N-cadherin antagonism is bronchoprotective in severe asthma models
Severe asthma induces substantial mortality and chronic disability due to intractable airway obstruction, which may become resistant to currently available therapies including corticosteroids and b-adrenergic agonist bronchodilators. A key effector of these changes is exaggerated airway smooth muscle (ASM) cell contraction to spasmogens. Unfortunately, no drugs in clinical use effectively prevent ASM hyperresponsiveness in asthma across all severities. Here we show that N-cadherin, a plasma membrane associated cell-cell adhesion protein upregulated in ASM cells derived from patients with severe asthma, is required for the development of airway obstruction induced by allergic airway inflammation in mice. Pharmacological inhibition of N-cadherin by ADH-1 reduced airway hyperresponsiveness independent of allergic inflammation. ADH-1 prevented bronchoconstriction and actively promoted bronchodilation of airways ex vivo. In human ASM cells, ADH-1 inhibited agonist-induced contraction by disrupting N-cadherin-d-catenin interactions, which decreased intracellular actin remodeling. These data provide evidence for an intercellular communication pathway mediating ASM contraction and identify N-cadherin as a potential therapeutic target for inhibiting bronchoconstriction in asthma. Overall design: To determine the importance of N-cadherin for ASM contraction and discovered that N-cadherin is essential for the development of AHR in allergen-challenged mice and contractile force development in human ASM cells through its effects on collective force transmission and actin remodeling.