Effect Of Gadolinium Chloride Research Articles

Gadolinium chloride ameliorates acute lung injury associated with severe acute pancreatitis in rats by regulating CYLD/NF-κB signaling

The present study was embarked on an investigation of the mechanisms behind the effects of Gadolinium chloride (GdCl3) on lung injury associated with severe acute pancreatitis (SAP) in rats. Rats were randomly distributed into three groups: sham operation group (SO), SAP group and SAP treated with GdCl3 group (SAP + GdCl3). Retrograde injection of 5% sodium taurocholate into the biliopancreatic duct was adopted to induce SAP. Lung tissue specimens were harvested for histological study, wet-to-dry weight ratio calculation and myeloperoxidase examination. Meanwhile, bronchoalveolar lavage fluid was analyzed for TNF-α and IL-1β activity and proteins content. Then the apoptosis ratio of alveolar macrophages (AMs) was detected. NF-κB activation and cylindromatosis (CYLD) expression in AMs were measured respectively. Results showed that GdCl3 treatment notably ameliorated lung injury induced by SAP, and simultaneously, the apoptosis ratio of AMs was significantly promoted. The NF-κB activation was obviously inhibited when CYLD expression was markedly up-regulated in AMs of SAP + GdCl3. Negative correlation was analyzed between CYLD and NF-κB in both SAP and SAP + GdCl3. These data demonstrate that GdCl3 ameliorates lung injury secondary to SAP in rats mainly by up-regulating CYLD expression and inhibiting NF-κB activation in AMs, which may play a vital role in lung injury.

Effect of Gadolinium Chloride on Liver Regeneration Following Thioacetamide-Induced Necrosis in Rats

Gadolinium chloride (GD) attenuates drug-induced hepatotoxicity by selectively inactivating Kupffer cells. The effect of GD was studied in reference to postnecrotic liver regeneration induced in rats by thioacetamide (TA). Rats, intravenously pretreated with a single dose of GD (0.1 mmol/Kg), were intraperitoneally injected with TA (6.6 mmol/Kg). Hepatocytes were isolated from rats at 0, 12, 24, 48, 72 and 96 h following TA intoxication, and samples of blood and liver were obtained. Parameters related to liver damage were determined in blood. In order to evaluate the mechanisms involved in the post-necrotic regenerative state, the time course of DNA distribution and ploidy were assayed in isolated hepatocytes. The levels of circulating cytokine TNFα was assayed in serum samples. TNFα was also determined by RT-PCR in liver extracts. The results showed that GD significantly reduced the extent of necrosis. The effect of GD induced noticeable changes in the post-necrotic regeneration, causing an increased percentage of hepatocytes in S phase of the cell cycle. Hepatocytes increased their proliferation as a result of these changes. TNFα expression and serum level were diminished in rats pretreated with GD. Thus, GD pre-treatment reduced TA-induced liver injury and accelerated postnecrotic liver regeneration. No evidence of TNFα implication in this enhancement of hepatocyte proliferation and liver regeneration was found. These results demonstrate that Kupffer cells are involved in TA-induced liver damage, as well as and also in the postnecrotic proliferative liver states.

Effects of Gadolinium Chloride and Glycine on Hepatic and Pancreatic Tissue Damage in Alcoholic Pancreatitis

Systemic complications in alcoholic pancreatitis are supposed to be aggravated by inflammatory liver damage. Resident macrophages including hepatic Kupffer cells play a pivotal role in mediating systemic complications in severe necrotizing pancreatitis (SNP). The aim of this study was to evaluate the effects of Kupffer cell inhibition on the inflammatory liver damage in experimental alcoholic pancreatitis. Rats were fed with either alcohol or control diet for 6 weeks before induction of SNP. Animals were allocated into 4 groups: healthy controls, controls with SNP, SNP with gadolinium chloride or glycine (permanent vs temporary inhibition of hepatic Kupffer cells) prophylaxis. Hepatic microcirculation and morphologic damage of the liver and pancreas were assessed. Alcohol feeding and SNP increased hepatic and pancreatic injury compared with SNP alone. Gadolinium chloride and glycine improved hepatic microcirculation. In contrast, pancreatic and hepatic morphological damage was reduced by gadolinium chloride but not by glycine. Alcohol exposure aggravates hepatic and pancreatic injury in SNP. Gadolinium chloride reduces both microcirculatory and morphological damage, whereas glycine did not improve histological damage.

