Hemodynamic Benefits of Matrix Metalloproteinase-9 Inhibition by Doxycycline During Experimental Acute Pulmonary Embolism

Abstract

The authors examined whether acute pulmonary embolism (APE) increases lung matrix metalloproteinase (MMP)-2 and MMP-9 activities and whether inhibition of MMPs with doxycycline attenuates the hemodynamic changes associated with APE. Anesthetized male Wistar rats were monitored for mean arterial blood pressure (MAP) and heart rate (HR). Rats in the control group (n = 5) received only saline IV; rats in the embolism (Emb) group (n = 8) received saline IV followed 10 minutes later by an injection of Sephadex microspheres (9 mg/kg) IV; rats in the doxycycline (Doxy) group (n = 4) received only doxycycline (30 mg/kg) IV, followed 10 minutes later by an injection of saline IV; rats in the Doxy + Emb group (n = 8) received the same dose of doxycycline followed 10 minutes later by the same amount of microspheres described above. Lung samples were homogenized and assayed by SDS-polyacrilamide gel electrophoresis gelatin zymography to evaluate lung MMP-2 and MMP-9 activities. Saline or doxycycline produced no significant changes in MAP, HR, and in MMP-2 and MMP-9 activities. Conversely, lung embolization significantly reduced MAP by > 32 mm Hg and HR by > 90 bpm for more than 60 minutes, and increased MMP-9 activity by 43% (all p < 0.05). No significant differences were observed in MMP-2 activity. However, lung embolization produced only transient hypotension in rats pretreated with doxycycline. In this group, MAP returned to baseline values 5 to 10 minutes after embolization. In addition, pretreatment with doxycycline blunted the increase in lung MMP-9 activity after lung embolization (p < 0.05). This study demonstrates for the first time that MMP-9 inhibition with doxycycline attenuates APE-induced hemodynamic changes in the animal model examined. These findings indicate that MMP-9 activation plays a role in the pathophysiology of APE and suggest that pharmacologic strategies targeting specific MMPs with selective inhibitors may prevent the detrimental acute hemodynamic consequences of APE.

Matrix Metalloproteinases in Lung: Multiple, Multifarious, and Multifaceted

“…In an acute model of pulmonary embolism in rats, within an hour MMP-9 activity increases by 43%, but interestingly, despite known expression of MMP2 by endothelial cells that are affected by embolization, no significant increase is observed in MMP2 activity. Pretreatment of rats with doxicycline attenuated the physiological impairments seen in pulmonary embolism and blunted the increase in lung MMP9 activity (207). This study exemplifies how pharmacological strategies targeting specific MMPs with selective inhibitors are necessary in treatment of disease.…”

Circulating matrix metalloproteinases and tissue inhibitors of metalloproteinases levels in pediatric patients with congenital heart disease: Relationship to cardiac functions

“…Finally it is seen that pharmacological inhibitors of matrix metalloproteinases such as doxycycline, zinc chelators and batimastat have been used as diagnostic and therapeutic tools in cancer, autoimmune and cardiovascular diseases (32,33). Therefore, the following question comes to mind for our study, wonder if the medications used by patients had impact on the matrix metalloproteinases levels?…”

“…In a rat model, Palei et al (32) observed that inhibition of matrix metalloproteinases with doxycycline, reduces the hemodynamic changes of acute pulmonary embolism. They found an overt increase in matrix metalloproteinase-2 and matrix metalloproteinase-9 activity of the lung in acute pulmonary embolism and then treatment with L-arginine brought relief in pulmonary hypertension and caused reduction of matrix metalloproteinase-2 and matrix metalloproteinase-9 activity.…”

Pathophysiology, Diagnosis and Treatment of Pulmonary Embolism Focusing on Thrombolysis - New approaches

“…Experimental evidence indicated that the pathophysiology of PE implies the activation of matrix metalloproteinases (MMPs) (Uzuelli et al, 2008;Dias-Junior et al, 2009;Souza-Costa et al, 2005;Souza-Costa et al, 2007;Palei et al, 2005;Fortuna et al, 2007). Indeed, hemodynamic derangements associated with this condition improved with the inhibition of MMPs.…”

“…This observation offers an explanation for the hemorrhagic transformation during stroke. It is possible that the MMP inhibitors may decrease the risk of intracerebral hemorrhage or other bleeding complication of TL for acute PE (Murata et al, 2008;Sumii & Lo, 2002;Machado et al, 2009) and may have beneficial hemodynamic effects (Fortuna et al, 2007;Palei et al, 2005).…”