The soluble guanylyl cyclase activator BAY 60-2770 inhibits murine allergic airways inflammation and human eosinophil chemotaxis.
Activators of soluble guanylyl cyclase (sGC) act preferentially in conditions of enzyme oxidation or haem group removal. This study was designed to investigate the effects of the sGC activator BAY 60-2770 in murine airways inflammation and human eosinophil chemotaxis.



C57Bl/6 mice treated or not with BAY 60-2770 (1 mg/kg/day, 14 days) were intranasally challenged with ovalbumin (OVA). At 48 h, bronchoalveolar lavage fluid (BALF) was performed, and circulating blood, bone marrow and lungs were obtained. Human eosinophils purified from peripheral blood were used to evaluate the cell chemotaxis.



OVA-challenge promoted marked increases in eosinophil number in BAL, lung tissue, circulating blood and bone marrow, all of which were significantly reduced by BAY 60-2770. The IL-4 and IL-5 levels in BALF were significantly reduced by BAY 60-2770. Increased protein expression of iNOS, along with decreases of expression of sGC (α1 and β1 subunits) and cGMP levels were detected in lung tissue of OVA-challenged mice. BAY 60-2770 fully restored to baseline the iNOS and sGC subunit expressions, and cGMP levels. In human isolated eosinophils, BAY 60-2770 (1-5 μM) had no effects on the cGMP levels and eotaxin-induced chemotaxis; however, prior incubation with ODQ (10 μM) markedly elevated the BAY 60-2770-induced cyclic GMP production, further inhibiting the eosinophil chemotaxis.



BAY 60-2770 reduces airway eosinophilic inflammation and rescue the sGC levels. In human eosinophils under oxidized conditions, BAY 60-2770 elevates the cGMP levels causing cell chemotaxis inhibition. BAY 60-2770 may reveal a novel therapeutic target for asthma treatment.
Department of Pharmacology, Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, 13084-971, SP, Brazil.
Lineu
L
Baldissera
Department of Pharmacology, Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, 13084-971, SP, Brazil.
Dalize M
DM
Squebola-Cola
Department of Pharmacology, Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, 13084-971, SP, Brazil.
Marina C
MC
Calixto
Department of Pharmacology, Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, 13084-971, SP, Brazil.
Ana P
AP
Lima-Barbosa
Department of Pharmacology, Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, 13084-971, SP, Brazil.
André L
AL
Rennó
Department of Pharmacology, Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, 13084-971, SP, Brazil.
Gabriel F
GF
Anhê
Department of Pharmacology, Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, 13084-971, SP, Brazil.
Antonio
A
Condino-Neto
Department of Pharmacology, Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, 13084-971, SP, Brazil.
Gilberto
G
De Nucci
Department of Pharmacology, Faculty of Medical Science, State University of Campinas (UNICAMP), Campinas, 13084-971, SP, Brazil. Electronic address: antunes@fcm.unicamp.br.
Edson
E
Antunes
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy / Q000276:immunology; D001565:Benzoates / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002633:Chemotaxis / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D000071756:Soluble Guanylyl Cyclase / Q000187:drug effects* / Q000378:metabolism
C528797:4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid; D018927:Anti-Asthmatic Agents; D001565:Benzoates; D001713:Biphenyl Compounds; D006845:Hydrocarbons, Fluorinated; D010047:Ovalbumin; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP
Bone marrow; Cyclic GMP; Eotaxin; Inducible nitric oxide synthase; Th2 cytokines