Resolution of leucocyte-mediated mucosal diseases. A novel in vivo paradigm for drug development

Removal of disease-driving inflammatory leucocytes is central to resolution of inflammation. The current pharmacological dogma teaches leucocyte elimination through apoptosis followed by phagocytosis. However, actual resolving roles of apoptotic-phagocytic processes have been difficult to demonstrate in the major diseases that are characterized by mucosal tissue inflammation. Many current in vivo observations rather demonstrate that leucocyte elimination occurs by transepithelial locomotion. Findings in diseased gut and bladder mucosae support this notion. Respiratory disease data are particularly compelling. Eosinophils and neutrophils abound in sputum and tracheal aspirates during treatment-induced recovery from severe asthma. Prolonged sputum neutrophilia, along with clinical improvement, follows upon smoking cessation in COPD. Eosinophils, neutrophils, lymphocytes, mast cells and dendritic cells also move in large numbers into the bronchial lumen at spontaneous inflammation resolution following allergen challenge in allergic rhinitis and asthma. A corresponding reduction of infiltrated cells in the bronchial mucosal tissue demonstrates efficiency of the transepithelial elimination pathway. Underscoring its operational role, drugs impeding transepithelial elimination of leucocytes aggravate mucosal/parenchymal inflammation. Hence, relying on lumen cell data alone can lead to paradoxical conclusions regarding anti-inflammatory drug efficacy. Conversely, drugs promoting non-injurious transepithelial elimination of leucocytes could resolve mucosal inflammatory diseases.