title: Acute lung injury induces cardiovascular dysfunction: effects of IL-6 and budesonide/formoterol.
abstract: Acute lung injury (ALI) is associated with systemic inflammation and cardiovascular dysfunction. IL-6 is a biomarker of this systemic response and a predictor of cardiovascular events, but its possible causal role is uncertain. Inhaled corticosteroids and long-acting β2 agonists (ICS/LABA) down-regulate the systemic expression of IL-6, but whether they can ameliorate the cardiovascular dysfunction related to ALI is uncertain. We sought to determine whether IL-6 contributes to the cardiovascular dysfunction related to ALI, and whether budesonide/formoterol ameliorates this process. Wild-type mice were pretreated for 3 hours with intratracheal budesonide, formoterol, or both, before LPS was sprayed into their tracheas. IL-6-deficient mice were similarly exposed to LPS. Four hours later, bronchoalveolar lavage fluid (BALF) and serum were collected, and endothelial and cardiac functions were measured, using wire myography of the aortic tissue and echocardiography, respectively. LPS significantly impaired vasodilatory responses to acetylcholine (P < 0.001) and cardiac output (P = 0.002) in wild-type but not IL-6-deficient mice. Intratracheal instillations of exogenous IL-6 into IL-6-deficient mice restored these impairments (vasodilatory responses to acetylcholine, P = 0.005; cardiac output, P = 0.025). Pretreatment with the combination of budesonide and formoterol, but not either alone, ameliorated the vasodilatory responses to acetylcholine (P = 0.018) and cardiac output (P < 0.001). These drugs also attenuated the rise in the systemic expression of IL-6 (P < 0.05) related to LPS. IL-6 contributes to the cardiovascular dysfunction related to LPS, and pretreatment with budesonide/formoterol reduces the systemic expression of IL-6 and improves cardiovascular dysfunction. ICS/LABA may reduce acute cardiovascular events related to ALI.
authors.affiliation: Division of Respiratory Medicine, University of British Columbia, Providence Heart and Lung Institute, St. Paul's Hospital, 1081 Burrard St., Vancouver, British Columbia V6Z 1Y6, Canada.
authors.forename: Koichi
authors.initials: K
authors.lastname: Suda
authors.forename: Masashi
authors.initials: M
authors.lastname: Tsuruta
authors.forename: Jihyoun
authors.initials: J
authors.lastname: Eom
authors.forename: Chris
authors.initials: C
authors.lastname: Or
authors.forename: Tammy
authors.initials: T
authors.lastname: Mui
authors.forename: Jen-Erh
authors.initials: JE
authors.lastname: Jaw
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Li
authors.forename: Ni
authors.initials: N
authors.lastname: Bai
authors.forename: Joseph
authors.initials: J
authors.lastname: Kim
authors.forename: Julie
authors.initials: J
authors.lastname: Man
authors.forename: David
authors.initials: D
authors.lastname: Ngan
authors.forename: Jee
authors.initials: J
authors.lastname: Lee
authors.forename: Søren
authors.initials: S
authors.lastname: Hansen
authors.forename: Seung-Won
authors.initials: SW
authors.lastname: Lee
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 / Q000378:metabolism; D055371:Acute Lung Injury / Q000473:pathology*; D000305:Adrenal Cortex Hormones / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D001993:Bronchodilator Agents / Q000494:pharmacology; D019819:Budesonide / Q000494:pharmacology*; D002318:Cardiovascular Diseases / Q000378:metabolism*; D004983:Ethanolamines / Q000494:pharmacology*; D000068759:Formoterol Fumarate; D007249:Inflammation; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D014664:Vasodilation
chemical_list: D000305:Adrenal Cortex Hormones; D001993:Bronchodilator Agents; D004983:Ethanolamines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D019819:Budesonide; D000109:Acetylcholine; D000068759:Formoterol Fumarate