Low-dose theophylline enhances the anti-inflammatory effects of steroids during exacerbations of COPD.
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is characterised by an abnormal inflammatory response mainly to cigarette smoke that flares up during exacerbations of the disease (ECOPD). Reduced activity of histone deacetylases (HDAC) contributes to enhanced inflammation in stable COPD. It was hypothesised that HDAC activity is further reduced during ECOPD and that theophylline, an HDAC activator, potentiates the anti-inflammatory effect of steroids in these patients. A study was performed to investigate HDAC activity during ECOPD and the effects of theophylline on the anti-inflammatory effects of steroids in a randomised single-blind controlled study.


METHODS
35 patients hospitalised with ECOPD and treated according to international guidelines (including systemic steroids) were randomised to receive or not to receive low-dose oral theophylline (100 mg twice daily). Before treatment and 3 months after discharge, HDAC and nuclear factor-kappaB (NF-kappaB) activity in sputum macrophages, the concentration of nitric oxide in exhaled air (eNO) and total antioxidant status (TAS), tumour necrosis factor alpha (TNFalpha), interleukin (IL)-6 and IL8 levels in sputum supernatants were measured.


RESULTS
Patients receiving standard therapy showed decreased NF-kappaB activity, eNO concentration and sputum levels of TNFalpha, IL6 and IL8, as well as increased TAS during recovery of ECOPD, but HDAC activity did not change. The addition of low-dose theophylline increased HDAC activity and further reduced IL8 and TNFalpha concentrations.


CONCLUSIONS
During ECOPD, low-dose theophylline increases HDAC activity and improves the anti-inflammatory effects of steroids.


BACKGROUND
NCT00671151.
Cosio
B G
BG
Department of Respiratory Medicine, Hospital Universitario Son Dureta, Palma de Mallorca, Spain. borja.cosio@ssib.es
Iglesias
A
A
Rios
A
A
Noguera
A
A
Sala
E
E
Ito
K
K
Barnes
P J
PJ
Agusti
A
A
D000368:Aged; D000704:Analysis of Variance; D000975:Antioxidants / Q000378:metabolism; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D016207:Cytokines / Q000378:metabolism; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000032:analysis; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D013183:Sputum / Q000737:chemistry; D013256:Steroids / Q000008:administration & dosage*; D013806:Theophylline / Q000008:administration & dosage*; D014797:Vital Capacity / Q000187:drug effects
D000975:Antioxidants; D001993:Bronchodilator Agents; D016207:Cytokines; D016328:NF-kappa B; D013256:Steroids; D009569:Nitric Oxide; D013806:Theophylline