Gadolinium promoted proliferation and enhanced survival in human cervical carcinoma cells

The effect of gadolinium chloride (Gd) on the proliferation of HeLa cells was investigated at lower concentration. The results obtained by MTT and cell cycle analysis showed that Gd promoted proliferation by inducing S phase entry in HeLa cells at the concentration less than 100 microM. It was further evidenced by both an increase in the levels of phosphorylation of retinoblastoma protein (pRb) and a remarkable increase in cyclin E expression. Moreover, the survival of cells, exposed to Gd up to 3-5 days, was increased compared with control. The attenuation of the serum deprivation-induced cell loss by Gd was associated with the sustained activation of FAK (PY(397)) and the delayed activation of JNKs pathway. Besides, it appeared that Gd promoted cell proliferation and survival in HeLa cells was not contributed to the ROS generation. Based on the present results, both positive and negative effects of the lanthanides as potential drugs or diagnostic agents are discussed.

Effect of Gadolinium Chloride on the Growth and Metastasizing of Lewis Pulmonary Adenocarcinoma in Mice

A single intraperitoneal injection of GdCl(3)in doses of 14 or 28 mg/kg to mice with intravenously transplanted Lewis pulmonary adenocarcinoma on days 3 or 8 after tumor transplantation reduced the mean number of tumor metastases in the lungs. The effect of GdCl(3)was more pronounced if it was injected at the stage of tumor dissemination (day 8). The positive antimetastatic effect of GdCl(3)was presumably due to its capacity to macrophage depression. The direct (not mediated through mononuclear phagocyte system cells) effect of GdCl(3)on tumor cells cannot also be excluded.

Effects of Gadolinium Chloride (GdCl 3) on the Appearance of Macrophage Populations and Fibrogenesis in Thioacetamide-Induced Rat Hepatic Lesions

Macrophages infiltrating injured tissue play an important part in fibrogenesis. To shed light on the functional roles of macrophages, we investigated the appearance of macrophage populations in thioacetamide (TAA)-induced rat hepatic lesions, with or without pretreatment with GdCl(3), a chemical capable of inhibiting Kupffer cell functions. In the GdCl(3)+TAA group rats received a single intraperitoneal injection of GdCl(3) (7.5mg/kg body weight) and, after 24h, a single intravenous injection of TAA (300mg/kg body weight). Rats in the TAA group received TAA only. Rats in both groups were examined on post-TAA injection (PTI) days 3, 5, and 7. In the TAA group, on PTI day 3, when TAA-induced hepatocyte injury was particularly prominent, the number of macrophages peaked, subsequently decreasing until PTI day 7. As compared with the TAA group, the GdCl(3)+TAA group showed significantly decreased numbers of ED1-immunolabelled cells (exudate macrophages) and ED2-immunolabelled cells (Kupffer cells) on PTI days 3, 5, and 7, and OX6-immunolabelled cells (antigen-presenting macrophages) on PTI days 3 and 5. Although less strikingly, the numbers of alpha-smooth muscle actin-positive myofibroblasts and fibrotic areas were decreased in the GdCl(3)+TAA group. By RT-PCR, the expression of TGF-beta1 mRNA was suppressed on PTI days 3 and 7 in the GdCl(3)+TAA group, and the suppressed expression was confirmed in vitro by treating rat macrophage-like cells (HS-P) with 1% GdCl(3). The study showed that GdCl(3) treatment decreased the numbers of macrophages appearing in hepatic lesions and inhibited TGF-beta1 mRNA expression in macrophages. Decreased numbers of macrophages may contribute to improvement of hepatic fibrosis.

