Concomitant administration of nitric oxide and glucocorticoids improves protection against bronchoconstriction in a murine model of asthma.
Glucocorticoids (GC) remain the first choice of treatment in asthma, but GC therapy is not always effective and is associated with side effects. In a porcine study in our laboratory, simultaneous administration of GC and nitric oxide (NO) attenuated the endotoxin-induced inflammatory response and made GC treatment more effective than inhaled NO or steroids alone. In the present study, we aimed to further investigate the interactions between NO and GC treatment in two murine models of asthma. Inflammation was induced by endotoxin, ovalbumin, or a combination of both. With an animal ventilator and a forced oscillation method (FlexiVent), lung mechanics and airway reactivity to methacholine in response to various treatments were assessed. We also describe histology and glucocorticoid receptor (GR) protein expression in response to inhaled NO treatment [40 ppm NO gas or NO donors sodium nitroprusside (SNP) or diethylamine NONOate (DEA/NO)]. SNP and GC provided protection against bronchoconstriction to a similar degree in the model of severe asthma. When GC-treated mice were given SNP, maximum airway reactivity was further reduced. Similar effects were seen after DEA/NO delivery to GC-treated animals. Using 1-H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ), a soluble guanylate cyclase inhibitor, we found this effect of NO donors to be mediated through a cGMP-independent mechanism. In the severe model, prolonged NO treatment restored or even increased the nuclear levels of GR. In conclusion, in our murine model of severe asthma GC treatment provided protection to only a limited degree against bronchoconstriction, while concomitant treatment with a NO donor was markedly more potent than the use of either NO or GC alone.
Dept. of Medical Sciences, Clinical Physiology, University Hospital, SE-751 85 Uppsala, Sweden. sofia.jonasson@medsci.uu.se
Sofia
S
Jonasson
Göran
G
Hedenstierna
Josephine
J
Hjoberg
D000280:Administration, Inhalation; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage*; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects*; D016085:Bronchoconstrictor Agents; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006834:Hydrazines / Q000008:administration & dosage; D006854:Hydrocortisone / Q000008:administration & dosage / Q000031:analogs & derivatives; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides; D016210:Methacholine Chloride; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000008:administration & dosage*; D020030:Nitric Oxide Donors / Q000008:administration & dosage*; D009599:Nitroprusside / Q000008:administration & dosage; D010047:Ovalbumin; D010069:Oxadiazoles / Q000494:pharmacology; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011810:Quinoxalines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000378:metabolism; D012121:Respiration, Artificial; D015656:Respiratory Mechanics / Q000187:drug effects; D000071756:Soluble Guanylyl Cyclase
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D018927:Anti-Asthmatic Agents; D016085:Bronchoconstrictor Agents; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D006834:Hydrazines; D008070:Lipopolysaccharides; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D011810:Quinoxalines; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; C440499:lipopolysaccharide, Escherichia coli O111 B4; D016210:Methacholine Chloride; D009599:Nitroprusside; D009569:Nitric Oxide; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D010047:Ovalbumin; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; C007133:hydrocortisone hemisuccinate; D006854:Hydrocortisone