Y-27632 is associated with corticosteroid-potentiated control of pulmonary remodeling and inflammation in guinea pigs with chronic allergic inflammation.
BACKGROUND
Previously, we showed that treatment with the Rho-kinase inhibitor Y-27632 was able to control airway responsiveness, inflammation, remodeling, and oxidative stress in an animal model of asthma, suggesting that this drug is beneficial in asthma. However, studies evaluating the effects of these inhibitors in conjunction with corticosteroids on chronic pulmonary inflammation have not been conducted. Therefore, we evaluated the effects of treatment with the Rho-kinase inhibitor Y-27632, with or without concurrent dexamethasone treatment, on airway and lung tissue mechanical responses, inflammation, extracellular matrix remodeling, and oxidative stress in guinea pigs with chronic allergic inflammation.


METHODS
The guinea pigs were subjected to seven ovalbumin or saline inhalation exposures. Treatment with Y-27632 (1 mM) and dexamethasone (2 mg/kg) started at the fifth inhalation. Seventy-two hours after the seventh inhalation, the pulmonary mechanics were evaluated and exhaled nitric oxide (ENO) levels were determined. The lungs were removed and histological analysis was performed using morphometry.


RESULTS
The treatment of guinea pigs with the Rho-kinase inhibitor and dexamethasone (ORC group) decreased ENO, the maximal mechanical responses after antigen challenge, inflammation, extracellular matrix remodeling and oxidative stress in the lungs. This therapeutic strategy reduced the levels of collagen and IFN-γ in the airway walls, as well as IL-2, IFN-γ, 8-iso-PGF2α and NF-κB in the distal parenchyma, when compared to isolated treatment with corticosteroid or Rho-kinase inhibitor (P < 0.05) and reduced the number of TIMP-1-positive cells and eosinophils in the alveolar septa compared to corticosteroid-treated animals (P < 0.05). The combined treatment with the Rho-kinase inhibitor and the corticosteroid provided maximal control over the remodeling response and inflammation in the airways and parenchyma.


CONCLUSIONS
Rho-kinase inhibition, alone or in combination with corticosteroids, can be considered a future pharmacological tool for the control of asthma.
Department of Medicine, School of Medicine, University of São Paulo, São Paulo, Brazil. pangelipigati@gmail.com.
Patricia Angeli
PA
Pigati
Department of Medicine, School of Medicine, University of São Paulo, São Paulo, Brazil. renatofragar@yahoo.com.br.
Renato Fraga
RF
Righetti
Department of Medicine, School of Medicine, University of São Paulo, São Paulo, Brazil. samanthasz@hotmail.com.
Samantha Souza
SS
Possa
Department of Medicine, Laboratory of Experimental Therapeutics, LIM-20, School of Medicine, University of São Paulo, São Paulo, Brazil. beatrizmsaraiva@gmail.com.|University City of São Paulo (UNICID), São Paulo, Brazil. beatrizmsaraiva@gmail.com.|Institute of Medical Assistance to the State Public Servant of São Paulo (IAMSPE), São Paulo, Brazil. beatrizmsaraiva@gmail.com.
Beatriz Saraiva
BS
Romanholo
Department of Medicine, School of Medicine, University of São Paulo, São Paulo, Brazil. adrianapalmeira@hotmail.com.
Adriana Palmeira Dias
AP
Rodrigues
Department of Medicine, School of Medicine, University of São Paulo, São Paulo, Brazil. anelize.sartori@hotmail.com.
Anelize Sartori Alves
AS
dos Santos
Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Ilha do Fundão, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. deboraxisto@gmail.com.
Débora Gonçalves
DG
Xisto
Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Ilha do Fundão, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. maryantunes@gmail.com.
Mariana Alves
MA
Antunes
Department of Medicine, School of Medicine, University of São Paulo, São Paulo, Brazil. cmaximoprado@gmail.com.
Carla Máximo
CM
Prado
Department of Medicine, School of Medicine, University of São Paulo, São Paulo, Brazil. leick51@yahoo.com.br.
Edna Aparecida
EA
Leick
Department of Medicine, School of Medicine, University of São Paulo, São Paulo, Brazil. mmartins@usp.br.
Milton de Arruda
Mde A
Martins
Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Ilha do Fundão, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. prmrocco@gmail.com.
Patrícia Rieken Macedo
PR
Rocco
Department of Medicine, School of Medicine, University of São Paulo, São Paulo, Brazil. iocalvo@uol.com.br.
Iolanda de Fátima Lopes Calvo
Ide F
Tibério
D056151:Airway Remodeling / Q000187:drug effects*; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006168:Guinea Pigs; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology*
D000577:Amides; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D011725:Pyridines; C108830:Y 27632