The effect of experimental diabetes on high mobility group box 1 protein expression in endotoxin-induced acute lung injury.

The incidence and prevalence of diabetes have recently increased. Hyperglycemia, which is commonly seen in intensive care medicine, is associated with increased morbidity and mortality. For instance, diabetes is associated with altered immune and hemostatic responses. High mobility group box 1 (HMGB1) protein plays a key role in various inflammatory diseases. This study investigated the increase in lung damage due to diabetes and the rise in HMGB1 levels in a lipopolysaccharide (LPS)-induced systemic inflammation rat model. Diabetes was induced by streptozotocin infusion 4 wk prior to LPS administration, followed by measurements of blood glucose and serum cytokine levels. Separate cohorts were sacrificed 12h post-LPS administration and analyzed for lung damage. Diabetic animals had significantly higher blood glucose and enhanced lung damage. In addition, levels of serum HMGB1, tumor necrosis factor-α, and interleukin-6 were increased in diabetic rats. Diabetes may exacerbate systemic inflammation as evidenced by higher serum HMGB1 and cytokine levels and enhanced lung damage in the rat systemic inflammation model.

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. DESIGN: Randomized, prospective animal study. SETTING: University medical center research laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: 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. MEASUREMENTS AND MAIN 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.