RESUMO
The effects of lipopolysaccharide (LPS) and desArg9Bradykinin (DBK) on the release of nitric oxide (NO) from macrophages of mice 8, 12 and 18 days after having been treated with low doses of streptozotocin (STZ; 5 × 45 mg/kg) were studied. The results showed that LPS stimulated the release of NO from macrophages of untreated animals by 50% whereas the bradykinin B(1) agonist desArg9Bradykinin (DBK) increased the level of NO by 20%. This increased NO production was totally abolished by incubating the cells with R-954, a selective bradykinin B(1) antagonist. The release of NO from macrophages of STZ-treated mice incubated in the presence of LPS was more marked and reached approximately 220, 300 and 270% respectively from cells collected 8, 12 and 18 days after the STZ treatment. These significant increases were completely blocked by R-954 and were even below control values. Similarly the results showed that DBK stimulated by 50-75% the release of NO from macrophages of STZ-treated mice. The most marked stimulation was noted when the cells were collected 18 days after the treatment of the animals with STZ. Again in this set of experiments the B(1) antagonist completely blocked the release of NO which went even below control values. The results clearly suggest the upregulation of bradykinin B(1) receptors in mouse macrophages in the early phase of STZ-induced diabetes, an event that could even precede the onset of the diabetic hyperglycemia.
Assuntos
Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/imunologia , Ativação de Macrófagos/imunologia , Macrófagos Peritoneais/imunologia , Animais , Glicemia/efeitos dos fármacos , Bradicinina/química , Bradicinina/farmacologia , Células Cultivadas , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/imunologia , Óxido Nítrico/metabolismo , Receptor B1 da Bradicinina/metabolismo , Estreptozocina/imunologia , Estreptozocina/farmacologiaRESUMO
OBJECTIVE: The effect of bradykinin (B(1) or B(2)) receptor antagonists was studied in allergic and immune-complex-induced lung inflammation. METHODS: Lungs of BALB/c mice were examined 24 h after induction of lung inflammation, either allergic (ovalbumin-sensitized submitted to two aerosol of antigen, one week apart) or immune-complex induced (intratracheal instillation of IgG antibodies followed by intravenous antigen). The bradykinin B(2) receptor antagonist, HOE-140 or bradykinin B(1) receptor antagonist, R-954 were given intraperitoneally (100 microg/kg), 30 min before induction. RESULTS: In allergic inflammation, pre-treatment with R-954 reduced eosinophil infiltration into the lungs, mucus secretion and the airway hyperreactivity to methacholine. Pre-treatment with HOE-140 increased eosinophil infiltration but did not affect the other parameters. In immune-complex inflammation, HOE-140 increased neutrophil infiltration but not their activation nor the hemorrhagic lesions. R-594 pre-treatment did not change the parameters examined. CONCLUSION: These results show important modulatory effects of bradykinin B(1) and B(2) receptor antagonists in both models of lung inflammation.
Assuntos
Antagonistas dos Receptores da Bradicinina , Bradicinina/análogos & derivados , Hipersensibilidade , Doenças do Complexo Imune , Pneumonia/imunologia , Pneumonia/prevenção & controle , Animais , Bradicinina/uso terapêutico , Antagonistas de Receptor B1 da Bradicinina , Antagonistas de Receptor B2 da Bradicinina , Broncoconstrição/efeitos dos fármacos , Eosinófilos/patologia , Masculino , Cloreto de Metacolina/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Muco/metabolismo , Ovalbumina/imunologia , Pneumonia/patologiaRESUMO
The participation of endothelins (ETs) in a model of neutrophil-dependent lung injury induced by intrabronchial instillation of rabbit antibodies to ovalbumin followed by i.v. injection of the antigens (Arthus reaction) was investigated. Hemorrhagic lesions were evaluated by measuring the extravasations of hemoglobin in lung parenchyma. From 5 min to 24 h after the Arthus reaction (AR), endothelin (ir-ET) levels in bronchoalveolar lavage fluid (BALF) and in plasma were measured by radioimmunoassay. BALF levels of ir-ET were not different between control and AR animals for the first 90 min after the antigen challenge but increased from 2 to 24 h after induction of AR. ET levels in the plasma did not change from the respective controls over the same 24 h period. Increased ir-ET in BALF was not affected by pretreatment with L-NAME (30 mg/kg, i.v.). A PAF antagonist (BN52021; 5 and 10 mg/kg, i.v.) increased ET content in BALF and decreased the intensity of the AR. Thiorphan (2 mg/kg, i.v.) inhibited the AR-induced hemorrhagic lesions in lungs. An ET(A) receptor antagonist, BQ-123 (1 mg/kg, i.v.) potentiated, whereas the ET(B) antagonist, BQ-788 (1 mg/kg, i.v.) inhibited the lung hemorrhage. It is concluded that ETs are released during and play a role in the lung AR.
