Hydroxymethylglutaryl co-enzyme A reductase inhibition attenuates endotoxin-mediated inflammatory responses

• Published in: British journal of surgery 2005-08, Vol.92 (8), p.1034-1040
• Main Authors: Joyce, M., Casey, R., Gang, C., Winter, D., Kelly, C. J., Bouchier-Hayes, D. J.
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Biological and medical sciences; Cell Adhesion; Cell Movement; Cholesterol - blood; Endothelial Cells - cytology; General aspects; Hydroxymethylglutaryl-CoA Reductase Inhibitors - toxicity; Leukocytes - cytology; Lipopolysaccharides - toxicity; Male; Medical sciences; Mesentery - enzymology; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Pravastatin - pharmacology; Random Allocation; Rats; Rats, Sprague-Dawley
• ISSN: 0007-1323; 1365-2168
• DOI: 10.1002/bjs.4985

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 µm; 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 µm 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. Conclusion: These data show that pravastatin produces anti‐inflammatory effects in response to injurious stimuli by attenuation of leucocyte–endothelial cell interactions. Copyright © 2005 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. Pravastatin has anti‐inflammatory effects