Effects of TRPV4 channel blocker on airway inflammation and airway defense reflexes in experimentally induced model of allergic asthma.

The transient receptor potential (TRP) channels regulate physiological and pathological processes. Changes in their activity and sensitivity may be involved in the pathophysiology of asthma. The present study investigates the effect of an inhaled TRPV4 channel blocker HC-067047 in an experimental guinea pig model of ovalbumin-induced allergic asthma. We monitored the effect of 50 nM, 100 nM, and 150 nM HC-067047 concentrations on airway defense reflexes in vivo and tracheal smooth muscle contractility in vitro. The anti-inflammatory action of HC-067047 was investigated by analysis of chronic inflammation markers from lung homogenates. The results suggest that HC-067047 can suppress airway defense reflexes in vivo and acetylcholine-induced contractility in vitro. Immunological analysis revealed that TRPV4 channel blockade leads to a decrease in the levels of inflammatory cytokines. An effect on airway defence reflexes and airway inflammation was observed using tested concentrations (50 mM, 100 mM, 150 mM) of HC-067047. The effects of HC-067047 on both airway defense reflexes and inflammation underline the role of TRPV4 channels in asthma and uncover therapeutic targets for developing innovative drugs in asthma therapy.

The anti-asthmatic potential of Rho-kinase inhibitor hydroxyfasudil in the model of experimentally induced allergic airway inflammation.

OBJECTIVE: This experimental study evaluated the anti-asthmatic potential of the Rho-kinase inhibitor hydroxyfasudil in the settings of allergen-induced allergen-induced experimental asthma. METHODS: Chronic allergic airway inflammation was caused by 28 days-sensitisation of guinea pigs with ovalbumin (OVA). Hydroxyfasudil was administered intraperitoneally in two doses for the last two weeks (1 mg/kg b.w.; 10 mg/kg b.w.). The degree of allergic inflammation was determined based on concentrations of inflammatory Th2 cytokines (IL-4, IL-13), Th1 cytokines (TNF-α and IFN-γ) in the lung homogenate and leukocyte count in the bronchoalveolar lavage fluid (BALF). The markers of remodelling and fibrosis, the growth factors (TGF-ß1, EGF), EGF receptor, collagen type III and V were estimated in lung homogenate. The changes in specific airway resistance (sRaw) were used as an in vivo bronchial hyperreactivity parameter. RESULTS: Hydroxyfasudil administration at both doses significantly reduced sRaw after a week of therapy. We observed a decline of IL-13, TNF-α and IFN-γ in lung homogenate and a lower presence of lymphocytes in BALF after 14 days of hydroxyfasudil administration at both tested doses. Hydroxyfasudil 14 days-treatment at both doses effectively reduced the concentrations of TGF-ß1, EGF receptors, collagen type III and V in BALF and modulated EGF levels. CONCLUSIONS: These findings indicate that RhoA/Rho-kinase is involved in the pathophysiology of allergic airway inflammation and suggest that Rho-kinase inhibitor hydroxyfasudil has therapeutic potential for asthma management.