TAS-203, an oral phosphodiesterase 4 inhibitor, exerts anti-inflammatory activities in a rat airway inflammation model

Eur J Pharmacol. 2019 Apr 15;849:22-29. doi: 10.1016/j.ejphar.2019.01.068. Epub 2019 Feb 1.

Abstract

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.

Keywords: Airway inflammatory disease; Chronic obstructive pulmonary disease; Goblet cell hyperplasia; MUC5AC; PDE4 inhibitor; TAS-203.

MeSH terms

  • Animals
  • Benzimidazoles / pharmacology*
  • Benzimidazoles / therapeutic use
  • Cigarette Smoking / adverse effects
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Goblet Cells / drug effects
  • Goblet Cells / pathology
  • Guinea Pigs
  • Hyperplasia / drug therapy
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Inflammation / pathology
  • Male
  • Mucin 5AC / biosynthesis
  • Mucin 5AC / metabolism
  • Phosphodiesterase 4 Inhibitors / pharmacology*
  • Phosphodiesterase 4 Inhibitors / therapeutic use
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Pulmonary Disease, Chronic Obstructive / metabolism
  • Pulmonary Disease, Chronic Obstructive / pathology
  • Rats
  • Respiratory System / drug effects*
  • Respiratory System / metabolism
  • Respiratory System / pathology
  • Triazoles / pharmacology*
  • Triazoles / therapeutic use

Substances

  • Benzimidazoles
  • Muc5ac protein, rat
  • Mucin 5AC
  • Phosphodiesterase 4 Inhibitors
  • Triazoles
  • TAS-203
  • Cyclic Nucleotide Phosphodiesterases, Type 4