The impacts of anti-inflammatory phosphodiesterase inhibitors on a
murine model of chronic pulmonary inflammation
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 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, however combining TRI to any of these
PDEIs did not synergistically augment this effect. The restoration of
HDAC-2 activity was favorably associated with the reduction of ROS
expression.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.