PMID- 30716315
OWN - NLM
STAT- MEDLINE
DCOM- 20190619
LR  - 20190619
IS  - 1879-0712 (Electronic)
IS  - 0014-2999 (Linking)
VI  - 849
DP  - 2019 Apr 15
TI  - TAS-203, an oral phosphodiesterase 4 inhibitor, exerts anti-inflammatory 
      activities in a rat airway inflammation model.
PG  - 22-29
LID - S0014-2999(19)30040-8 [pii]
LID - 10.1016/j.ejphar.2019.01.068 [doi]
AB  - Cyclic adenosine monophosphate (cAMP) is a key intracellular second messenger, 
      which is degraded by phosphodiesterase 4 (PDE4). PDE4 suppresses cAMP levels, and 
      thus stimulates the activity of inflammatory cells. Therefore, PDE4 has been 
      considered as a therapeutic target for airway inflammatory diseases including 
      asthma and chronic obstructive pulmonary disease (COPD). Roflumilast, an approved 
      PDE4 inhibitor, has been shown to have clinical benefits in COPD. However, 
      central nervous system-related side effects including nausea and vomiting have 
      limited the therapeutic index of roflumilast. Moreover, although airway mucus 
      hypersecretion is the characteristic feature, which is associated with the 
      severity and prognosis, the inhibitory effect of roflumilast on sputum production 
      is limited to a minority of patients. In this study, we demonstrate the 
      inhibitory effects of TAS-203, which is an orally active PDE4 inhibitor 
      associated with a lowered emetic effect, on airway inflammation and mucus 
      hypersecretion. A cell-based assay showed TAS-203 treatment suppressed epidermal 
      growth factor (EGF)-induced mucin MUC5AC expression. TAS-203 also suppressed 
      monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-5 and IL-13 
      production in a Sephadex-induced airway inflammation model, and the number of 
      infiltrating cells in bronchoalveolar lavage (BAL) fluid. TAS-203 caused marked 
      reduction of goblet cell hyperplasia in a histopathological analysis of airway 
      epithelium. Furthermore, TAS-203 suppressed 5-hydroxytryptamine (5-HT)-induced 
      airway hyperresponsiveness (AHR). In addition, we preliminarily confirmed TAS-203 
      prevents airway MUC5AC production in BAL fluid, and shows lower specific airway 
      resistance (sRaw) in a cigarette smoke-induced COPD-like model. Our data suggest 
      that TAS-203 might be useful in the treatment of airway inflammatory disease.
CI  - Copyright (c) 2019 Elsevier B.V. All rights reserved.
FAU - Demizu, Shunsuke
AU  - Demizu S
AD  - Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., 3 
      Okubo, Tsukuba, Ibaraki 300-2611, Japan; Laboratory of Cell Biology and 
      Biochemistry, Tokyo Metropolitan University, Tokyo 192-0397, Japan. Electronic 
      address: s-demizu@taiho.co.jp.
FAU - Asaka, Naomasa
AU  - Asaka N
AD  - Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., 3 
      Okubo, Tsukuba, Ibaraki 300-2611, Japan.
FAU - Kawahara, Hiroyuki
AU  - Kawahara H
AD  - Laboratory of Cell Biology and Biochemistry, Tokyo Metropolitan University, Tokyo 
      192-0397, Japan.
FAU - Sasaki, Eiji
AU  - Sasaki E
AD  - Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., 3 
      Okubo, Tsukuba, Ibaraki 300-2611, Japan.
LA  - eng
PT  - Journal Article
DEP - 20190201
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 0 (Benzimidazoles)
RN  - 0 (Muc5ac protein, rat)
RN  - 0 (Mucin 5AC)
RN  - 0 (Phosphodiesterase 4 Inhibitors)
RN  - 0 (Triazoles)
RN  - 223909-92-0 (TAS-203)
RN  - EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4)
SB  - IM
MH  - Animals
MH  - Benzimidazoles/*pharmacology/therapeutic use
MH  - Cigarette Smoking/adverse effects
MH  - Cyclic Nucleotide Phosphodiesterases, Type 4/*metabolism
MH  - Disease Models, Animal
MH  - Gene Expression Regulation/drug effects
MH  - Goblet Cells/drug effects/pathology
MH  - Guinea Pigs
MH  - Hyperplasia/drug therapy
MH  - Inflammation/drug therapy/metabolism/pathology
MH  - Male
MH  - Mucin 5AC/biosynthesis/metabolism
MH  - Phosphodiesterase 4 Inhibitors/*pharmacology/therapeutic use
MH  - Pulmonary Disease, Chronic Obstructive/*drug therapy/metabolism/pathology
MH  - Rats
MH  - Respiratory System/*drug effects/metabolism/pathology
MH  - Triazoles/*pharmacology/therapeutic use
OTO - NOTNLM
OT  - Airway inflammatory disease
OT  - Chronic obstructive pulmonary disease
OT  - Goblet cell hyperplasia
OT  - MUC5AC
OT  - PDE4 inhibitor
OT  - TAS-203
EDAT- 2019/02/05 06:00
MHDA- 2019/06/20 06:00
CRDT- 2019/02/05 06:00
PHST- 2018/08/30 00:00 [received]
PHST- 2019/01/14 00:00 [revised]
PHST- 2019/01/17 00:00 [accepted]
PHST- 2019/02/05 06:00 [pubmed]
PHST- 2019/06/20 06:00 [medline]
PHST- 2019/02/05 06:00 [entrez]
AID - S0014-2999(19)30040-8 [pii]
AID - 10.1016/j.ejphar.2019.01.068 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 2019 Apr 15;849:22-29. doi: 10.1016/j.ejphar.2019.01.068. Epub 
      2019 Feb 1.