Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation

Abstract

Several studies have demonstrated the importance of Rho-kinase in the modulation of smooth muscle contraction, airway hyperresponsiveness, and inflammation. However, the effects of repeated treatment with a specific inhibitor of this pathway have not been previously investigated. We evaluated the effects of repeated treatment with Y-27632, a highly selective Rho-kinase inhibitor, on airway hyperresponsiveness, oxidative stress activation, extracellular matrix remodeling, eosinophilic inflammation, and cytokine expression in an animal model of chronic airway inflammation. Guinea pigs were subjected to seven ovalbumin or saline exposures. The treatment with Y-27632 (1 mM) started at the fifth inhalation. Seventy-two hours after the seventh inhalation, the animals' pulmonary mechanics were evaluated, and exhaled nitric oxide (E(NO)) was collected. The lungs were removed, and histological analysis was performed using morphometry. Treatment with Y-27632 in sensitized animals reduced E(NO) concentrations, maximal responses of resistance, elastance of the respiratory system, eosinophil counts, collagen and elastic fiber contents, the numbers of cells positive for IL-2, IL-4, IL-5, IL-13, inducible nitric oxide synthase, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, transforming growth factor-β, NF-κB, IFN-γ, and 8-iso-prostaglandin F2α contents compared with the untreated group (P < 0.05). We observed positive correlations among the functional responses and inflammation, remodeling, and oxidative stress pathway activation markers evaluated. In conclusion, Rho-kinase pathway activation contributes to the potentiation of the hyperresponsiveness, inflammation, the extracellular matrix remodeling process, and oxidative stress activation. These results suggest that Rho-kinase inhibitors represent potential pharmacological tools for the control of asthma.

Coming to terms with tissue engineering and regenerative medicine in the lung

“…In turn, these ECM components are themselves modulated by diseases such as asthma, COPD, and pulmonary fibrosis (i.e., many of the same diseases that are indications for lung transplantation). Factors such as altered oxygen levels (2,16,69,110,120,157,210,221,226), environmental influences (23,211), and inflammatory and profibrotic mediators (3,4,9,30,154,209,229) can modulate the expression of collagens, fibronectin, elastin. and other important lung ECM components.…”

“…Furthermore, dynamic compressive strain of the epithelial layer that is associated with bronchoconstriction of a circular airway can promote epithelial properties such as solute transport, viral gene delivery (199), and secretion of ECM-modifying proteins such as tissue factor (147). The mechanisms involved in mechanotransduction are still under investigation, but they could include Rho kinase (197), among other factors, which is in turn influenced by the ECM (154).…”

Efeito do inibidor de proteinase de origem vegetal EcTI, sobre a lesão pulmonar induzida pela elastase em camundongos C57BI6

“…Esta alteração funcional se associou ao controle da resposta de inflamação, remodelamento e estresse oxidativo (Angeli et al, 2008, Starling et al, 2009, Prado et al, 2010. Este efeito de atenuação da resposta constritora pelo bloqueio da iNOS parece depender também da modulação da Rhoquinase (Possa et al, 2012) Além disso, os resultados de Prado et al, (2011) também demonstraram que a inibição de iNOS é capaz de reduzir a expressão celular de MMP-9, TIMP-1 e TGF-beta nas paredes vasculares dos brônquios dos animais sensibilizados por ovalvumina. O remodelamento da matriz extracelular nas vias aéreas pode estar explicado em decorrência deste mecanismo de ação, já que todos estes mediadores atuam na produção de colágeno e fibras elásticas.…”

Efeitos dos inibidores de NF Kappa-B e Rho Quinase em um modelo de asma animal: comparação com o tratamento com corticosteroides

“…Vários estudos de nosso grupo de pesquisa já demonstraram associação entre inflamação pulmonar alérgica crônica e aumento de óxido nítrico exalado e da expressão de iNOS (tanto em vais aéreas quanto parênquima pulmonar) no modelo de asma experimental em cobaias (Angeli et al, 2008;Nakashima et al, 2008;Ruiz-Schütz et al, 2008;Starling et al, 2009;Prado et al, 2011;Marques et al, 2012;Possa et al, 2012). Embora o NO por si mesmo não seja inerentemente citotóxico, ele pode agir como um agente citotóxico ou citoprotetor, dependendo das condições intracelulares.…”

“…Foi recentemente demonstrado que a inibição da Rho-quinase específica pelo Y-27632 está associada com a redução no recrutamento de eosinófilos nas vias aéreas e no parênquima pulmonar em cobaias com inflamação alérgica pulmonar crônica, além de contribuir para a redução do processo de remodelamento, demonstrando menor conteúdo de colágeno e fibras elásticas nas paredes das vias aéreas e tecido pulmonar (Possa et al, 2012;e Righetti et al, 2014). …”