Introdução: Estima-se que 10% dos doentes com asma tm sintomas e limitaes importantes, como exacerbaes freqentes ou reduo persistente da funo respirat ria As alteraes do parnquima pulmonar distal tem sido recentemente abordadas na fisiopatologia da asma. Apesar do uso de corticoster ides, pacientes com asma refratria tm mais estresse oxidativo, assim como apresentam ativaao da iNOS. Alm disso, muitos dos dispositivos utilizados para administrao de ester ides inalat rios geram partculas que no chegam efetivamente s vias areas distais e ao parnquima pulmonar. Objetivos: Avaliamos os efeitos do tratamento com montelucaste ou dexametasona tratamentos associados ou no a um inibidor especfio da iNOS (1400W) na resposta eosinoflica, remodelamento da matriz extracelular, estresse oxidativo, contedo de actina, clulas positivas para IL4, IL5, MMP9, TIMP1, IFN, TGF do parnquima em cobaias com inflamao crnica pulmonar. Métodos: As cobaias foram inaladas com ovalbumina (grupo OVA) 2X/semana por 4semanas. Ap s a 4 inalao, as cobaias foram tratadas diariamente com montelucaste (grupo OVAM 10mg/Kg/PO/dia) ou dexametasona (grupo OVAD 5mg/Kg/IP/dia). O inibidor da iNOS, 1400W (grupo OVAW 1mg/kg/dia) foi administrado intraperitonealmente nos ltimos 4 dias (OVAW, OVADW e grupos OVAMW). Ap s 72 horas da 7 inalao, as cobaias foram anestesiadas, e os fragmentos de tecido pulmonar distal foram submetidos avaliao histopatol gica. Resultados: Houve um aumento no infiltrado eosinoflco, nas clulas positivas para IL4, IL5, TIMP1, MMP9, iNOS, IFN TGF, contedo de actina, isoprostano PGF2 alfa, fibras colgenas e elsticas nos animais OVA em comparao com animais SAL (p<0,05). Houve uma diminuio no nmero de eosin filos, clulas positivas para IL4, IL5, MMP9, TIMP1, IFN, TGF, contedo de actina, colgeno e isoprostano PGF2 alfa em todos os grupos tratados em comparao com animais OVA (p<0,05). O contedo de fibras elsticas foram reduzidas somente nos grupos OVAMW, OVADW e OVAW em comparao com animais OVA (p<0,05). A associao de 1400W e o tratamento com montelucaste (grupo OVAMW) potencializou a reduo do contedo de actina, fibras elsticas, isoprostano PGF2 alfa de clulas positivas para IL4, IL5, TIMP1, IFN TGF e iNOS em relao ao grupo montelucaste (OVAM) (p<0,05). Os tratamentos com 1400W e dexametasona (grupo OVADW) contriburam para uma maior reduo do contedo das fibras elsticas, actina e isoprostanoPGF2 alfa e o nmero de clulas positivas para IL4, IL5, IFN e TIMP1 em relao ao grupo dexametasona (OVAD) (p<0,05). Conclusões: O tratamento com corticoster ides associados inibio da iNOS contribuiu para uma maior reduo da remodelao da matriz extracelular, diminuiu o estresse oxidativo, e tambm foi eficiente para atenuar a resposta inflamat ria Th2 no parnquima pulmonar distal. Por outro lado, o tratamento com montelucaste associado à inibição da iNOS mostrou uma maior eficácia para reduzir o teor de fibras elásticas, a ativação do estresse oxidativo, conteúdo de actina e expressão das células positivas para IL4, IL5 no parênquima pulmonar distal. Estas associações podem representar futuras ferramentas farmacológicas para o controle das alterações histopatológicas pulmonares distais induzidas pela inflamação crônica / Introduction: It is estimated that 10% of asthma patients have symptoms and important limitations such as frequent exacerbations or persistent reduction of resiratory function, despite the use of corticosteroids. The alterations of distal lung parenchyma have been recently evaluated on asthma pathophysiology, particulary in patients with refractory asthma and difficcult to control. These patients have increased oxidative stress responses, mainly with significant activation of iNOS. Aims: We evaluated the effects of montelukast or dexamethasone treatments associated or not to an iNOS inhibitor (1400W) on eosinophilic response, extracellular matrix remodeling, oxidative stress, actin content, IL4, IL5, MMP9, TIMP1, IFN gama, TGF beta positive cells of distal lung parenchyma in guinea pigs with chronic alergic inflammation. Methods: Guinea Pigs were inhaled with ovalbumin (OVA group) twice a week for four weeks. After 4th inhalation, GP were treated with montelukast (OVAM group-10mg/Kg/PO/day) or dexamethasone (OVAD group-5mg/Kg/IP/day). The treatment with iNOS inhibitor 1400W (OVAW group-1mg/kg/day) was given daily in the last 4 days (OVAW, OVADW and OVAMW groups). After 72 hours of 7th inhalation, GP were anesthetized, lung strips were retired and submitted to histopathological evaluation. Results: There was an increase in eosinophilic infiltrate, in the number of positive cells for IL4, IL5, TIMP1, MMP9, iNOS, IFN gama TGF beta, actin, isoprostane PGF2 alpha, elastic and collagen fiber contents in OVA animals comparing to SAL group (p<0,05). There was a decrease in the number of eosinophils, IL4, IL5, MMP9, TIMP1, IFN gama, TGF beta positive cells, collagen, actin and isoprostane PGF2 alpha content in all treated groups compared to OVA animals (p<0.05), but the treatment with montelukast did not reduce the positive cells for IFN gama, compared to OVA (p>0.05). Elastic fiber content were reduced only in OVAMW, OVADW and OVAW groups compared to OVA animals (p<0.05). The association of 1400W and montelukast treatments potentiated the reduction of actin, elastic fibres and isoprostane PGF2 alpha contents and the number of IL4, IL5, TIMP1, IFN gama, TGF beta and iNOS positive cells compared to montelukast group (p<0.05). The treatments with 1400W and dexamethasone contributed to a greater reduction of elastic fibers, actin and isoprostane PGF2 alpha contents and the number of IL4, IL5, IFNgama and TIMP1 positive cells compared to dexamethasone group (p<0.05). Conclusions: Corticosteroid treatment associated to iNOS inhibition contributes to a greater reduction of extracellular matrix remodeling, decreases the oxidative stress, and also is efficient to attenuate the Th2 inflammatory response in distal lung parenchyma. On the other hand, montelukast treatment associated to iNOS inhibition showed a higher efficacy to reduce elastic fibres content, oxidative stress activation, actin content and IL4 and IL5 expression in distal lung parenchyma. These associations may represent future pharmacological tools for controlling distal pulmonary histopathological alterations induced by chronic inflammation
| Identifer | oai:union.ndltd.org:IBICT/oai:teses.usp.br:tde-25052012-173836 |
| Date | 09 March 2012 |
| Creators | Flavia Castro Ribas de Souza |
| Contributors | Iolanda de Fátima Lopes Calvo Tibério, Fernanda Magalhães Arantes Costa, Carla Máximo Prado |
| Publisher | Universidade de São Paulo, Ciências (Fisiopatologia Experimental), USP, BR |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da USP, instname:Universidade de São Paulo, instacron:USP |
| Rights | info:eu-repo/semantics/openAccess |
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