbit platelet-rich plasma was incubated with [32P]orthophosphate, after which the platelets were washed, further incubated in the absence or presence of verapamil and subsequently stimulated with PAF-acether or thrombin. In the absence of verapamil, a rapid increase in radioactivity in phosphatidic acid was observed in platelets stimulated with PAF-acether or thrombin. This was inhibited by verapamil over the concentration range 10(-7) to 10(-4) M, at which concentration the rise in phosphatidic acid was completely abolished. In unstimulated platelets, 10(-4) M verapamil induced an increase in radioactivity in polyphosphoinositides but not significantly in phosphatidylinositol. When these verapamil-treated platelets were stimulated with PAF-acether or thrombin, there was a rapid, sustained loss of the additional radioactivity induced in the polyphosphoinositides by verapamil. Polyphosphoinositide radioactivity remained unchanged in platelets stimulated in the absence of verapamil. Verapamil may stimulate formation of a separate pool of polyphosphoinositide which is susceptible to agonist-induced phospholipase C, and failure to re-synthesize this polyphosphoinositide could result from inhibition of phosphatidic acid synthesis.
Assuntos
Plaquetas/metabolismo , Ácidos Fosfatídicos/biossíntese , Fosfatidilinositóis/metabolismo , Verapamil/farmacologia , Animais , Plaquetas/efeitos dos fármacos , Depressão Química , Técnicas In Vitro , Lipídeos/sangue , Radioisótopos de Fósforo , Fator de Ativação de Plaquetas/farmacologia , Coelhos , Trombina/farmacologiaRESUMO
The effects of an intravenous injection (i.v.) of Sephadex beads (20 mg kg(-1)) were examined on bronchial responsiveness to ACh (1-200 microg kg(-1) i.v.) as well as on cell accumulation in guinea-pig lung. Bronchial hyperreactivity to ACh, measured as increase in pulmonary insufflation pressure (PIP), was observed 3 h following the i.v. injection of Sephadex beads. However, no significant increase in bronchial reactivity to ACh was measured at 6 and 12 h following Sephadex injection. A second later increase in bronchial hyperresponsiveness was observed at 24 h. Bronchoalveolar lavage performed at 3 h following Sephadex treatment showed that there was no significant increase in total or differential cell number. At 6 h and 12 h, a significant increase in total cell counts was observed. At 24 h, a greater than 5-fold increase in cell number was observed and was related to a marked eosinophil, neutrophil and macrophage infiltration. A platelet-activating factor (PAF) antagonist, CV-3988 (10 mg kg(-1) i.v.), and a thromboxane A2 (TxA2) antagonist, L655,240 (10 mg kg(-1) i.v.), significantly attenuated the Sephadex-induced bronchial hyperresponsiveness to ACh observed at 3 h. The results show that an i.v. injection of Sephadex beads in guinea pigs can induce an early bronchial hyperresponsiveness to ACh that is mediated by the release of both PAF and TxA2 and is independent of airway cell infiltration.
Assuntos
Hiper-Reatividade Brônquica , Dextranos/toxicidade , Indicadores e Reagentes/toxicidade , Fator de Ativação de Plaquetas/metabolismo , Tromboxano A2/metabolismo , Acetilcolina/farmacologia , Animais , Hiper-Reatividade Brônquica/induzido quimicamente , Hiper-Reatividade Brônquica/metabolismo , Cobaias , Vasodilatadores/farmacologiaRESUMO
In the present study, the effect of a tumor necrosis factor receptor binding protein (TNFbp) on the cell infiltration induced by lipopolysaccharide (LPS) and Sephadex beads in guinea pig lung was examined. The intratracheal injection of LPS (2.5 micrograms) induced a six-fold increase in total cell number recovered in bronchoalveolar lavage (BAL) fluid at 24 hr. This increase in bronchopulmonary inflammation was mainly due to a neutrophil and macrophage infiltration, representing 60% and 35% of the total cells, respectively. The intravenous or intratracheal injection of Sephadex beads to guinea pigs induced a three-fold increase in total cell number recovered in BAL at 24 h and was characterized by a prominent eosinophil, macrophage, and neutrophil infiltration representing 36%, 42%, and 16% of the total cells, respectively. In addition, bronchial tissues isolated from Sephadex-treated guinea pigs showed an increased in vitro reactivity to both histamine and acetylcholine. TNFbp (1-50 micrograms) induced a dose-dependent inhibition of cell infiltration induced by LPS. In contrast TNFbp neither attenuated the bronchopulmonary cell infiltration observed 24 h following intravenous or intratracheal administration of Sephadex beads nor inhibited the increase in bronchial reactivity. These results show that TNF plays an important role in cell infiltration induced by LPS, but not that induced by Sephadex, in the guinea pig lung.
