Low-dose theophylline restores corticosteroid responsiveness in rats with smoke-induced airway inflammation.
Patients with chronic obstructive pulmonary disease (COPD) respond poorly to corticosteroids. Histone deacetylase-2 (HDAC-2) plays a pivotal role in many cases of steroid insensitivity. The main aim of this study was to restore the smoking-induced reduction in corticosteroid sensitivity by increasing HDAC-2 activity using low-dose theophylline. Rats were exposed to cigarette smoke (CS) and treated with budesonide and two doses of theophylline. Besides the pathologic examination and cell counting in the bronchoalveolar lavage fluid (BALF), the expression of HDAC-2 and CXC chemokine ligand-8 (CXCL-8) were measured. Airway inflammation induced by CS was demonstrated by pathologic changes of lung tissue and increased level of CXCL-8. CS exposure also markedly decreased HDAC-2 expression. Moreover, a negative correlation was found between HDAC-2 activity and a lung destruction index. The index was restored to control levels with inhaled corticosteroid treatment in combination with a low, not a high, dose of theophylline. These results indicate that low-dose theophylline might provide protection from smoke damage and improve the anti-inflammatory effects of steroids by increasing HDAC-2 activity.
Department of Respiratory Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, PR China.
Xianwen
X
Sun
Qingyun
Q
Li
Yi
Y
Gong
Lei
L
Ren
Huanying
H
Wan
Weiwu
W
Deng
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D019819:Budesonide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D056464:Histone Deacetylase 2 / Q000378:metabolism; D007249:Inflammation / Q000097:blood / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D016209:Interleukin-8 / Q000097:blood; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012906:Smoke / Q000009:adverse effects*; D015208:Smoke Inhalation Injury / Q000097:blood / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects; D013806:Theophylline / Q000494:pharmacology*
D000305:Adrenal Cortex Hormones; D016209:Interleukin-8; D012906:Smoke; D019819:Budesonide; D013806:Theophylline; C533426:Hdac2 protein, rat; D056464:Histone Deacetylase 2