Rho/Rho-kinase signalling in respiratory systems

AT Demiryurek. University of Gaziantep, Faculty of Medicine, Department of Medical Pharmacology, 27310, Turkey

Rho/Rho-kinase pathway play an important role in the regulation of baseline tone and vasoconstrictor responses in the pulmonary vascular bed. Rho/Rho-kinase pathway has been shown to play an important role in the vasoconstriction and vascular remodeling seen in pulmonary disorders. Rho-kinase inhibition causes pulmonary vasodilation. Rho-kinase inhibitors have been shown to reduce pulmonary hypertension in many animal models, and in humans, Rho-kinase inhibition with fasudil shows modest, immediate reductions in pulmonary vascular resistance in patients with severe pulmonary hypertension. The expression of Rho-kinase has been shown to increase after chronic hypoxia. Rho-kinase inhibition have been reported to inhibit sustained pulmonary vasoconstriction in response to acute and chronic hypoxia.

Rho-kinase may play an important role in the pathogenesis of acute lung injury. Pretreatment with Rho-kinase inhibitors attenuates lung edema, neutrophil migration, and prevents lung injury. Decreased RhoA activity or inhibition of Rho kinase stimulate cell migration. Moreover, Rho-kinase inhibition induces vascular smooth muscle and airway epithelial cell apoptosis.

Rho/Rho-kinase pathway modulate diverse cellular responses in airway smooth muscle cells including the regulation of calcium influx and cell proliferation. Rho-kinase inhibitors have been shown to act as a bronchodilator and vasodilator through relaxation of smooth muscle. Rho/Rho-kinase is involved in the pathophysiology of asthma. Rho/Rho-kinase pathway are activated by a variety of stimuli associated with the development of airway hyperresponsiveness. Rho-kinase inhibitors have therapeutic potential for prohibiting airflow limitation, airway hyperresponsiveness, beta-adrenergic desensitization, eosinophilic airway inflammation and airway remodeling. Rho-kinase is up-regulated by inflammatory stimuli and that Rho-kinase inhibition increases endothelial nitric oxide synthase expression and inhibits inflammatory cell migration. Rho-kinase are also important in regulating allergic airway responses. However, the role of Rho/Rho-kinase in the respiratory distress syndrome remains to be determined.

In conclusion, Rho/Rho-kinase signaling plays an important role in pulmonary circulation and airways, and Rho-kinase inhibitors have many potential therapeutic applications in respiratory diseases.