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1.
Mem. Inst. Oswaldo Cruz ; 100(supl.1): 121-125, Mar. 2005.
Artigo em Inglês | LILACS | ID: lil-402187

RESUMO

The prevalence of atopic diseases and diabetes is increasing worldwide though the concurrence of these pathologies in individual patients is found less frequent than it would be predicted. Moreover, co-existence of diabetes and allergy is generally marked by attenuation of their respective symptoms, and effective treatment of one disease exacerbates the other. This review gives an update of the state-of-the-art concerning the intercurrence of allergy and diabetes, particularly focusing on the consequences to the allergen-evoked vascular and cellular changes. It is proposed that the reduction in mast cell numbers and reactivity may be a pivotal mechanism behind the mutual exclusion phenomenon.


Assuntos
Animais , Humanos , Ratos , Diabetes Mellitus Experimental/imunologia , Hipersensibilidade/imunologia , Mastócitos/imunologia , Diabetes Mellitus Experimental/complicações , Glucocorticoides/antagonistas & inibidores , Glucocorticoides/metabolismo , Glucocorticoides/farmacologia , Hipersensibilidade/etiologia , Antagonistas da Insulina/farmacologia , Insulina/farmacologia , Mastócitos/efeitos dos fármacos
2.
Mem. Inst. Oswaldo Cruz ; 100(supl.1): 131-136, Mar. 2005.
Artigo em Inglês | LILACS | ID: lil-402189

RESUMO

Phosphodiesterases (PDEs) are responsible for the breakdown of intracellular cyclic nucleotides, from which PDE4 are the major cyclic AMP metabolizing isoenzymes found in inflammatory and immune cells. This generated greatest interest on PDE4 as a potential target to treat lung inflammatory diseases. For example, cigarette smoke-induced neutrophilia in BAL was dose and time dependently reduced by cilomilast. Beside the undesired side effects associated with the first generation of PDE4 inhibitors, the second generation of selective inhibitors such as cilomilast and roflumilast showed clinical efficacy in asthma and chronic obstrutive pulmonary diseases trials, thus re-enhancing the interest on these classes of compounds. However, the ability of PDE4 inhibitors to prevent or modulate the airway remodelling remains relatively unexplored. We demonstrated that selective PDE4 inhibitor RP 73-401 reduced matrix metalloproteinase (MMP)-9 activity and TGF-beta1 release during LPS-induced lung injury in mice and that CI-1044 inhibited the production of MMP-1 and MMP-2 from human lung fibroblasts stimulated by pro-inflammatory cytokines. Since inflammatory diseases of the bronchial airways are associated with destruction of normal tissue structure, our data suggest a therapeutic benefit for PDE4 inhibitors in tissue remodelling associated with chronic lung diseases.


Assuntos
Humanos , /antagonistas & inibidores , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Inibidores de Fosfodiesterase/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico
3.
Mem. Inst. Oswaldo Cruz ; 100(supl.1): 167-172, Mar. 2005. ilus, graf
Artigo em Inglês | LILACS | ID: lil-402194

RESUMO

As many metalloproteinases (MMPs), macrophage elastase (MMP-12) is able to degrade extracellular matrix components such as elastin and is involved in tissue remodeling processes. Studies using animal models of acute and chronic pulmonary inflammatory diseases, such as pulmonary fibrosis and chronic obstrutive pulmonary disease (COPD), have given evidences that MMP-12 is an important mediator of the pathogenesis of these diseases. However, as very few data regarding the direct involvement of MMP-12 in inflammatory process in the airways were available, we have instilled a recombinant form of human MMP-12 (rhMMP-12) in mouse airways. Hence, we have demonstrated that this instillation induced a severe inflammatory cell recruitment characterized by an early accumulation of neutrophils correlated with an increase in proinflammatory cytokines and in gelatinases and then by a relatively stable recruitment of macrophages in the lungs over a period of ten days. Another recent study suggests that resident alveolar macrophages and recruited neutrophils are not involved in the delayed macrophage recruitment. However, epithelial cells could be one of the main targets of rhMMP-12 in our model. We have also reported that a corticoid, dexamethasone, phosphodiesterase 4 inhibitor, rolipram and a non-selective MMP inhibitor, marimastat could reverse some of these inflammatory events. These data indicate that our rhMMP-12 model could mimic some of the inflammatory features observed in COPD patients and could be used for the pharmacological evaluation of new anti-inflammatory treatment. In this review, data demonstrating the involvement of MMP-12 in the pathogenesis of pulmonary fibrosis and COPD as well as our data showing a pro-inflammatory role for MMP-12 in mouse airways will be summarized.


Assuntos
Animais , Humanos , Mediadores da Inflamação/metabolismo , Pulmão/enzimologia , Metaloproteinases da Matriz/metabolismo , Metaloendopeptidases/metabolismo , Doença Pulmonar Obstrutiva Crônica/enzimologia , Modelos Animais de Doenças , Matriz Extracelular/enzimologia , Mediadores da Inflamação/imunologia , Inflamação/enzimologia , Inflamação/patologia , Pulmão/patologia , Metaloendopeptidases/imunologia , Doença Pulmonar Obstrutiva Crônica/patologia
4.
Mem. Inst. Oswaldo Cruz ; 92(supl.2): 201-4, Dec. 1997. tab, graf
Artigo em Inglês | LILACS | ID: lil-202033

RESUMO

In the present study, we have performed a comparative analysis of the effect of selective inhibitors of phosphodiesterase (PDE) type III, IV and V on eosinophil chemotaxis triggered by platelet activating factor (PAF) and leukotriene B4 (LTB4) in vitro. The effect of the analogues N6-2'-O-dibutyryladenosine 3':5' cyclic monophosphate (Bt2 cyclic AMP) and N2-2'-O-dibutyrylguanosine 3':5' cyclic monophosphate (Bt2 cyclic GMP) has also been determined. The eosinophils were obtained from the peritoneal cavity of naive Wistar rats and purified in discontinuous Percoll gradients to 85-95 per cent purity. We observed that pre-incubation of eosinophils with the PDE type IV inhibitor rolipram suppressed the chemotactic response triggered by PAF and LTB4 in association with an increase in the intracellular levels of cyclic AMP. In contrast, neither zaprinast (type V inhibitor) nor type III inhibitors milrinone and SK&F 94836 affected the eosinophil migration. Only at the highest concentration tested did the analogue Bt2 cyclic AMP suppress the eosinophil chemotaxis, under conditions where Bt2 cyclic GMP was ineffective. We have concluded that inhibition of PDE IV, but not PDE III or V, was able to block the eosinophil chemotaxis in vitro, suggesting that the suppresive activity of selective PDE IV inhibitors on tissue eosinophil accumulation may, at least, be partially dependent on their ability to directly inhibit the eosinophil migration.


Assuntos
Animais , Ratos , Fatores Quimiotáticos de Eosinófilos , Técnicas In Vitro , Inibidores de Fosfodiesterase , Movimento Celular/efeitos dos fármacos , Leucotrieno B4 , Fator de Ativação de Plaquetas
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