Rho kinase as a therapeutic target in the treatment of asthma and chronic obstructive pulmonary disease.

Asthma is a complex inflammatory disease of the airways involving reversible bronchoconstriction. Chronic obstructive pulmonary disease is typified by inflammation and airflow limitation that has an irreversible component. There is now substantial evidence that Rho kinase is involved in many of the pathways that contribute to the pathologies associated with these respiratory diseases including bronchoconstriction, airway inflammation, airway remodelling, neuromodulation and exacerbations due to respiratory tract viral infection.

The impact of respiratory syncytial virus infection on endothelin receptor function and release in sheep bronchial explants.

We investigated the impact of respiratory syncytial virus (RSV) infection, an important asthma precipitant, on endothelin receptor function and release in sheep bronchial explants. RSV infection was confirmed using polymerase chain reaction and immunohistochemistry. Since sheep airway smooth muscle contains only endothelin-A receptors, sarafotoxin (Stx) S6c did not cause airway contraction.

A rho kinase inhibitor, Y-27632 inhibits pulmonary eosinophilia, bronchoconstriction and airways hyperresponsiveness in allergic mice.

Asthma is a complex inflammatory disorder involving obstruction, constriction, oedema, remodelling and hyperresponsiveness of the airways. These effects are induced by a raft of mediators, many of which exert their actions by stimulating specific G-protein-coupled receptors linked to a signal transduction pathway involving the monomeric GTPase; rho, and a downstream effector; rho kinase. The aim of this study was to determine whether administration of a selective inhibitor of rho kinase, Y-27632, attenuates airway inflammation, bronchoconstriction and hyperresponsiveness in a murine model of acute allergic inflammation.

A novel role for tachykinin neurokinin-3 receptors in regulation of human bronchial Ganglia neurons.

The neuropeptide tachykinins and their receptors have been implicated in the pathogenesis of lung disease, although the role of the tachykinin neurokinin-3 receptor has not been elucidated. Using confocal microscopy, we identified tachykinin neurokinin-3 receptors on human bronchial parasympathetic ganglion neurons. Electrophysiologic recordings demonstrated that activation of sensory nerve fibers, either by antidromic stimulation or capsaicin, depolarized these neurons.

Altered expression and in vivo lung function of protease-activated receptors during influenza A virus infection in mice.

Protease-activated receptors (PARs) are widely distributed in human airways, and recent evidence indicates a role for PARs in the pathophysiology of inflammatory airway disease. To further investigate the role of PARs in airway disease, we determined the expression and function of PARs in a murine model of respiratory tract viral infection. PAR-1, PAR-2, PAR-3, and PAR-4 mRNA and protein were expressed in murine airways, and confocal microscopy revealed colocalization of PAR-2 and cyclooxygenase (COX)-2 immunostaining in basal tracheal epithelial cells.

The single mediator approach to asthma therapy: is it so unreasonable?

Asthma involves a complex syndrome of respiratory pathologies that ultimately results in bronchial obstruction and reduced lung ventilatory capacity. Inflammation of the respiratory tract underlies this disease and can be linked to the production and release of multiple mediators of bronchoconstriction and airway wall restructuring and obstruction. Disease triggers vary between patients and include allergens, exercise, inhaled irritants and virus infections.

An endothelin receptor antagonist, SB-217242, inhibits airway hyperresponsiveness in allergic mice.

Within the airways, endothelin-1 (ET-1) can exert a range of prominent effects, including airway smooth muscle contraction, bronchial obstruction, airway wall edema, and airway remodeling. ET-1 also possesses proinflammatory properties and contributes to the late-phase response in allergic airways. However, there is no direct evidence for the contribution of endogenous ET-1 to airway hyperresponsiveness in allergic airways.

Role of endothelin-converting enzyme, chymase and neutral endopeptidase in the processing of big ET-1, ET-1(1-21) and ET-1(1-31) in the trachea of allergic mice.

The present study examined the roles of endothelin-converting enzyme (ECE), neutral endopeptidase (NEP) and mast cell chymase as processors of the endothelin (ET) analogues ET-1(1-21), ET-1(1-31) and big ET-1 in the trachea of allergic mice. Male CBA/CaH mice were sensitized with ovalbumin (10 microg) delivered intraperitoneal on days 1 and 14, and exposed to aerosolized ovalbumin on days 14, 25, 26 and 27 (OVA mice). Mice were killed and the trachea excised for histological analysis and contraction studies on day 28.

Enhanced ET(A) receptor-mediated contractile function is associated with reduced ET(A) receptor density in sheep bronchial explants maintained in culture.

We are interested in developing an airway explant culture system using sheep bronchi in which to establish respiratory viral infection and from which tissue can be used for functional, biochemical and immunohistochemical studies involving the endothelins (ETs). Freshly harvested sheep bronchial airway smooth muscle contains a homogeneous population of the ET(A) receptor. However, the potency of ET-1 and maximum contractile response of sheep bronchial explants to ET-1 increased with time in culture, despite these parameters remaining constant for carbachol in explants maintained for up to 48 h.

Impact of parainfluenza-3 virus infection on endothelin receptor density and function in guinea pig airways.

We examined the impact of parainfluenza-3 (P-3) respiratory tract viral infection on the density and function of endothelin (ET) receptor subtypes (ET(A) and ET(B)) in guinea pig tracheal smooth muscle. Total specific binding of [(125)I]ET-1 and the relative proportions of ET(A) and ET(B) binding sites for this ligand were assessed at day 0 (control) and at 2, 4, 8 and 16 days post-inoculation. At day 0, the proportions of ET(A) and ET(B) binding sites were 30% and 70% respectively.

Airway nerves: detection and visualisation.

The importance of understanding the roles of nerves in regulating lung function cannot be overestimated if we are to successfully address the therapeutic management of respiratory diseases such as asthma and chronic obstructive pulmonary disease. Critical to this understanding is a more complete appreciation of airway innervation patterns, densities and functions. Accordingly, there is increasing demand for cost-effective techniques that enable the detection and visualisation of airway nerves.