The effect of gadolinium chloride on Kupffer cell function in vitro: Clair Lee, George Yeoh, John K Olynyk, University of Western Australia, Fremantle, WA Australia

The effect of gadolinium chloride on Kupffer cell function in vitro: Clair Lee, George Yeoh, John K Olynyk, University of Western Australia, Fremantle, WA Australia

Prevention of primary nonfunction after canine liver allotransplantation: The effect of gadolinium chloride

Purpose Effective suppression of Kupffer cell function is believed to contribute to the prevention of preservation/reperfusion injury. In this study, effect of gadolinium, a synthetic Kupffer cell suppressant, on the reperfusion injury was examined using a canine partial liver transplantation model. Methods About a 70% partial liver segment was harvested and reimplanted in a mongrel recipient dog weighing 20 to 25 kg. Gadolinium chloride (10 mg/kg) was infused via the cephalic vein 24 hours before harvest of the partial liver (gadolinium group, n = 5). Serum aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and morphologic grading of graft were compared with those of a control group ( n = 5). Statistical analysis was done with an independent t-test. Results Average total ischemic time was 4 hours and 27 minutes. At 1 hour after reperfusion, there were no significant differences in AST, ALP, or LDH levels, or pathologic scores. At 48 hours after reperfusion, AST ( P = .03) and LDH ( P = .05) levels were significantly lower in the gadolinium group. Conclusion Kupffer cell blockade using gadolinium chloride may be effective to reduce ischemia reperfusion injury, but the effect is not evident at an early stage of reperfusion.

Effect of liver macrophage depression on the development of liver metastases of HA-1 tumor in mice.

Gadolinium chloride (5 mg/kg) administered to mice 24 h before intravenous transplantation of HA-1 hepatoma cells decreased the volume density of tumor implants in the liver, reduced the intensity of degenerative and necrotic changes developing under the effect of growing tumor metastases, and prolonged the life span of tumor-bearing mice. Development of metastases was not associated with changes in cathepsin B activity in the liver, while activity of cathepsin L decreased only during the early period (4 days) after injection of gadolinium chloride. Injection of gadolinium chloride led to labilization of liver cell lysosomes because of overload with gadolinium chloride particles. The positive effect of gadolinium chloride was probably associated with depression of liver macrophages at the stage of tumor cell invasion and with subsequent migration of monocytes/macrophages preventing the growth of formed metastatic nodes in the liver.

Mechanism of superoxide anion production by hepatic sinusoidal endothelial cells and Kupffer cells during short-term ethanol perfusion in the rat.

The aim of this study was to clarify the candidate cells for and the mechanism of superoxide anion (O2*-) release into the hepatic sinusoids during short-term exposure to ethanol. The rat liver was perfused continuously with ethanol (a substrate for alcohol dehydrogenase) or tert-buthanol (not a substrate for alcohol dehydrogenase) for 20 min at a final concentration of 40 mM. In order to detect O2*- production, MCLA (2-methyl-6-[p-methoxyphenyl]-3,7-dihydroimidazo[1,2-a]pyrazin-3-one), a Cypridina luciferin analogue, was simultaneously infused and MCLA-enhanced chemiluminescence was measured. The effects of gadolinium chloride (GdCL3) (a suppressor of Kupffer cells (KCs)), staurosporine (ST) (an inhibitor of serine-threonine kinases, including protein kinase C), diphenyleneiodonium chloride (DPI) (an inhibitor of NADPH oxidase), ibuprofen (IB) (an inhibitor of cyclooxygenase) and 4-methylpyrazole (4MP) (an inhibitor of ethanol metabolism) on the ethanol-induced chemiluminescence were also evaluated. Sites where O2*- could be released were determined by histochemical detection of nitro blue tetrazolium reduction. Both ethanol and tert-buthanol rapidly caused O2*- release. GdCL3 suppressed the ethanol-induced O2*- release by 61%. Staurosporine and DPI, but neither IB nor 4-MP, also significantly inhibited the ethanol-induced O2*- release. In the histochemical examination, ethanol-stimulated liver showed blue formazan precipitate on both sinusoidal endothelial cells (SECs) and Kupffer cells (KCs), whereas the GdCl3-pretreated liver had the precipitate only on SECs. This study shows that ethanol itself stimulates both SECs and KCs to release O2*- via activation of NADPH oxidase probably involving protein kinase C (PKC).

