title: Doxycycline Attenuates Lipopolysaccharide-Induced Microvascular Endothelial Cell Derangements.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Surgery, Texas A&M University Health Science Center College of Medicine and Baylor Scott and White Health, Temple, Texas.
authors.forename: Katie
authors.initials: K
authors.lastname: Wiggins-Dohlvik
authors.forename: Hayden W
authors.initials: HW
authors.lastname: Stagg
authors.forename: Min Suk
authors.initials: MS
authors.lastname: Han
authors.forename: Himakarnika
authors.initials: H
authors.lastname: Alluri
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Oakley
authors.forename: Chinchusha
authors.initials: C
authors.lastname: Anasooya Shaji
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Davis
authors.forename: Binu
authors.initials: B
authors.lastname: Tharakan
mesh_terms: D000199:Actins / Q000187:drug effects; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects; D051177:Catenins / Q000187:drug effects; D004318:Doxycycline / Q000494:pharmacology*; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects; D020782:Matrix Metalloproteinases / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000199:Actins; D000900:Anti-Bacterial Agents; D051177:Catenins; D008070:Lipopolysaccharides; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline