Effects of an angiotensin-converting enzyme inhibitor on the inflammatory response in in vivo and in vitro models.
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.
Hagiwara
Satoshi
S
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, Oita, Japan.
Iwasaka
Hideo
H
Matumoto
Shigekiyo
S
Hidaka
Seigo
S
Noguchi
Takayuki
T
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*
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D016207:Cytokines; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D004656:Enalapril