Phosphodiesterase 4 and its inhibitors in inflammatory diseases

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题名:	Phosphodiesterase 4 and its inhibitors in inflammatory diseases
作者:	金秀蓮;Jin, S-L Catherine;Ding, Shiau-Li;Lin, Shih-Chang
贡献者:	生醫理工學院生命科學系
关键词:	Animals;Cyclic AMP - metabolism;Cyclic Nucleotide Phosphodiesterases, Type 4 - chemistry;Cyclic Nucleotide Phosphodiesterases, Type 4 - genetics;Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism;Humans;Inflammation - drug therapy;Leukocytes - drug effects;Phosphodiesterase Inhibitors - metabolism;Phosphodiesterase Inhibitors - pharmacology;Signal Transduction - physiology
日期:	2012-06-01
上传时间:	2026-04-23 11:13:36 (UTC+8)
出版者:	Chang Gung Medical Journal;China (Republic : 1949- )
摘要:	摘要： Type 4 cyclic nucleotide phosphodiesterases (PDE4) are a family of low km 3',5'-cyclic adenosine monophosphate (cAMP)-specific phosphodiesterases including at least 20 isozymes encoded by four genes (PDE4A, PDE4B, PDE4C, and PDE4D) in mammals. Each PDE4 gene plays a special, nonredundant role in the control of cell function even though the four subfamilies share the highly conserved catalytic domain and upstream conserved region (UCR) 1 and UCR2 motifs of the regulatory domain. By their wide tissue distribution as well as differential expression and regulation among various cell types, PDE4s are viewed as critical regulators of intracellular cAMP levels, cAMP signaling, and signal compartmentalization. By increasing cAMP levels, PDE4 inhibitors show a broad spectrum of anti-inflammatory effects in almost all inflammatory cells. Many PDE4 inhibitors have been evaluated in clinical trials for various inflammatory conditions. Developed inhibitors, including the recently approved and marketed roflumilast, have considerable efficacy, but they also have adverse effects such as nausea and emesis which limit their dosing and subsequently their immunomodulatory activity. Thus, the development of PDE4 inhibitors with improved therapeutic indexes has been a major focus of pharmaceutical research for the treatment of chronic inflammatory diseases. Recent PDE4 gene knockout studies strongly suggest that PDE4 inhibitors with PDE4B selectivity may retain the anti-inflammatory effects while limiting side effects. Development of PDE4 inhibitors with different delivery routes, such as topical application and inhalation, is also a promising approach for the treatment of pulmonary inflammatory conditions and dermatitis. This review includes a brief overview of the domain structure and function of PDE4 isozymes, the role of PDE4s in inflammatory cell responses, and the potential therapeutic utility of PDE4 inhibitors in inflammatory diseases. 其他題名： Chang Gung Med J 出版者： China (Republic : 1949- ) 出版日期： 2012-05 出處： Chang Gung medical journal, 2012-05, Vol.35 (3), p.197 識別號： ISSN: 2309-835X 識別號： EISSN: 2309-835X 識別號： DOI: 10.4103/2319-4170.106152 識別號： PMID: 22735051
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