Modulation of the oscillatory mechanics of lung tissue and the oxidative stress response induced by arginase inhibition in a chronic allergic inflammation model

BMC Pulmonary Medicine

Iolanda FLC Tibério³  Edna A Leick⁴  Milton A Martins⁴  Marisa Dolhnikoff¹  Carla M Prado²  Luciana C Caperuto²  Patrícia Angeli Pigati⁴  Julie CP da Silva⁴  Claudia M Starling⁴  Rosana B Franco⁴  Nathalia Montouro Pinheiro⁴  Renato F Righetti⁴  Luciana RCRB Aristoteles³ 

[1] Department of Clinical Medicine and Pathology, School of Medicine, University of Sao Paulo, 01246-903 São Paulo, SP, Brazil;Department of Biological Sciences, Universidade Federal de São Paulo, Diadema, SP, Brazil;Faculty of Medicine, University of São Paulo, Av. Dr. Arnaldo, 455 - Sala 1210, 01246-903 São Paulo, SP, Brazil;Department of Clinical Medicine, School of Medicine, University of Sao Paulo, 01246-903 São Paulo, SP, Brazil

关键词: Oxidative stress;    nor-NOHA;    Guinea-pig;    Nitric oxide;    iNOS;    Arginase;    Lung parenchyma;   

Others  :  1109722
DOI  :  10.1186/1471-2466-13-52

 received in 2012-11-10, accepted in 2013-08-07,  发布年份 2013

【 摘 要 】

Background

The importance of the lung parenchyma in the pathophysiology of asthma has previously been demonstrated. Considering that nitric oxide synthases (NOS) and arginases compete for the same substrate, it is worthwhile to elucidate the effects of complex NOS-arginase dysfunction in the pathophysiology of asthma, particularly, related to distal lung tissue. We evaluated the effects of arginase and iNOS inhibition on distal lung mechanics and oxidative stress pathway activation in a model of chronic pulmonary allergic inflammation in guinea pigs.

Methods

Guinea pigs were exposed to repeated ovalbumin inhalations (twice a week for 4 weeks). The animals received 1400 W (an iNOS-specific inhibitor) for 4 days beginning at the last inhalation. Afterwards, the animals were anesthetized and exsanguinated; then, a slice of the distal lung was evaluated by oscillatory mechanics, and an arginase inhibitor (nor-NOHA) or vehicle was infused in a Krebs solution bath. Tissue resistance (Rt) and elastance (Et) were assessed before and after ovalbumin challenge (0.1%), and lung strips were submitted to histopathological studies.

Results

Ovalbumin-exposed animals presented an increase in the maximal Rt and Et responses after antigen challenge (p<0.001), in the number of iNOS positive cells (p<0.001) and in the expression of arginase 2, 8-isoprostane and NF-kB (p<0.001) in distal lung tissue. The 1400 W administration reduced all these responses (p<0.001) in alveolar septa. Ovalbumin-exposed animals that received nor-NOHA had a reduction of Rt, Et after antigen challenge, iNOS positive cells and 8-isoprostane and NF-kB (p<0.001) in lung tissue. The activity of arginase 2 was reduced only in the groups treated with nor-NOHA (p <0.05). There was a reduction of 8-isoprostane expression in OVA-NOR-W compared to OVA-NOR (p<0.001).

Conclusions

In this experimental model, increased arginase content and iNOS-positive cells were associated with the constriction of distal lung parenchyma. This functional alteration may be due to a high expression of 8-isoprostane, which had a procontractile effect. The mechanism involved in this response is likely related to the modulation of NF-kB expression, which contributed to the activation of the arginase and iNOS pathways. The association of both inhibitors potentiated the reduction of 8-isoprostane expression in this animal model.

【 授权许可】

   
2013 Aristoteles et al.; licensee BioMed Central Ltd.

【 图 表 】

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