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tor, tumor necrosis factor, and other cytokines. 4 All of these To evaluate the role of nitric oxide (NO) in hepatic micromediators may be involved in the pathogenesis of liver injury, circulation and liver injury during endotoxemia, we studied probably initiated by microvascular disturbance caused by O 2 transport in the hepatic microcirculation of endotoxinleukocyte adhesion to endothelial cells in the hepatic sinuinfused rats. Rats were continuously infused with Escherichia soids. [5][6][7] Nitric oxide (NO) also increases during endotoxcoli lipopolysaccharide (LPS) (0.8 mg/kg/h) for 7 hours. LPS emia 8,9 and sepsis, 10 produced by Kupffer cells, macrophages, increased the plasma levels of NO 0 2 / NO 0 3 and aspartate hepatocytes, and sinusoidal endothelial cells. 9 Overproductransaminase (AST), and decreased the bile flow rate and tion of NO plays a toxic role in septic shock. 11 Peroxynitrite hepatic adenosine triphosphate (ATP) level. Hepatic microcirgenerated from superoxide and NO may be involved in sevculation was evaluated by two methods: reflectance spectroeral types of tissue injury. 12,13 On the contrary, NO attenuates photometry showed a decrease in the oxygenation of hemoglohepatic injury during endotoxemia. 14-17 Thus, the roles of bin (Hb) in the liver, and dual-spot microspectroscopy NO in endotoxemia are controversial. Nishida et al. recently indicated that LPS administration decreased blood velocity, reported that inhibition of NO synthesis in endotoxemia led the oxygenation of Hb, and O 2 release from sinusoids to hepato an increase in the leukocytes adhering to the sinusoidal tocytes. The observed decreases in the O 2 transport paramewall and a decrease in the number of sinusoids displaying ters were prominent in pericentral sinusoids. All of these blood flow. 5 These results imply a deterioration of O 2 transphenomena were further aggravated by the administration of port in hepatic microcirculation; however, there has as yet N w -nitro-L-arginine methyl ester (L-NAME) (5 mg/kg/h) plus been no experimental evidence of this. LPS, and by aminoguanidine (AMG) (5 mg/kg/h) plus LPS,Dual-spot microspectroscopy is useful for evaluating heand these could be reversed by the concomitant administrapatic microcirculation to quantify sinusoidal O 2 transport tion of L-arginine (L-Arg) (100 mg/kg/h). These results suggest parameters such as red blood cell velocity, intrasinusoidal that deterioration of hepatic oxygen transport and liver funchemoglobin (Hb) concentration, Hb oxygenation, and the tion induced by endotoxin can be ameliorated by NO. (HEPArate of O 2 transfer from sinusoids to hepatocytes. 18 In the TOLOGY 1997;26:336-342.) present study, we used this method to quantitatively study periportal and pericentral sinusoidal O 2 transport in endoCholestatic liver injury is commonly observed in septic toxin-infused rat livers. patients. 1 Endotoxin, a major exogenous product of bacteria, causes similar morphological and functional alterations in MATERIALS AND METHODS the liver. 2 Because the addit...

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Glomerular mesangial cell (MC) proliferation is one of the causative factors of glomerular diseases and one of their prominent pathological features. Rapamycin can inhibit MC proliferation and slow the progression to chronic renal fibrosis. The present study was designed to observe the role of rapamycin in MC proliferation and to explore the mechanism by which rapamycin acts on Akt and MAPK/ERK1/2 pathways in mesangial cells. MTT assay and flow cytometry were used to evaluate the proliferation and the cell cycle phase of glomerular mesangial cells respectively. The mRNA expression level of p70S6K was detected by RT-qPCR. Western blotting was performed to determine p70S6K, PI3K/Akt, and PI3K/MAPK protein expression. We found that rapamycin could reduce mesangial cell proliferation and arrest the cell cycle in the G1 phase, however the inhibition effect of 1000 nmol/L rapamycin was not higher than that in the 100 nmol/L group. The results of western blotting showed that 1000 nmol/L rapamycin more significantly inhibited the phosphorylation of p70S6K than 100 nmol/L, suggesting there should be another signaling pathway that activates the proliferation of MCs. Moreover, our results revealed that 1000 nmol/L rapamycin led to Raf1-MEK1/2-ERK pathway activation through a p70S6K-PI3K-mediated feedback loop in MCs. This study demonstrated that high-dose rapamycin leads to ERK1/2 activation through a p70S6K/PI3K/MAPK feedback loop in rat MCs, thus reducing the inhibitory effect of rapamycin on MC proliferation.