Assuntos
Reação de Arthus/imunologia , Endotelinas/metabolismo , Hemorragia/imunologia , Pneumopatias/imunologia , Pneumonia/imunologia , Animais , Complexo Antígeno-Anticorpo , Reação de Arthus/sangue , Reação de Arthus/etiologia , Líquido da Lavagem Broncoalveolar/química , Diterpenos/farmacologia , Antagonistas do Receptor de Endotelina A , Antagonistas do Receptor de Endotelina B , Endotelinas/análise , Endotelinas/sangue , Fibrinolíticos/farmacologia , Ginkgolídeos , Hemoglobinas/análise , Hemorragia/etiologia , Hemorragia/metabolismo , Lactonas/farmacologia , Pneumopatias/etiologia , Pneumopatias/metabolismo , Masculino , Neutrófilos/imunologia , Oligopeptídeos/farmacologia , Ovalbumina , Peptídeos Cíclicos/farmacologia , Piperidinas/farmacologia , Pneumonia/patologia , Ratos , Ratos WistarRESUMO
Data from the Hemophilia Growth and Development Study (HGDS) were used to evaluate the association between hemophilia morbidity, measured by abnormalities in coordination and gait (CG), and intellectual ability and academic achievement. The CG abnormalities observed in the HGDS participants (n = 333) were primarily due to hemophilia-related morbidity. Although HGDS participants performed within the average range for age on measures of intellectual ability, there were meaningful differences between CG outcomes at baseline and throughout the 4 years of study. Participants without CG abnormalities consistently achieved higher scores than those with CG abnormalities on Reading, Spelling, and Arithmetic subtests of the Wide Range Achievement Test-Revised. Our findings suggest that lowered achievement is related to the functional severity of hemophilia.
Assuntos
Cognição , Deficiências do Desenvolvimento/etiologia , Hemofilia A/complicações , Adolescente , Adulto , Criança , Humanos , Testes de Inteligência , Masculino , Testes NeuropsicológicosRESUMO
An intravenous injection of Sephadex beads has been used to induce lung inflammation and bronchial hyperreactivity in small animals. In the present study, we injected Sephadex beads (0.3-5.5 mg/paw) into rat paws and followed the resulting inflammation plethysmometrically. Our results show that Sephadex beads induced a significant and dose-dependent increase in the hindpaw volume at 5 min; it was maximal at 30-60 min and declined at 4 h. However, the paw volume remained significantly increased for up to 21 days. The initial 4-hour-oedema was confirmed by histopathology of the paw tissues, but the persistent increase in paw volume was related to a chronic inflammatory (granulomatous) response. The Sephadex-induced oedema was predominantly due to serotonin (5-HT) release since specific antagonists such as methysergide (1 mg/kg) and pizotifen (0.1-2 mg/kg) administered both systemically and locally were able to inhibit the oedema (10-100 microgram/paw) as could pretreatment with compound 48/80. In addition, platelet-activating factor (PAF) was also shown to be involved, since systemic pretreatment using the specific PAF antagonist BN 52021 (1 mg/kg) was able to inhibit the increase in paw volume induced by Sephadex. Effective doses of indomethacin (2 mg/kg), L-NAME (1 mg/kg), pyrilamine (1-2 mg/kg), ondansetron (1 mg/kg) and HOE 140 (1 mg/kg) did not affect the Sephadex-induced oedema, thus ruling out the participation of prostaglandins, nitric oxide, histamine, 5-HT3 receptors and bradykinin in its development. Since the late increases in paw volume induced by Sephadex were reduced by pretreatment of the animals with the immunosuppressive drugs rapamycin and dexamethasone but not cyclosporin, our results also suggested that distinct immunological pathways may be involved in the modulation of the chronic phase of inflammation induced by Sephadex beads in rat paws.
