We have previously reported that healing of rat calvarial defects was enhanced by application of alpha tricalcium phosphate (alphaTCP) combined with simvastatin, a cholesterol synthesis inhibitor. The purpose of the present study was to investigate the cellular and molecular mechanisms in this phenomenon. Rat calvarial defects were grafted with alphaTCP with or without simvastatin or left untreated. Animals were sacrificed on 3, 7, 10, 14, and 21 days postoperatively and histological changes in the defect region were assessed. Gene expression patterns were examined by RT-PCR. Proliferation and migration of osteoprogenitor cells from the dura mater were increased in simvastatin group from day 3 to day 10 (p < 0.01). New bone formation was significantly increased in simvastatin group on day 14 and day 21 (p < 0.01). BMP-2 expression was significantly higher in simvastatin group on day 3 and day 14 (p < 0.05) and maintained until day 21. Increased upregulation of TGF-beta1 was also observed in the simvastatin group on day 7 (p < 0.05) which was maintained until day 14. These findings suggest that the proliferation and recruitment of osteoprogenitor cells were critical steps in early stage of bone healing and that these steps were enhanced by TGF-beta1 and BMP-2, which were stimulated by simvastatin.
Within the limits of the study, the combination of mechanical and chemical treatment proved to be the most effective treatment for disinfection of the anodized implant surface.
To determine the role of phosphoinositide 3-OH kinase (PI3K) pathways in the acute vascular permeability increase associated with ventilator-induced lung injury, we ventilated isolated perfused lungs and intact C57BL/6 mice with low and high peak inflation pressures (PIP). In isolated lungs, filtration coefficients ( Kf) increased significantly after ventilation at 30 cmH2O (high PIP) for successive periods of 15, 30 (4.1-fold), and 50 (5.4-fold) min. Pretreatment with 50 μM of the PI3K inhibitor, LY-294002, or 20 μM PP2, a Src kinase inhibitor, significantly attenuated the increase in Kf, whereas 10 μM Akt inhibitor IV significantly augmented the increased Kf. There were no significant differences in Kf or lung wet-to-dry weight (W/D) ratios between groups ventilated with 9 cmH2O PIP (low PIP), with or without inhibitor treatment. Total lung β-catenin was unchanged in any low PIP isolated lung group, but Akt inhibition during high PIP ventilation significantly decreased total β-catenin by 86%. Ventilation of intact mice with 55 cmH2O PIP for up to 60 min also increased lung vascular permeability, indicated by increases in lung lavage albumin concentration and lung W/D ratios. In these lungs, tyrosine phosphorylation of β-catenin and serine/threonine phosphorylation of Akt, glycogen synthase kinase 3β (GSK3β), and ERK1/2 increased significantly with peak effects at 60 min. Thus mechanical stress activation of PI3K and Src may increase lung vascular permeability through tyrosine phosphorylation, but simultaneous activation of the PI3K-Akt-GSK3β pathway tends to limit this permeability response, possibly by preserving cellular β-catenin.
In rabbit livers, it is not well known which segments of the hepatic vasculature are predominantly contracted by various vasoconstrictors. We determined effects of histamine, norepinephrine, and KCl on hepatic vascular resistance distribution in isolated rabbit livers perfused via the portal vein with 5% albumin-Krebs solution at a constant flow rate. Hepatic capillary pressure was measured by double vascular occlusion pressure (Pdo) and was used to determine portal (Rpv) and hepatic venous (Rhv) resistances. A bolus injection of either histamine or norepinephrine dose-dependently increased portal venous pressure but not Pdo, resulting in a dose-dependent increase in Rpv and no changes in Rhv. KCl (50 mM), when injected in anterogradely perfused livers, contracted the presinusoidal vessels selectively with liver weight loss. Although KCl significantly increased Rhv in retrogradely perfused livers, the increase in Rpv by 400% of baseline predominated over the increase in Rhv by 85% of baseline. In the retrogradely perfused livers, KCl produced an initial liver weight loss followed by a profound weight gain. We conclude that histamine and norepinephrine selectively contract the presinusoidal vessels. The results on KCl effects suggest that this selective presinusoidal constriction might be possibly due to predominant distribution of functionally active vascular smooth muscle in the presinusoidal vessels rather than the hepatic vein in rabbit livers.
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