The effect of gadolinium chloride on Kupffer cell phenotype and cytokine production after administration of bacterial endotoxin to rats

The effect of gadolinium chloride on Kupffer cell phenotype and cytokine production after administration of bacterial endotoxin to rats

Effects of gadolinium ions upon rat prostatic cancer cell lines of markedly different metastatic potential

The effects of gadolinium chloride, a non-specific blocker of mechanosensitive ion channels (MSICs), upon the motility and proliferation of two Dunning rat prostatic tumour cell lines of markedly different metastatic potential were investigated. Gadolinium (2–10 μM) caused a dose-dependent increase in the distance moved in ‘wound’ assays over a 48-h testing period. The highly metastatic MAT-LyLu cell line was significantly more sensitive to Gd3+, the weakly metastatic AT-2 cells responding only at the highest concentration (10 μM) used. There was no effect on the cells’ proliferative rates. These data suggest that mechanosensitive channels could play a role in metastasis by modulating cell migration.

Effects of the Kupffer cell inactivator gadolinium chloride on rat liver oxygen uptake and content of mitochondrial cytochromes

The effect of gadolinium chloride (GdCl3) on the content of rat liver mitochondrial cytochromes was investigated in relation to the basal rate of O2 uptake and Kupffer cell functioning, assessed in liver perfusion studies. (1) A single dose of GdCl3 (10 mg/kg) produced a significant diminution in Kupffer cell functioning, evidenced by the decreases in colloidal carbon uptake and in carbon-induced O2 uptake observed at 6–24 h after treatment, without changes in the sinusoidal lactate dehydrogenase efflux as index of tissue viability; at 48 h after GdCl3 administration, carbon phagocytosis was recovered to control values, whereas carbon-induced O2 uptake remained lower than control values. (2) GdCl3 also caused a 34% decrease in the basal rate of O2 consumption of the liver at 24 h after treatment, which returned towards control values at 48 h. (3) The content of mitochondrial cytochromes c1 and c at 24 h after GdCl3 treatment was significantly reduced by 40 and 32%, respectively, which returned to control values at 48 h, without changes in that of cytochromes b and a+a3. It is concluded that GdCl3-induced decrease in liver O2 consumption is a reversible phenomenon that seems to be due to a diminution in the content of mitochondrial cytochromes c1 and c.

Gadolinium chloride-induced macrophage blockade prevents rejection of human insulinoma cell xenograft in rats.

The effect of gadolinium chloride (GdCl3)-induced Kupffer cell blockade on the survival of discordant insulinoma cell xenografts was investigated. Insulinoma cells isolated by means of collagenase from human insulinoma and subsequently cultured were transplanted through the portal vein into the liver of streptozotocin-induced diabetic, male, CFY inbred rats. In the control, streptozotocin-treated rats, the decrease in blood glucose level was only transitory, in contrast with the GdCl3-pretreated diabetic rats, which remained normoglycemic during the 2-week observation period. Histologically, in the liver and lung of rats pretreated with GdCl3, large areas of extensively proliferating insulinoma cells were seen, whereas no insulinoma cells were seen in either the liver or the lung of diabetic control rats, not treated with GdCl3. These studies suggest that the Kupffer cells play significant roles in the recognition of xenoantigens and the induction of xenograft rejection.

