Suppressive effects of nitric oxide-releasing prednisolone NCX-1015 on the allergic pleural eosinophil recruitment in rats.
BACKGROUND
The addition of a nitric oxide (NO)-releasing moiety to prednisolone was shown to enhance the anti-inflammatory activity of this glucocorticoid in some experimental conditions, but its effectiveness in the context of eosinophilic inflammation remains to be elucidated.


OBJECTIVE
This study compared the anti-inflammatory effect of prednisolone to a NO-releasing derivative of prednisolone, NCX-1015, using a model of allergen-evoked eosinophil recruitment in rats. The efficacy of a NO-donor compound, DETA-NONOate, was also assessed for comparison.


METHODS
Wistar rats were actively sensitized with Al(OH)(3) plus ovalbumin and 14 days later challenged with antigen intrapleurally. Treatments were performed locally 1 h before challenge. Cysteinyl-leucotrienes (Cys-LT) and eotaxin were measured by ELISA.


RESULTS
Antigen challenge induced an eosinophil infiltration at 12 h, maximal at 24 h. It also caused an increase in the levels of Cys-LTs in the pleural exudate and in the expression of 5-lipoxygenase (5-LO) in infiltrated leucocytes at 6 h, peaking at 12 h and persisting for at least 24 h. Treatment with equimolar doses of prednisolone and NCX-1015 inhibited the late eosinophil infiltration, although the dose required to produce maximal inhibition was about one-tenth that of prednisolone. Cys-LT generation and 5-LO expression were inhibited by NCX-1015 but not by prednisolone. Treatment with prednisolone combined with the NO-donor DETA-NONOate led to a greater inhibition of the eosinophilia and Cys-LT generation as compared with either drug alone. Administration of the steroid receptor antagonist RU 486, 1 h before prednisolone and NCX-1015, abolished the inhibitory effect of the former, under conditions where it only partially affected the latter.


CONCLUSIONS
Our findings indicate that NCX-1015 provided a greater anti-inflammatory effect than prednisolone on the allergic eosinophil recruitment in rats, suggesting that NO-releasing steroids can be considered as a promising therapeutic approach to allergic diseases.
Oliveira
M S S
MS
Laboratório de Inflamação, Instituto Oswaldo Cruz, FIOCRUZ, Manguinhos, Rio de Janeiro, Brazil.
de O Barreto
E
E
Zamuner
S
S
Pires
A L A
AL
Ferreira
T P T
TP
Cordeiro
R S B
RS
Lagente
V
V
Martins
M A
MA
Wallace
J L
JL
e Silva
P M R
PM
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D054413:Chemokine CCL11 / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004802:Eosinophilia / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004804:Eosinophils / Q000166:cytology; D006967:Hypersensitivity / Q000150:complications* / Q000188:drug therapy; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D015289:Leukotrienes / Q000378:metabolism; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology; D020030:Nitric Oxide Donors / Q000627:therapeutic use*; D009603:Nitroso Compounds / Q000627:therapeutic use; D010047:Ovalbumin / Q000276:immunology; D035422:Pleural Cavity / Q000378:metabolism / Q000473:pathology; D010998:Pleurisy / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D011239:Prednisolone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors
D000893:Anti-Inflammatory Agents; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D015289:Leukotrienes; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D011965:Receptors, Glucocorticoid; C112381:cysteinyl-leukotriene; C418962:prednisolone 21-((4'-nitrooxymethyl)benzoate); C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D015735:Mifepristone; D010047:Ovalbumin; D011239:Prednisolone; D001094:Arachidonate 5-Lipoxygenase; D003545:Cysteine