Doxycycline attenuates acute lung injury following cardiopulmonary bypass: involvement of matrix metalloproteinases.

Abstract

Acute lung injury (ALI) was one of the major complications after cardiopulmonary bypass (CPB). Matrix metalloproteinases (MMPs) play an important role in ALI following CPB. In this study, we investigated the effects of doxycycline (DOX), a potent MMP inhibitor, on MMP-9 and ALI in the rat model of CPB. 48 adult male Sprague-Dawley rats were randomized into four groups: group I (Control group, underwent cannulation + heparinization only); group II (CPB group, underwent 60-minutes of normothermic CPB); group III (Low-dose treatment group, underwent 60-minutes of normothermic CPB with DOX gavage 30 mg/kg ×1 week ahead of CPB); and group IV (High-dose treatment group, underwent 60-minutes of normothermic CPB with DOX gavage 60 mg/kg ×1 week ahead of CPB). The effects of doxycycline on ALI were determined by measuring the lung Wet/Dry ratio, the inflammation of bronchoalveolar lavage fluid (BALF) and the ultrastructural changes of the lungs. The role of doxycycline on MMP-9 was assessed by the plasma concentration, the activity and the expression in lung tissue. Our results demonstrated that the lung Wet/Dry weight ratio and the inflammatory mediators (TNF-α, IL-1β) in BALF were decreased significantly with doxycycline treatment. The lung damages were attenuated by doxycycline. The levels of plasma concentration, the activity and the expression of MMP-9 in lung tissue were suppressed with doxycycline and the effects were dose dependent. Doxycycline could suppress the expression of MMP-9 and cytokines, and improve the ALI following CPB.