Doxycycline Prevents Acute Pulmonary Embolism-Induced Mortality and Right Ventricular Deformation in Rats

Abstract

Acute pulmonary embolism (APE) is a critical cardiopulmonary condition associated with right ventricular (RV) failure and death. While pharmacological inhibition of matrix metalloproteinases (MMPs) attenuated APE-induced hemodynamic alterations, no previous study has evaluated whether this approach decreases APE-induced mortality and RV deformation. We tested this hypothesis in rats. Wistar rats received an intraperitoneal injection of 30 mg/kg doxycycline (or saline) and after 30 min a sterile suspension of 300 μm microsphere (21 mg/kg or saline) was injected into the tail vein. After 24 h, surviving animals were killed and the RVs were collected and used for histological and morphometric analyses. RV samples were also homogenized and assayed by SDS-polyacrilamide gel electrophoresis gelatin zymography to evaluate MMP-2 and MMP-9 activity. In situ zymography was carried out in RV to assess MMP activity and neutrophil accumulation in myocardial tissue was determined by myeloperoxidase activity measurement. Dihydroethidium was used to assess RV reactive oxygen species concentrations. APE caused 72.5% mortality during the first hour of follow up. Pretreatment with doxycycline was associated with significant decrease in APE-induced mortality rate to 50% (P<0.05). Embolized animals showed significant RV dilation, and pretreatment with doxycycline blunted this alteration (P<0.05). APE increased the number of RV neutrophils and MMP-9 levels (P<0.05). Pretreatment with doxycycline blunted APE-induced increases in RV myocardial ROS concentrations and MMP gelatinolytic activity (both P<0.05). These findings show that MMP inhibition with doxycycline protects against APE-induced mortality and RV enlargement. These beneficial effects are probably due to attenuation of APE-induced oxidative stress and increases in ventricular proteolytic activity and suggest that doxycycline may have promising protective effects in patients with APE.