title: Single-dose rosuvastatin ameliorates lung ischemia-reperfusion injury via upregulation of endothelial nitric oxide synthase and inhibition of macrophage infiltration in rats with pulmonary hypertension.
abstract: OBJECTIVE
  Lung ischemia-reperfusion (IR) injury during cardiopulmonary surgery is associated with postoperative morbidity and mortality, particularly in patients with pulmonary hypertension (PH). Using a rat model for monocrotaline-induced PH, we investigated the protective effect of rosuvastatin against IR injury in lungs affected by PH and attempted to elucidate its mechanism of action.
  
  
  METHODS
  Male Sprague-Dawley monocrotaline-treated rats were divided into 4 groups (n = 8-9): sham, control + IR, statin + IR, and statin + mevalonolactone + IR. Lung ischemia was induced by left pulmonary artery occlusion (1 hour), followed by reperfusion (4 hours). Rosuvastatin (2 mg/kg) was injected 18 hours before reperfusion and mevalonolactone (1 mg/kg) was injected immediately before reperfusion. The arterial oxygen tension/inspired oxygen fraction ratio was used as a measure of lung oxygenation. Left lung tissue was analyzed for the wet-to-dry lung weight ratio and protein expression of endothelial nitric oxide synthase (eNOS) and phospho-eNOS. Macrophage recruitment was assessed by CD68 immunostaining.
  
  
  RESULTS
  Our results showed that rosuvastatin decreased IR lung injury (control + IR vs statin + IR) in terms of the arterial oxygen tension/inspired oxygen fraction ratio (272 ± 43 vs 442 ± 13), wet-to-dry ratio (5.7 ± 0.7 vs 4.8 ± 0.6), and macrophage infiltration (8.0 ± 0.6/field vs 4.0 ± 0.5/field) (P < .05 for all). eNOS and phospho-eNOS were downregulated by IR, which was blocked by rosuvastatin. Effects of rosuvastatin were blunted by mevalonolactone.
  
  
  CONCLUSIONS
  Single-dose rosuvastatin decreased IR injury in lungs affected by PH via 2 anti-inflammatory mechanisms: preserving eNOS function and inhibiting macrophage infiltration.
authors.affiliation: Division of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsuo
authors.affiliation: Department of Molecular Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Saiki
authors.affiliation: Division of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Adachi
authors.affiliation: Division of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kawamoto
authors.affiliation: Department of Molecular Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Fukushige
authors.affiliation: Department of Molecular Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Horii
authors.affiliation: Division of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: yoshisaiki@med.tohoku.ac.jp.
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Saiki
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D005464:Fluorobenzenes / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D055370:Lung Injury / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D008297:Male; D008798:Mevalonic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D016686:Monocrotaline; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010100:Oxygen / Q000097:blood; D010766:Phosphorylation; D011654:Pulmonary Edema / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control; D011743:Pyrimidines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*; D015854:Up-Regulation; D000097382:CD68 Molecule
chemical_list: D000893:Anti-Inflammatory Agents; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008798:Mevalonic Acid; D016686:Monocrotaline; D052250:Nitric Oxide Synthase Type III; D010100:Oxygen; D011743:Pyrimidines; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides; C539355:CD68 protein, rat; D000097382:CD68 Molecule; C015367:mevalonolactone; C496316:Nos3 protein, rat