Yoshizumi Takemura

Action of N-acylated ambroxol derivatives on secretion of chloride ions in human airway epithelia.

We report the effects of new N-acylated ambroxol derivatives (TEI-588a, TEI-588b, TEI-589a, TEI-589b, TEI-602a and TEI-602b: a, aromatic amine-acylated derivative; b, aliphatic amine-acylated derivative) induced from ambroxol (a mucolytic agent to treat human lung diseases) on Cl(-) secretion in human submucosal serous Calu-3 cells under a Na(+)/K(+)/2Cl(-) cotransporter-1 (NKCC1)-mediated hyper-secreting condition. TEI-589a, TEI-589b and TEI-602a diminished hyper-secretion of Cl(-) by diminishing the activity of NKCC1 without blockade of apical Cl(-) channel (TEI-589a>TEI-602a>TEI-589b), while any other tested compounds including ambroxol had no effects on Cl(-) secretion. These indicate that the inhibitory action of an aromatic amine-acylated derivative on Cl(-) secretion is stronger that that of an aliphatic amine-acylated derivative, and that 3-(2,5-dimethyl)furoyl group has a strong action in inhibition of Cl(-) secretion than cyclopropanoyl group. We here indicate that TEI-589a, TEI-589b and TEI-602a reduce hyper-secretion to an appropriate level in the airway, providing a possibility that the compound can be an effective drug in airway obstructive diseases including COPD by reducing the airway resistance under a hyper-secreting condition.

Procaterol-stimulated Increases in Ciliary Bend Amplitude and Ciliary Beat Frequency in Mouse Bronchioles

The beating cilia play a key role in lung mucociliary transport. The ciliary beating frequency (CBF) and ciliary bend amplitude (CBA) of isolated mouse bronchiolar ciliary cells were measured using a light microscope equipped with a high-speed camera (500 Hz). Procaterol (aβ 2-agonist) increased CBA and CBF in a dose dependent manner via cAMP. The time course of CBA increase is distinct from that of CBF increase: procaterol at 10 nM first increased CBA and then CBF. Moreover, 10 pM procaterol increased CBA, not CBF, whereas 10 nM procaterol increased both CBA and CBF. Concentration-response studies of procaterol demonstrated that the CBA curve was shifted to a lower concentration than the CBF curve, which suggests that CBA regulation is different from CBF regulation. Measurements of microbead movements on the bronchiole of lung slices revealed that 10 pM procaterol increased the rate of ciliary transport by 37% and 10 nM procaterol increased it by 70%. In conclusion, we have shown that increased CBA is of particular importance for increasing the bronchiolar ciliary transport rate, although CBF also plays a role in increasing it.

INFLUENCE OF DEPLETION OF ALVEOLAR MACROPHAGES ON APOPTOSIS IN CANDIDA-INDUCED ACUTE LUNG INJURY

Apoptosis plays an important role in acute lung injury (ALI), and alveolar macrophages (AMs) are known to secrete proinflammatory cytokines and promote alveolar inflammation. The authors have previously reported that AMs can be depleted by inhalation of 1 mM 2-chloroadenosine (2-CA). In this study, the authors evaluated the effect of AM depletion by 2-CA inhalation on apoptosis in Candida-induced ALI. The results of in situ terminal deoxynucleotidyl transferase–mediated dUTP biotin nick end-labeling (TUNEL) and immunohistochemical studies and measurement of cytokine levels and caspase 3 activities in lung homogenates indicated that the Fas-FasL system and apoptosis of alveolar epithelial cells are suppressed by depletion of AMs by 2-CA inhalation.