title: Endotoxin-induced cardiovascular dysfunction in mice: effect of simvastatin.
abstract: Lung infections are associated with acute lung injury (ALI), systemic inflammation, and vascular events. Clinical studies suggest that statins improve health outcomes of patients with pneumonia and ALI. The mechanisms by which this occurs are unknown. The aim of this study was to determine whether statins attenuate systemic inflammation and cardiovascular dysfunction related to ALI in mice. Simvastatin (SS; 20 mg/kg) or vehicle solution was instilled intraperitoneally into mice 24 h before and again just prior to intratracheal LPS instillation (1 μg/g). These mice were then anesthetized with 2.0% isoflurane and underwent a short surgical procedure to instill LPS. Four hours later, IL-6 levels in bronchoalveolar lavage fluid and in arterial and venous serum were measured. Cardiac function was evaluated using 2-D echocardiography, and endothelial function was determined using wire myography on aortic sections. LPS induced a significant increase in serum IL-6 levels. SS reduced venous (P = 0.040) but not arterial concentrations of IL-6 (P = 0.112). SS improved the maximal vasodilatory response of the aorta to ACh (P = 0.004) but not to sodium nitroprusside (P = 1.000). SS also improved cardiac output (P = 0.023). Vasodilatory response to ACh was impaired when aorta from untreated mice was incubated with ex vivo IL-6 (P = 0.004), whereas in the aorta from mice pretreated with SS, the vasodilatory response did not change with IL-6 incubation (P = 0.387). SS significantly improved LPS-induced cardiovascular dysfunction possibly by reducing systemic expression of IL-6 and its downstream signaling pathways. These findings may explain how statins improve health outcomes in patients with ALI.
authors.affiliation: Division of Respiratory Medicine, The University of British Columbia, the Providence Heart and Lung Institute and The James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research (St. Paul's Hospital), Vancouver, British Columbia, Canada.
authors.forename: Koichi
authors.initials: K
authors.lastname: Suda
authors.forename: Jihyoun
authors.initials: J
authors.lastname: Eom
authors.forename: Jen-Erh
authors.initials: JE
authors.lastname: Jaw
authors.forename: Tammy
authors.initials: T
authors.lastname: Mui
authors.forename: Ni
authors.initials: N
authors.lastname: Bai
authors.forename: Chris
authors.initials: C
authors.lastname: Or
authors.forename: David
authors.initials: D
authors.lastname: Ngan
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Li
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Masashi
authors.initials: M
authors.lastname: Tsuruta
authors.forename: Sheena
authors.initials: S
authors.lastname: Tam
authors.forename: S Paul
authors.initials: SP
authors.lastname: Man
authors.forename: Stephan
authors.initials: S
authors.lastname: Van Eeden
authors.forename: Don D
authors.initials: DD
authors.lastname: Sin
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D055371:Acute Lung Injury / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002318:Cardiovascular Diseases / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D007249:Inflammation / Q000097:blood / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009599:Nitroprusside / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology; D014680:Veins / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D014665:Vasodilator Agents; D009599:Nitroprusside; D019821:Simvastatin; D000109:Acetylcholine