Tracheal microenvironment, ANP metabolism and airway tone

Asthma is a chronic inflammatory disease, characterized by reversible airflow obstruction and airway hyperresponsiveness. There has been a sharp increase in the prevalence, morbidity, mortality and economic burden associated with this disorder over the last several decades, which triggers the development of various antiasthmatic agents [1]. Maintenance of airway tone is the key in asthma therapy. This role is currently performed by bronchodilators. b2adrenoceptor (b2-AR) agonists are gold standard asthma therapeutics, resulting in bronchodilation via the b2-ARcyclic adenosine monophosphate (cAMP) signaling. However, chronic application of b2-AR agonists is associated with desensitization of downstream signaling, worsening of airway hyperreactivity, and increased incidence of asthma-related clinical events [2]. Therefore, researchers are attempting to identify novel non-b-agonist bronchodilators, in which natriuretic peptides are attractive candidates. The natriuretic peptides are hormones with important roles in water and salt homeostasis. Heart has long been thought as the only site of natriuretic peptide production. However, recent studies show that lung is another source, especially for atrial natriuretic peptide (ANP). For example, airway epithelium and smooth muscle cells have been shown to synthesize ANP, exerting only paracrine effects, and its expression can be enhanced by hypoxia [3]. Tracheal chondrocytes express both neutral endopeptidase (NEP) and natriuretic peptide receptor-C (NPR-C) [4]. Due to its unique downstream signaling and effective regulatory mechanism, ANP has been considered to be a promising candidate in novel bronchodilator development. Like many peptide hormones, ANP is secreted as a propeptide and then converted into its active form by a specific transmembrane protease, herein Corin [5]. ANP is a potent relaxant of both intrinsic and extrinsic stimuli-induced airway contraction. Through its receptor, ANP leads to cyclic guanosine monophosphate (cGMP) accumulation in the airway smooth muscles and results in bronchodilation [3]. As ANP has potent physiological effect, its activity is regulated tightly and will be diminished rapidly when it enters the circulation. Two main mechanisms contribute to this process: the clearance receptor natriuretic peptide receptor-C (NPR-C) mediated ANP endocytosis, and the extracellular peptidase (mainly neutral endopeptidase, NEP) mediated ANP degradation [6]. All these properties make ANP an ideal candidate of bronchodilators and prompt researchers to explore its efficacy in clinical studies [7]. Inhalation is widely accepted as the optimal route of medication administration for asthma. Benefits of pulmonary drug delivery include increased local therapeutic Qipu Wang, Kuikui Jiang and Wanying Zhang contributed equally to this work.