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Background: This prospective, controlled experimental study was planned to investigate the effects of levosimendan on transforming growth factor (TGF)-beta3 and Smad1, Smad2 and Smad3 expression in the early stages of sepsis., Methods: Twenty-four rats were randomized into four groups: (1) sham-operated controls, (2) dobutamine group--subjected to abdominal hypertension and peritonitis-induced sepsis using cecal ligation and puncture (CLP), then treated with 10 microg x kg(-1) min(-1) intravenous (IV) dobutamine infusion, (3) levosimendan group--as in 2, then treated with levosimendan IV bolus 200 microg x kg(-1) followed by 200 microg x kq(-1) min(-1) IV infusion, and (4) a control group as in 2, with no treatment. All rats were killed 8 hours after CLP. Aorta tissue samples were analyzed by immunohistochemical staining., Results: CLP caused mild interleukin (IL)-1 immunostaining in both control and dobutamine groups. Immunoreactivity of tumor necrosis factor (TNF)-alpha was mild in both sham and control groups. TGF-beta3 immunostaining was mildly increased in groups sham, control and dobutamine, whereas it was found moderate in group levosimendan. Smad1, Smad2 and Smad3 were found moderately increased only in group levosimendan., Conclusion: Beneficial effects of levosimendan on hemodynamics and global oxygen transport were reported in experimental and clinical trials. Besides its potency on C++ ion sensitivity, it should influence inflammatory cytokine production by diminishing TGF-beta3 and Smad1, Smad2 and Smad3 expression.

The effects of levosimendan on acute lung injury induced by peritonitis and abdominal hypertension in the early stages of sepsis in rats were investigated. Twenty-four adult male Wistar rats were randomized into: (1) sham, (2) subjected to abdominal hypertension and peritonitis induced lung injury using cecal ligation and puncture, then treated by dobutamine, (3) subjected to abdominal hypertension and peritonitis induced lung injury using cecal ligation and puncture, then treated by levosimendan, and (4) controls subjected to abdominal hypertension and peritonitis induced lung injury using cecal ligation and puncture with no treatment. In the control and levosimendan groups, cecal ligation and puncture resulted in moderate IL-1beta immunolabelling in lung tissue; marked IL-1beta immunolabelling was demonstrated in the dobutamine group. TNF-alpha immunolabelling was negative in both the sham and levosimendan groups, but moderate and weak immunoreactivities were observed in the dobutamine and control groups, respectively. There were almost no TUNEL positive cells in the sham, but they were prominent in the control. TUNEL positive cells were significantly less in the levosimendan treated lungs when compared to control and dobutamine groups. Immunoreactivity of eNOS was stronger in the dobutamine group when compared with the levosimendan group. In addition, iNOS immunoreactivity was strongly detected in the control group; this immunoreactivity was less in the levosimendan group than the dobutamine group. In this experimental sepsis model, treatment with levosimendan had a marked effect on attenuating or decreasing apoptosis and inflammation in the lung.