Doxycycline Attenuates Lipopolysaccharide-Induced Microvascular Endothelial Cell Derangements.

Abstract

INTRODUCTION Lipopolysaccharide (LPS) is known to induce vascular derangements. The pathophysiology involved therein is unknown, but matrix metalloproteinases (MMPs) may be an important mediator. We hypothesized that in vitro LPS provokes vascular permeability, damages endothelial structural proteins, and increases MMP activity; that in vivo LPS increases permeability and fluid requirements; and that the MMP inhibitor doxycycline mitigates such changes. METHODS Rat lung microvascular endothelial cells were divided into four groups: control, LPS, LPS plus doxycycline, and doxycycline. Permeability, structural proteins β-catenin and Filamentous-actin, and MMP-9 activity were examined. Sprauge Dawley rats were divided into sham, IV LPS, and IV LPS plus IV doxycycline groups. Mesenteric postcapillary venules were observed. Blood pressure was measured as animals were resuscitated and fluid requirements were compared. Statistical analysis was conducted using Student's t-test and ANOVA. RESULTS In vitro LPS increased permeability, damaged adherens junctions, induced actin stress fiber formation, and increased MMP-9 enzyme activity. In vivo, IV LPS administration induced vascular permeability. During resuscitation, significantly more fluid was necessary to maintain normotension in the IV LPS group. Doxycycline mitigated all derangements observed. CONCLUSIONS We conclude that LPS increases permeability, damages structural proteins, and increases MMP-9 activity in endothelial cells. Additionally, endotoxemia induces hyperpermeability and increases the amount of IV fluid required to maintain normotension in vivo. Doxycycline mitigates such changes both in vitro and in vivo. Our findings illuminate the possible role of matrix metalloproteinases in the pathophysiology of lipopolysaccharide-induced microvascular hyperpermeability and pave the way for better understanding and treatment of this process.

DOI: 10.1097/SHK.0000000000000556

Cite this paper

@article{WigginsDohlvik2016DoxycyclineAL, title={Doxycycline Attenuates Lipopolysaccharide-Induced Microvascular Endothelial Cell Derangements.}, author={Katie C Wiggins-Dohlvik and Hayden Wilson Stagg and Min Suk Han and Himakarnika Alluri and Ryan P Oakley and Chinchusha Anasooya Shaji and Matthew Louis Turner Davis and Binu Tharakan}, journal={Shock}, year={2016}, volume={45 6}, pages={626-33} }