Role of hepatocytes in direct clearance of lipopolysaccharide in rats

Background & Aims: The liver is the clearance organ for lipopolysaccharide (LPS). The aim of this study was to investigate the biliary excretion of LPS using fluorescein isothiocyanate (FITC)-labeled LPS. Methods: After FITC-LPS was injected intravenously into rats, the cellular localization of fluorescence in the liver was examined and the biliary excretion of fluorescence was measured. The effects of gadolinium chloride, a blocker of Kupffer cells, and colchicine, an inhibitor of microtubules, on the biliary excretion of fluorescence was investigated, and bile was analyzed using high-performance liquid chromatography. Results: Laser scanning confocal microscopy showed that fluorescence was taken up by hepatocytes 5 minutes after injection of FITC-LPS into the portal vein. When FITC-LPS was injected into the portal vein, fluorescence was rapidly secreted into bile, peaking at 20 minutes, and 25.1% of the injected dose appeared in bile within 60 minutes. When the same dose of FITC-LPS was injected into the tail vein, 15.8% appeared in bile within 60 minutes. Chromatography showed that FITC-LPS was excreted into bile in an unchanged form over a period of 20 minutes after injection. Colchicine significantly reduced the biliary excretion of fluorescence, but gadolinium chloride had no effect. Conclusions: LPS was directly and effectively processed by hepatocytes and secreted into the bile canalicular system via a microtubule-dependent vesicular pathway.

Effects of Gadolinium Chloride on the Rat Lung Following Intratracheal Instillation

Effects of Gadolinium Chloride on the Rat Lung Following Intratracheal Instillation. Yoneda, S., Emi, N., Fujita, Y., Ohmichi, M., Hirano, S., and Suzuki, K. T. (1995). Fundam. Appl. Toxicol. 28, 65-70. The metabolic behavior, clearance, and pulmonary effects of gadolinium (Gd), one of the rare earth elements, were investigated after single intratracheal instillation of gadolinium chloride (GdCl 3) in male Wistar rats. There was a dose-related increase in Gd content of lung tissue. Gd content in the supernatant of bronchoalveolar lavage fluid (BALF) did not exceed 5 μg Gd/ BALF even at a dose of 100 μg Gd/rat. Gd in the lung tissue decreased very slowly with a biological half-life of 136 days at a dose of 50 μg Gd/rat. On the other hand, Gd content in the supernatant of BALF was not detectable after 31 days. These results suggest that intratraeheally instilled Gd can be retained in epithelial lining fluid only to a limited extent as soluble forms and is deposited in the lung tissue probably in insoluble forms which are metabolized very slowly. Calcium (Ca) content in BALF increased more rapidly than other toxicological indices such as lactate dehydrogenase activity, protein concentration, and inflammatory cell counts. In the lung tissue, levels of Ca in Gd-instilled groups did not differ from the control value. Although these data suggest that the origin of Ca may be blood plasma, biological and/or toxicological significance of increased Ca is not known. The number of neutrophils reached the maximum at 12 hr after instillation, indicating that Gd has the potency to cause acute lung toxicity. Summarizing the observation, Gd instilled intratracheally into rats was deposited in the lung tissue in nonsoluble forms with an extremely long half-life, while the metal caused a rapid and selective infiltration of serum Ca before acute lung toxicity.

Octreotide, the reticuloendothelial system, and experimental liver tumour.

The inhibitory effect of octreotide on the growth of liver tumour is probably mediated (at least in part) by stimulation of the hepatic reticuloendothelial system (RES) activity. This study therefore investigated the effect of octreotide on the hepatic and splenic RES (assessed by the uptake of technetium 99m labelled albumin colloid, 99mTc-AC) in normal and tumour bearing rats and in animals treated with gadolinium chloride. The effects of gadolinium chloride and octreotide alone or in combination on the growth of liver tumour were also studied. Octreotide significantly stimulates both hepatic and splenic uptake of 99mTc-AC in normal rats and tumour bearing rats. In controls, the uptake of 99mTc-AC was significantly reduced by gadolinium chloride and was not changed by octreotide. RES blockade with gadolinium chloride significantly increased (p < 0.001) tumour growth compared with controls (hepatic replacement 42%; 95% confidence intervals (CI), 27.6 to 56.4 v 16.7%, 95% CI, 11.1 to 21.3%) whereas octreotide significantly inhibited (p < 0.001) the percentage hepatic replacement by tumour (0.7%; 95% CI, 0 to 2.3 v 16.7%; 95% CI, 11.1 to 21.3). This study highlights the importance of the RES in the development of liver tumour. Furthermore, octreotide inhibited the growth of liver tumour in rats with RES blockade, albeit to a lesser degree than in normal animals. These findings suggest that octreotide inhibits the growth of hepatic tumour by mechanisms other than stimulation of RES activity.

Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen

Acetaminophen is a mild analgesic and antipyretic agent that is safe and effective when taken in therapeutic doses. Ingestion of overdoses, however, may lead to acute liver failure accompanied by centrilobular degeneration and necrosis. Although the toxicity of acetaminophen is generally thought to be caused by direct interaction of its reactive metabolites with cellular macromolecules, recent studies have suggested that nonparenchymal cells also may contribute to tissue injury indirectly through the release of cytotoxic mediators. We analyzed the potential role of hepatic macrophages in acetaminophen hepatotoxicity by examining the effects of modulating the activity of these cells on tissue injury. Treatment of male Long Evans Hooded rats with acetaminophen (800 mg/kg) was found to induce extensive centrilobular hepatic necrosis. Pretreatment of the rats with either dextran sulfate or gadolinium chloride, two inhibitors of hepatic macrophage functioning, completely blocked hepatic necrosis, as well as increases in serum transaminase levels induced by acetaminophen. Interestingly, treatment of rats with the macrophage activator, lipopolysaccharide (LPS), also reduced tissue injury induced by acetaminophen. To exclude the possibility that the effects of gadolinium chloride, dextran sulfate, or LPS were due to alterations in acetaminophen metabolism, we analyzed the effects of these agents on various pharmacokinetic properties of this analgesic. Dextran sulfate and gadolinium chloride had no effect on the half-life of a low dose of acetaminophen (20 mg/ kg), or on the activity of any of its individual pathways of metabolism, including the formation of acetaminophenmercapturic acid. LPS treatment of rats caused a general depression of acetaminophen metabolism involving all of the known pathways of metabolic clearance, resulting in a decrease in the blood half-life of the drug. However, the fraction of the dose converted to the toxic metabolite (NAPQI) was not different from that ob served in rats given acetaminophen alone. Collectively, these data indicate that the protection afforded the animals by pretreatment with macrophage modulators was not due to suppression of the formation of NAPQI and hence support the hypothesis that macrophages may contribute directly to acetaminophen hepatotoxicity by an independent mechanism.

Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen

Acetaminophen is a mild analgesic and antipyretic agent that is safe and effective when taken in therapeutic doses. Ingestion of overdoses, however, may lead to acute liver failure accompanied by centrilobular degeneration and necrosis. Although the toxicity of acetaminophen is generally thought to be caused by direct interaction of its reactive metabolites with cellular macromolecules, recent studies have suggested that nonparenchymal cells also may contribute to tissue injury indirectly through the release of cytotoxic mediators. We analyzed the potential role of hepatic macrophages in acetaminophen hepatotoxicity by examining the effects of modulating the activity of these cells on tissue injury. Treatment of male Long Evans Hooded rats with acetaminophen (800 mg/kg) was found to induce extensive centrilobular hepatic necrosis. Pretreatment of the rats with either dextran sulfate or gadolinium chloride, two inhibitors of hepatic macrophage functioning, completely blocked hepatic necrosis, as well as increases in serum transaminase levels induced by acetaminophen. Interestingly, treatment of rats with the macrophage activator, lipopolysaccharide (LPS), also reduced tissue injury induced by acetaminophen. To exclude the possibility that the effects of gadolinium chloride, dextran sulfate, or LPS were due to alterations in acetaminophen metabolism, we analyzed the effects of these agents on various pharmacokinetic properties of this analgesic. Dextran sulfate and gadolinium chloride had no effect on the half-life of a low dose of acetaminophen (20 mg/kg), or on the activity of any of its individual pathways of metabolism, including the formation of acetaminophen-mercapturic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Gadolinium Chloride on the Rat Lung Following Intratracheal Instillation

Effects of Gadolinium Chloride on the Rat Lung Following Intratracheal Instillation