Y-27632 is associated with corticosteroid-potentiated control of pulmonary remodeling and inflammation in guinea pigs with chronic allergic inflammation

Abstract

BackgroundPreviously, 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.MethodsThe 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.ResultsThe 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.ConclusionsRho-kinase inhibition, alone or in combination with corticosteroids, can be considered a future pharmacological tool for the control of asthma.

Anti-inflammatory activity of Barleria lupulina: Identification of active compounds that activate the Nrf2 cell defense pathway, organize cortical actin, reduce stress fibers, and improve cell junctions in microvascular endothelial cells

“…Therefore, one possibility is that activation of the Nrf2 pathway by HAE-BL reduces ROS and thereby reduces RhoA activity, ultimately resulting in reduced Rho kinase activity and reduced stress fibers. Interestingly, the Rho kinase inhibitor Y-27632 has been shown to reduce stress fibers and improve microvascular barrier function in vitro (Hoang et al, 2004; van Nieuw Amerongen et al, 2000) and reduce inflammation in vivo (Chen et al, 2011; Henry et al, 2005; Pigati et al, 2015; Schaafsma et al, 2008; Tasaka et al, 2005). Another likely possibility is that by reducing ROS through Nrf2, HAE-BL prevents ROS-mediated inhibition of tyrosine phosphatases at adherens junctions (Mittal et al, 2014; Ostman et al, 2011).…”

O efeito do anti-IL-17 na inflama~ção, remodelamento e estresse oxidativo em modelo experimental de inflamação pulmonar alérgica crônica exacerbado por LPS

“…As quimiocinas são de baixo peso molecular (8)(9)(10)(11)(12) com, aproximadamente 70 a 80 aminoácidos. Existem mais de 50 quimiocinas, sendo que todas têm estruturas terciárias similares, que consistem num terminal amina (que atua como domínio de sinalização), seguido de uma longa alça (que contém importantes determinantes de ligação), três folhas β e uma hélice C-terminal.…”

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Efeitos do inibidor específico para serinoprotease rBmTI-A em modelo experimental de inflamação pulmonar alérgica crônica em camundongos Balb/c

“…O paradigma Th1/Th2 foi mantido até alguns anos atrás quando foi identificado um terceiro subconjunto de células efetoras T CD4+ nomeadas Th17, devido à produção de IL-17 (Oppmann et al, 2000;Cua et al, 2003). (Covar, 2007;O'Byrne et al, 2009 (Tulic e Hamid, 2003;Mauad et al, 2004;Prado et al, 2006;Pigati et al, 2015).…”

“…Em modelos de doenças respiratórias, alguns inibidores de proteases foram testados e seus potenciais efeitos anti-inflamatórios nas vias aéreas foram demonstrados (Chen et al, 2006;Lin et al, 2014;Pigati et al, 2015;Martins-Olivera et al, 2016;Almeida-Reis et al, 2017;Theodoro-Junior et al, 2017 (Tanaka et al, 1999;Sasaki et al, 2004 (Lourenco et al, 2017).…”