Impacts of anti‐inflammatory phosphodiesterase inhibitors on a murine model of chronic pulmonary inflammation. Issue 4 (29th July 2021)

• Record Type: Journal Article
• Authors: Zheng, Xiao‐Fang; Chen, Dan‐Dan; Zhu, Xiao‐Ling; Le Grange, Jehane Michael; Zhou, Lu‐Qian; Zhang, Jin‐Nong
• Is Part Of: Pharmacology research & perspectives. Volume 9:Issue 4(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-07-29
• Subjects: cigarette smoke -- histone deacetylase‐2 -- lung inflammation -- phosphodiesterase inhibitors; Pharmacology -- Periodicals; Drug development -- Periodicals; 615.105
• DOI: 10.1002/prp2.840
• Languages: English
• ISSNs: 2052-1707

Abstract

Abstract: Chronic obstructive pulmonary disease (COPD) often tends to respond poorly to glucocorticoid (GC) therapy. Reduced Histone deacetylase‐2 (HDAC‐2) activity is an important mechanism behind this GC insensitivity. In this study, we investigated the effects of three phosphodiesterase inhibitors (PDEIs), with an anti‐inflammatory propensity, on cigarette smoke (CS)‐induced pulmonary inflammation and HDAC‐2 activity. Male C57BL/6 mice were exposed to cigarette smoke (CS) over the course of 30 weeks. Administration of the PDEIs commenced from the 29th week and followed a schedule of once daily treatments, 5 days a week, for 2 weeks. Roflumilast (ROF) was administered intragastrically (5 mg·kg −1 ), while pentoxifylline (PTX) (10 mg·kg −1 ) and theophylline (THEO) (10 mg·kg −1 ) were administered intraperitoneally, either alone or in combination with a GC (triamcinolone acetonide or TRI, 5 mg·kg −1, i.m., single injection). Lung morphometry, as well as the activity of HDAC‐2, pro‐inflammatory cytokines and reactive oxygen species (ROS) were assessed at the end of the 30‐week course. CS exposure was associated with a reduction in HDAC‐2 activity and the up‐regulation of ROS expression. PTX, ROF, and THEO administration led to the partial restoration of HDAC‐2 activity, which was favorably associated with the reduction of ROS expression. However, combining TRI to any of these PDEIs did not synergistically augment HDAC‐2 activity. Inactivation of HDAC‐2 due to long‐term CS exposure is closely related to exaggerated oxidative stress, and this reduced HDAC‐2 activity could partially be restored through the use of PDEIs. This finding provides a potential novel approach for further clinical research. Abstract : Long‐term cigarette smoke exposure is associated with a reduction in histone deacetylase‐2 (HDAC‐2) activity and the up‐regulation of IL‐8, TNF‐a and reactive oxygen species (ROS) expressions. Pentoxifylline (PTX), roflumilast (ROF) or theophylline (THEO) administration partially restores the HDAC‐2 activity, which is favorably associated with the reduction of ROS expression.