title: Effects of an angiotensin-converting enzyme inhibitor on the inflammatory response in in vivo and in vitro models.
abstract: OBJECTIVE
  Sepsis remains a major health threat in intensive care medicine. The renin-angiotensin system (ACE) affects inflammatory responses. In addition, angiotensin-converting enzyme inhibitors act to ameliorate lung injury. To investigate whether the widely used ACE inhibitor enalapril, used to treat hypertension, could inhibit secretion of cytokines and high-mobility group box 1 (HMGB1) protein, thus reducing lung damage in a rat model of lipopolysaccharide (LPS)-induced sepsis.
  
  
  METHODS
  Randomized, prospective animal study.
  
  
  METHODS
  University medical center research laboratory.
  
  
  METHODS
  Male Wistar rats.
  
  
  METHODS
  LPS was administered intravenously to rats, with or without intraperitoneal pretreatment with enalapril. In addition, mouse macrophage RAW264.7 cells were stimulated with LPS, with and without simultaneous enalapril treatment.
  
  
  RESULTS
  Histologic examination showed marked reduction of interstitial congestion, edema, inflammation, and hemorrhage in lung tissue harvested 12 hours after treatment with both agents compared with LPS administration alone. Plasma concentration of angiotensin II was strongly induced by LPS; this induction was inhibited by the enalapril pretreatment. Likewise, LPS-induced secretion of proinflammatory cytokines and HMGB1 protein was inhibited by enalapril. The presence of HMGB1 protein in the lung was examined directly by immunohistochemistry; the number of stained cells was significantly lower in LPS-treated animals that also received enalapril. In the in vitro studies, enalapril administration inhibited the phosphorylation of IkappaB.
  
  
  CONCLUSIONS
  The ACE inhibitor enalapril blocked the LPS-induced inflammatory response and protected against the acute lung injury normally associated with endotoxemia in this rat sepsis model. Given these results, enalapril is a strong candidate as a therapeutic agent for sepsis.
authors.affiliation: Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, Oita, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hagiwara
authors.forename: Hideo
authors.initials: H
authors.lastname: Iwasaka
authors.forename: Shigekiyo
authors.initials: S
authors.lastname: Matumoto
authors.forename: Seigo
authors.initials: S
authors.lastname: Hidaka
authors.forename: Takayuki
authors.initials: T
authors.lastname: Noguchi
mesh_terms: D055371:Acute Lung Injury / Q000517:prevention & control; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D004656:Enalapril / Q000494:pharmacology*; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000188:drug therapy*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D016207:Cytokines; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D004656:Enalapril