TSLP impairs mucociliary transport by inhibiting JAK signaling in both central and peripheral airways

Mucociliary transport (MCT) is the dominant mechanical host defense system in human airways. Although the importance of the peripheral airway in the pathophysiology of bronchial asthma has recently attracted attention, the characteristics of MCT in the peripheral airway during asthma remain unclear. This study aimed to investigate MCT velocity in the central and peripheral airways and the effects of thymic stromal lymphopoietin (TSLP) on MCT. Central and peripheral airways were isolated from freshly obtained porcine airways immediately after slaughter. The airway specimens were mounted in a custom-built fluorescence microscopy-based measurement system. MCT velocity and ciliary beat frequency (CBF) were measured under the following conditions: without stimulation, in the presence of a low concentration of acetylcholine (ACh), and after stimulation TSLP, which reflects the pathophysiological condition of bronchial asthma. MCT velocity in the peripheral airways was slower than that in the central airways at less than one tenth (median: 75.40 μm/sec vs. 2.63 μm/sec). Under physiologically low ACh concentrations, MCT velocity was increased in the peripheral airway but not in the central airway. TSLP addition partially inhibited MCT velocity in both the central and peripheral airways by approximately two-thirds to one-half. TSLP also partially inhibited the CBF in both the central and peripheral airways from approximately two-thirds to one-third. Furthermore, TSLP receptor (TSLPR) expression was confirmed in airway tissues by immunohistochemical staining. The inhibitory effects of TSLP on MCT velocity were completely abolished by pre-incubation with a Janus kinase (JAK) inhibitor. In conclusion, TSLP has the potential to reduce MCT velocity, especially in the peripheral airways, by inhibiting TSLPR signaling pathways, resulting in impaired CBF. The characteristics of MCT differ between the central and peripheral airways. Importantly, TSLP-induced MCT impairment may aggravate mucus plug formation in the peripheral airways in patients with bronchial asthma.