Effect of doxycyline in chronic obstructive pulmonary disease - An exploratory study.

PURPOSE

Various mechanisms, including oxidative stress, inflammation, and protease-antiprotease imbalance are proposed for the progressive decline in lung function in chronic obstructive pulmonary disease (COPD). Doxycycline, a broad spectrum tetracycline antibiotic, is reported to have non-antimicrobial matrix metalloproteinases (MMP) inhibitory action in various inflammatory conditions. The effect of doxycycline in COPD is hereby assessed in the present randomized prospective study.

PATIENTS AND METHODS

The first group of COPD patients (n = 30; mild (n = 3), moderate (n = 6), severe (n = 7), very severe (n = 14) as per GOLD II & III criteria was prescribed the standard therapy, a combination of (i) short acting anti-muscarinic agent (SAMA) + short acting β2 agonist (SABA) inhaled and (ii) corticosteroid inhaled (ICS) + long acting β2 agonist (LABA) (iii) ICS + LABA + LAMA. Whereas doxycycline (100 mg), was used daily once or twice as per Body Mass Index (BMI), as an add-on to existing standard therapy for the second group of patients (n = 30; mild (n = 2), moderate (n = 7), severe (n = 8), very severe (n = 13). All recruited patients were followed-up after 3 months of treatment. Lung function index FEV1(%) predicted, FEV1/FVC (%), quality of life status including COPD Assessment Test (CAT), St. George's Respiratory Questionnaire (SGRQ) were assessed. Routine blood cell count also was performed.

RESULTS

Biochemical analysis included estimation of oxidative stress markers, inflammatory cytokines and proteases in plasma of both the groups. Reduction in oxidative stress is evidenced by a significant decrease in Lipid hydro peroxides (LPO), total oxidative stress (TOS) and increase in glutathione peroxidase (GSH-PX), reduced glutathione (GSH) and total anti-oxidant capacity (TAO) nitrite and nitrate (NOx) along with peroxynitrate following 3 months of add-on doxycycline treatment. Reduced levels of cytokines such as interleukin IL-6, TNF-α, IL-8 were also observed. Multivariate analysis identified TNF-α major effective discriminant among pre and post doxycycline treated COPD patients. The expression of TNF-α was inversely correlated with FEV1/FVC (%) changes. The levels of MMP-2 and MMP-9/tissue inhibitors of metalloproteinases (TIMP)-1 ratio (MMP-9/ TIMP-1), also decreased significantly and the decline could be associated with TOS. A significant increase in bilirubin and reduced glutathione (GSH) level was noticed in standard therapy group.

CONCLUSION

These data suggest that the improvement in lung function and quality of life in COPD patients may probably be attributed to the antioxidant, anti-inflammatory and anti-MMP activity of doxycycline. The potential therapeutic role of long-term doxycycline, in addition to its traditional antibiotic effect, definitely warrants further attention.