RESUMO
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 ß2 agonist (SABA) inhaled and (ii) corticosteroid inhaled (ICS) + long acting ß2 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.