Phosphodiesterase-4(PDE4)functions as a catalyzing enzyme targeting hydrolyzation of intracellular cyclic adenosine monophosphate(cAMP)and inhibition of PDE4 has been proven to be a competitive strategy for dermatological and pulmonary inflammation.However,the pathological role of PDE4 and the therapeutic feasibility of PDE4 inhibitors in chronic ulcerative colitis(UC)are less clearly understood.This study introduced apremilast,a breakthrough in discovery of PDE4 inhibitors,to explore the therapeutic capacity in dextran sulfate sodium(DSS)-induced experimental murine chronic UC.In the inflamed tissues,overexpression of PDE4 isoforms and defective cAMP-mediating pathway were firstly identified in chronic UC patients.Therapeutically,inhibition of PDE4 by apremilast modu-lated cAMP-predominant protein kinase A(PKA)-cAMP-response element binding protein(CREB)signaling and ameliorated the clinical symptoms of chronic UC,as evidenced by improvements on mucosal ulcerations,tissue fibrosis,and inflammatory infiltrations.Consequently,apremilast maintained a normal intestinal physical and chemical barrier function and rebuilt the mucosal homeostasis by inter-fering with the cross-talk between human epithelial cells and immune cells.Furthermore,we found that apremilast could remap the landscape of gut microbiota and exert regulatory effects on antimicrobial re-sponses and the function of mucus in the gut microenvironment.Taken together,the present study revealed that intervene of PDE4 provided an infusive therapeutic strategy for patients with chronic and relapsing UC.

Laboratory of Anti-inflammation and Immunopharmacology,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;School of Pharmacy,University of Chinese Academy of Sciences,Beijing 100049,China;Department of Gastroenterology,Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China

[1]Heng Li;Yao Zhang;Moting Liu;Chen Fan;Chunlan Feng;Qiukai Lu;Caigui Xiang;Huimin Lu;Xiaoqian Yang;Bing Wu;Duowu Zou;Wei Tang-.Targeting PDE4 as a promising therapeutic strategy in chronic ulcerative colitis through modulating mucosal homeostasis)[J].药学学报（英文版）,2022(01):228-245

Phosphodiesterase,Therapeutically,ulcerations,rebuilt,remap,infusive

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