Assuntos
Diterpenos , Edema/etiologia , Fator de Ativação de Plaquetas/fisiologia , Serotonina/fisiologia , Animais , Bradicinina/fisiologia , Ciclosporina/farmacologia , Dexametasona/farmacologia , Dextranos/administração & dosagem , Edema/patologia , Edema/fisiopatologia , Ginkgolídeos , Histamina/farmacologia , Imunossupressores/farmacologia , Mediadores da Inflamação/fisiologia , Injeções Intravenosas , Lactonas/farmacologia , Masculino , Metisergida/farmacologia , Fator de Ativação de Plaquetas/antagonistas & inibidores , Polienos/farmacologia , Ratos , Antagonistas da Serotonina/farmacologia , Sirolimo , p-Metoxi-N-metilfenetilamina/farmacologiaRESUMO
The present study evaluated the effect of platelet activating factor (PAF) instilled into rat airways on vascular permeability assessed in isolated lung tissues by Evans blue (EB)-labelled plasma protein extravasation. It was found that intratracheal instillation of PAF induces a dose-dependent increase of EB extravasation in the bronchi (upper and inner) but not in the lung parenchyma. The contribution of eicosanoids to PAF-induced increase of vascular permeability was investigated by treating the animals with selected inhibitors prior to PAF administration. Mepacrine (5 mg/kg), L-663,536 (10 mg/kg), indomethacin (4 mg/kg) and dazoxiben (10 mg/kg) significantly reduced EB extravasation in the bronchi. The PAF antagonists BN-52021 (5 mg/kg), WEB-2086 (1 mg/kg), WEB-2170 (5 mg/kg) and PCA-4248 (3 mg/kg) were all effective in reducing the extravasation. These results suggest that PAF-induced increase of vascular permeability in rat bronchi is mediated by cyclooxygenase and lipoxygenase products of arachidonic acid metabolism.
Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Pulmão/irrigação sanguínea , Fator de Ativação de Plaquetas/farmacologia , Animais , Proteínas Sanguíneas/metabolismo , Brônquios/irrigação sanguínea , Azul Evans , Extravasamento de Materiais Terapêuticos e Diagnósticos , Imidazóis/farmacologia , Indometacina/farmacologia , Masculino , Fator de Ativação de Plaquetas/administração & dosagem , Fator de Ativação de Plaquetas/antagonistas & inibidores , Quinacrina/farmacologia , Ratos , Ratos Wistar , TraqueiaRESUMO
The present study was designed to investigate the ability of thromboxane to modulate the clearance rate of 125I-albumin through bovine aortic endothelial cell (BAEC) monolayer grown on polycarbonate micropore membrane. Stimulation of BAEC with the TXA2 mimetic U44069 (10(-8), 10(-7) and 10(-6) M) elicited a dose-dependent increase of labeled albumin passage across BAEC monolayers. This effect was markedly reduced by the TXA2 antagonist L655240 (10(-7) and 10(-6) M). Our results suggest that TXA2 may modulate the permeability of endothelial cells directly through activation of specific receptors.
Assuntos
Aorta/metabolismo , Endotélio Vascular/metabolismo , Endoperóxidos Sintéticos de Prostaglandinas/farmacologia , Animais , Aorta/efeitos dos fármacos , Bovinos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Células Cultivadas , Endotélio Vascular/efeitos dos fármacos , Radioisótopos do Iodo , Microscopia Eletrônica , Albumina Sérica/farmacologia , Trombina/farmacologiaRESUMO
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 , SirolimoRESUMO
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 per cent , 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 per cent , 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
Animais , Cobaias , Hiper-Reatividade Brônquica/tratamento farmacológico , Pneumopatias/etiologia , Polienos/farmacologia , Contagem de Células , Dextranos , Esquema de Medicação , Hiper-Reatividade Brônquica/induzido quimicamente , Inflamação/induzido quimicamente , Líquido da Lavagem Broncoalveolar/citologia , Polienos/administração & dosagemRESUMO
In the present study we investigated the involvement of lipid mediators in an experimental model of immune-complex alveolitis induced in rat lungs by intrabronchial instillation of rabbit antibodies to ovalbumin followed by i.v. injection of the antigen. It was found that the reaction did not induce detectable oedema, as measured by the dry:wet weight ratio. A marked influx of neutrophils was observed in the bronchoalveolar lavage fluid, progressing from 6 to 24 h in parallel with the development of haemorrhagic lesions in lung parenchyma. The intensity of these lesions, evaluated by the concentration of extravascular haemoglobin, was not significantly affected by pretreatment of the animals with a cyclo-oxygenase inhibitor (indomethacin), a thromboxane inhibitor (econazole) or a thromboxane antagonist (L-655,240). However, the antagonists of platelet activating factor (PAF), WEB-2086 and BN-52021, and the lipoxygenase inhibitors, nor-dihydroguaiaretic acid and L-663,536, all significantly inhibited the haemorrhagic lesions. A peptide leukotriene antagonist (L-660,711) had no effect. Furthermore, the PAF antagonists inhibited the levels of LTB4, but not of PGE2 and thromboxane, released into the bronchoalveolar space 1 h after induction of the reaction. These results suggest that the haemorrhagic lesions in this model of immune-complex alveolitis are mediated by PAF and leukotrienes, possibly LTB4.