Hydroxymethylglutaryl co-enzyme A reductase inhibition attenuates endotoxin-mediated inflammatory responses.
BACKGROUND
The aim of this study was to investigate whether inhibition of hydroxymethylglutaryl co-enzyme A reductase attenuates leucocyte-endothelial cell interactions and alters expression of endothelial constitutive nitric oxide synthase (ecNOS) and inducible nitric oxide synthase (iNOS) following exposure to endotoxin.


METHODS
Male Sprague-Dawley rats were randomized into control, lipopolysaccharide (LPS) and pravastatin + LPS groups (seven per group). Pravastatin sodium was gavaged at 0.4 mg per kg per day for 5 days, after which LPS 15 mg/kg was administered via the jugular vein. Intravital microscopy was used to determine leucocyte-endothelial cell interactions.


RESULTS
Following the administration of LPS there was a significant reduction in leucocyte rolling velocity at 10 min (mean(s.e.m.) 69(3) versus 102(6) per cent of baseline value; P = 0.041), an increase in the number of adherent leucocytes at 10 min (4.5(0.5) versus 2.8(0.3) per 100 microm; P = 0.044) and an increase in the number of leucocytes undergoing transendothelial migration at 30 min (4.2(0.4) versus 1.7(0.4) per field; P = 0.008) compared with controls. Pretreatment with pravastatin significantly attenuated LPS-induced leucocyte-endothelial cell interactions (rolling velocity 89(6) per cent at 10 min, P = 0.038; adherent leucocytes 3.0(0.5) per 100 microm at 10 min, P = 0.038; migrating leucocytes 1.9(0.5) per field at 30 min, P = 0.001). This endothelial protection was associated with maintenance of ecNOS and reduced iNOS expression within mesenteric tissues.


CONCLUSIONS
These data show that pravastatin produces anti-inflammatory effects in response to injurious stimuli by attenuation of leucocyte-endothelial cell interactions.
Joyce
M
M
Department of Surgery, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland. mylesjoyce@esatclear.ie
Casey
R
R
Gang
C
C
Winter
D
D
Kelly
C J
CJ
Bouchier-Hayes
D J
DJ
D000704:Analysis of Variance; D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D002784:Cholesterol / Q000097:blood; D042783:Endothelial Cells / Q000166:cytology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D007962:Leukocytes / Q000166:cytology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D008643:Mesentery / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D017035:Pravastatin / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008070:Lipopolysaccharides; D002784:Cholesterol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D017035:Pravastatin