Assuntos
Hiper-Reatividade Brônquica/patologia , Proteínas de Transporte/farmacologia , Pneumonia/patologia , Receptores do Fator de Necrose Tumoral/antagonistas & inibidores , Choque Séptico/induzido quimicamente , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Ligação Competitiva , Hiper-Reatividade Brônquica/etiologia , Líquido da Lavagem Broncoalveolar/citologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Dextranos/administração & dosagem , Dextranos/toxicidade , Feminino , Cobaias , Injeções , Injeções Intravenosas , Contagem de Leucócitos/efeitos dos fármacos , Leucócitos/patologia , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/toxicidade , Masculino , Microesferas , Pneumonia/etiologia , Receptores do Fator de Necrose Tumoral/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral , Proteínas Recombinantes/farmacologia , Choque Séptico/complicações , Choque Séptico/patologia , Traqueia , Receptores Chamariz do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa/administração & dosagem , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Rapamycin is a macrolide antibiotic whose potent immunosuppressor activity was recently described in vivo and in vitro. The aim of the present work was to determine if rapamycin could affect an established inflammatory response. Conscious pathogen-free Dunkin-Hartley guinea pigs (300-400 g) were injected intravenously with Sephadex beads (G50, superfine, 10 to 40 microns, 24 mg/kg) to induce lung inflammation and bronchial hyperreactivity. Bronchoalveolar lavage (BAL) fluid was collected 2, 12 and 24 h after Sephadex administration and the cells were counted. Bronchial tissue was used to construct dose-response (contraction, g) curves to histamine and acetylcholine 24 h after the Sephadex injection, using a cascade system. Results are presented as area under the log dose-response curves. Test animals were injected with rapamycin (5 mg/kg) or its vehicle by the intramuscular route either 2 or 12 h after Sephadex injection and BAL fluid collected 24 h after Sephadex administration. Rapamycin administration 2 h after Sephadex reduced eosinophil and lymphocyte numbers in BAL by 52 and 55%, respectively, but not ex vivo bronchial hyperreactivity induced by Sephadex injection. However, rapamycin administration 12 h after Sephadex reduced BAL eosinophil and lymphocyte numbers (55 and 62%, respectively) and bronchial hyperreactivity. The increase in neutrophil numbers in BAL induced by Sephadex injection was not modified by rapamycin. Since lymphocyte numbers in BAL were significantly increased in Sephadex-treated animals at 12 h but not at 2 h after Sephadex injection, the present results suggest that the inhibition of bronchial hyperreactivity by rapamycin may be dependent on the presence of lymphocytes elicited into the airways by Sephadex injection.
Assuntos
Hiper-Reatividade Brônquica/tratamento farmacológico , Pneumopatias/etiologia , Polienos/farmacologia , Animais , Hiper-Reatividade Brônquica/induzido quimicamente , Líquido da Lavagem Broncoalveolar/citologia , Contagem de Células/efeitos dos fármacos , Dextranos , Esquema de Medicação , Cobaias , Inflamação/induzido quimicamente , Polienos/administração & dosagem , SirolimoAssuntos
Brônquios/fisiologia , Pulmão/fisiologia , SRS-A/metabolismo , Acetilcolina/farmacologia , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Broncoconstrição/efeitos dos fármacos , Histamina/farmacologia , Humanos , Imunoglobulina E , Técnicas In Vitro , Indometacina/farmacologia , Cinética , Leucotrieno E4 , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , SRS-A/análogos & derivados , Serotonina/farmacologiaRESUMO
Eosinophilic leukocytes accumulate in high numbers in the lungs of asthmatic patients, and are believed to be important in the pathogenesis of asthma. A potent eosinophil chemoattractant is produced in the asthmatic lung. This small protein, the chemokine eotaxin, is synthesized by a number of different cell types, and is stimulated by interleukin-4 and interleukin-13, which are produced by T-helper (Th)2 lymphocytes. Low molecular weight compounds have been developed that can block the eotaxin receptor C-C chemokine receptor (CCR)3, and prevent stimulation by eotaxin. This provides the potential for orally available drugs that can prevent eosinophil recruitment into the lung and the associated damage and dysfunction.
Assuntos
Asma/fisiopatologia , Quimiocinas CC/fisiologia , Eosinófilos/fisiologia , Pulmão/fisiopatologia , Animais , Medula Óssea/patologia , Medula Óssea/fisiopatologia , Quimiocina CCL11 , Humanos , Receptores CCR3 , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/fisiologia , Células Th2/fisiologiaRESUMO
Rat spleen lymphocytes prelabelled with [14C] arachidonate were suspended in fresh medium in the presence or absence of exogenous non-radioactive fatty acids added in ethanol. It was found that fatty acids stimulate thromboxane B2, PGE2, HHT and HETE formation. The effect is specific for unsaturated fatty acids. It occurs at 50 micron concentrations and is apparent after 20 minutes incubation. Unsaturated fatty acids may serve an important role in the regulation of prostaglandin and hydroxy fatty acid metabolism in vivo. This may indicate a mechanism for the action of fatty acids on the immune response.
Assuntos
Ácidos Graxos Insaturados/farmacologia , Lipoxigenase/metabolismo , Linfócitos/efeitos dos fármacos , Prostaglandina-Endoperóxido Sintases/metabolismo , Animais , Ácido Araquidônico , Ácidos Araquidônicos/metabolismo , Dinoprostona , Técnicas In Vitro , Linfócitos/metabolismo , Prostaglandinas E/biossíntese , Ratos , Ratos Endogâmicos , Baço/efeitos dos fármacos , Baço/metabolismo , Tromboxano B2/biossínteseRESUMO
Eosinophils have been implicated in a broad range of diseases, notably allergic conditions (for example, asthma, rhinitis and atopic dermatitis) and other inflammatory disorders (for example, inflammatory bowel disease, eosinophilic gastroenteritis and pneumonia). These disease states are characterized by an accumulation of eosinophils in tissues. Severe tissue damage ensues as eosinophils release their highly cytotoxic granular proteins. Defining the mechanisms that control recruitment of eosinophils to tissues is fundamental to understanding these disease processes and provides targets for novel drug therapy. An important discovery in this context was the identification of an eosinophil-specific chemoattractant, eotaxin. Over the past six years there has been intensive investigation into the biological effects of eotaxin and its role in specific disease processes and this is the subject of this review.
Assuntos
Quimiocinas CC , Fatores Quimiotáticos de Eosinófilos/metabolismo , Citocinas/metabolismo , Eosinófilos/metabolismo , Hipersensibilidade/metabolismo , Animais , Medula Óssea/metabolismo , Medula Óssea/patologia , Quimiocina CCL11 , Fatores Quimiotáticos de Eosinófilos/imunologia , Citocinas/imunologia , Eosinófilos/imunologia , Humanos , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/patologiaRESUMO
The effect of diets containing different types of common natural oils on physical properties of red cells was investigated by using rabbits. The rabbits were fed for 18 months on a standard diet in which 8% of its energy content was provided by safflower oil and 32% energy by either more safflower oil or fish oil, linseed oil, olive oil or palm oil. Erythrocyte deformability was significantly decreased by the fish oil diet compared with each of the other diets. Osmotic fragility was significantly less (66 mM) for red cells from rabbits fed on the linseed oil diet, and significantly greater (71 mM) for red cells from rabbits on the fish oil diet, than for red cells from rabbits on the other three diets which did not differ significantly from each other (68 mM). With rabbits on the standard diet, the resistance of their erythrocytes to osmotic haemolysis was increased by chlorpromazine at concentrations below and decreased by concentrations above 30 microM. The dietary oils caused significant changes in the effects of chlorpromazine on osmotic fragility. The concentration at which the effect of chlorpromazine reversed from antihaemolytic to prohaemolytic was decreased by the safflower and linseed oil diets and increased by the fish oil diet, compared with the olive and palm oil diets. Analysis of the fatty acid compositions of the dietary oils on the one hand and of the red cell phospholipids on the other established, specifically, that in the presence of 30 microM chlorpromazine the percentage haemolysis was directly proportional to the linoleate content of the red cell phospholipids.