Modulation of the oscillatory mechanics of lung tissue and the oxidative stress response induced by arginase inhibition in a chronic allergic inflammation model.
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.
Department of Clinical Medicine, School of Medicine, University of Sao Paulo, 01246-903 São Paulo, SP, Brazil. laristoteles@hotmail.com
Luciana R C R B
LR
Aristoteles
Renato F
RF
Righetti
Nathalia Montouro
NM
Pinheiro
Rosana B
RB
Franco
Claudia M
CM
Starling
Julie C P
JC
da Silva
Patrícia Angeli
PA
Pigati
Luciana C
LC
Caperuto
Carla M
CM
Prado
Marisa
M
Dolhnikoff
Milton A
MA
Martins
Edna A
EA
Leick
Iolanda F L C
IF
Tibério
D000280:Administration, Inhalation; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002908:Chronic Disease; D015237:Dinoprost / Q000378:metabolism; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006967:Hypersensitivity / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D010047:Ovalbumin / Q000009:adverse effects; D018384:Oxidative Stress / Q000502:physiology*; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D015656:Respiratory Mechanics / Q000502:physiology*
D016328:NF-kappa B; D010047:Ovalbumin; D015237:Dinoprost; D052247:Nitric Oxide Synthase Type II; D001119:Arginase