Time Course of Intraoperative Cytokine Levels in Liver Transplant Recipients

Santiago, F.; Bueno, Pablo; Olmedo, C.; Comino, A.; Hassan, Laila; Ferrón-Celma, I.; Muffak, Karim; Serradilla, M.; Mansilla, Alfonso; Ramia, J. M.; Villar, Jesús; Garrote, Daniel; Ramı́rez, Ángel; Ferrón, José Antonio

doi:10.1016/j.transproceed.2006.08.064

Cited by 18 publications

(12 citation statements)

References 9 publications

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“…Santiago and associates 4 found that TNF-s and IL-10 levels gradually increased as the operation progressed and reached their maximums after reperfusion, which also was true in our study. Boros and associates 22 and Arranz and associates 23 reported that TNF-α and IL-1 did not rise significantly until reperfusion, and that the IL-6 level showed a sharp rise after the initiation of surgery.…”

Section: Discussionsupporting

confidence: 90%

“…Combined with underlying liver failure, the transplant surgery itself is a stressor promoting the secretion of cytokines. [3][4][5] Studies on the proinflammatory and antiinflammatory cytokine balance involved in maintaining immunologic homeostasis during liver transplant surgery are rare. We conducted this study to determine which cytokines are involved in maintaining the balance between proinflammatory and anti-inflammatory cytokines before and during liver transplant.…”

Section: Proinflammatory and Anti-inflammatory Cytokine Balance In Pamentioning

confidence: 99%

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Proinflammatory and Anti-Inflammatory Cytokine Balance in Patients With Cirrhotic Hepatitis During Live-Donor Liver Transplant

Koh

Joo²,

Cho³

et al. 2012

Exp Clin Transplant

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Objectives: The immune system releases cytokines during the stress response, and the balance between proinflammatory and anti-inflammatory cytokines is important. This prospective study was done to determine which cytokines are responsible for maintaining cytokine balance during live-donor liver transplant surgery. Materials and Methods: Recipients undergoing livedonor liver transplant surgery due to cirrhotic hepatitis were allocated to a recipient group (n=44), and healthy donors were placed in the donor group (n=45). In donors, blood sampling for cytokine level analysis was performed after anesthetic induction (before the start of surgery, time point 1). In recipients, blood samples were collected before the start of surgery (time point 1), 60 minutes after the start of the anhepatic period (time point 2), and 60 minutes after reperfusion (time point 3). The proinflammatory cytokines measured were interleukin-1β, interleukin-6, and tumor necrosis factor-α; the anti-inflammatory cytokines were interleukin-10 and interleukin-4. Cytokines were quantified using sandwich enzyme-linked immunoassays. The time course of proinflammatory and anti-inflammatory cytokine concentrations during surgery in the recipient group was evaluated.Results: Interleukin-6, interleukin-10 and tumor necrosis factor-α showed significant changes in concentration during surgery, with interleukin-6 reaching levels 40 times higher than the preoperative value at the anhepatic stage. Interleukin-10 reached a peak at the neohepatic phase, with values 60 times higher than the preoperative value. The preoperative concentrations of interleukin-6 and interleukin-10 in the recipient group were higher than those in the donor group with a median of 4.48 vs 1.98 pg/mL (P < .001) and 2.98 vs 1.22 (P = .026). Conclusions: Interleukin-6 and interleukin-10 play a major role in cytokine balance before and during live-donor liver transplant surgery.

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Section: Discussionsupporting

confidence: 90%

Section: Proinflammatory and Anti-inflammatory Cytokine Balance In Pamentioning

confidence: 99%

Proinflammatory and Anti-Inflammatory Cytokine Balance in Patients With Cirrhotic Hepatitis During Live-Donor Liver Transplant

Koh

Joo²,

Cho³

et al. 2012

Exp Clin Transplant

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“…The innate immune system is thought to play important roles in the initiation and modulation of liver regeneration after liver resection or injury, and a hallmark of this involvement is the increase in circulating interleukin-6 (IL-6) that occurs shortly after partial hepatectomy (PH) in humans 2 and rodents. 3 In mice, the increase in IL-6 is thought to originate from liver macrophages 4 and to depend on tumor necrosis factor (TNF) receptor-1 and nuclear factor kappa B (NF-κB) signaling.…”

Section: Introductionmentioning

confidence: 99%

Toll-like receptor 4 and myeloid differentiation factor 88 provide mechanistic insights into the cause and effects of interleukin-6 activation in mouse liver regeneration

Vaquero¹,

Campbell²,

Haque³

et al. 2011

Hepatology

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Partial hepatectomy (PH) consistently results in an early increase of circulating interleukin- 6 (IL-6), which is thought to play a major role in liver regeneration. Activation of this cytokine after PH requires the adaptor protein, MyD88, but the specific MyD88-related receptors involved remain unidentified. It is also unknown whether the magnitude of IL-6 elevation determines the extent of subsequent hepatocyte proliferation. Here, we uncovered artifacts in the assessment of circulating IL-6 levels when using cardiac puncture in mice after PH. By using retro-orbital bleed sampling, we show that the circulating levels of IL-6 after PH were not directly correlated with the extent of hepatocyte DNA synthesis in individual mice. The IL-6 increase after PH was attenuated in all lipopolysaccharide-hyporesponsive mouse strains studied (e.g., C3H/HeJ, Tlr4 null, Cd14 null, Tlr2,4,9 null, and Tlr2,4-Caspase1 null) and was severely abrogated in Myd88 null mice. Despite attenuated IL-6 levels, Tlr4 null mice showed normal signaling downstream of IL-6 and normal hepatocyte proliferation. In contrast, Myd88 null mice showed severe impairments in signal transducer and activator of transcription 3 phosphorylation and Socs3 induction, but had enhanced and prolonged extracellular signal-related kinase 1 and 2 phosphorylation in the first 6 hours after PH. Unexpectedly, these changes were associated with accelerated initiation of hepatocyte proliferation, as assessed by hepatocyte bromodeoxyuridine incorporation, phospho-histone H3 immunostaining, and cyclin E and A protein expression. Conclusion TLR-4 signaling contributes to IL-6 activation after PH, but the Tlr4-independent component appears sufficient for ensuring intact signaling downstream of IL-6. The lack of correlation between IL-6 levels and hepatocyte proliferation after PH, and the accelerated start of hepatocyte proliferation in Myd88 null mice despite abrogated cytokine activation, may highlight relevant antiproliferative effects of IL-6 signaling, possibly via Socs3, in the regulation of liver regeneration.

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“…Our data showed that UGT1A6 mRNA in extrahepatic tissues, including kidney, small intestine, lung and brain, are upregulated during the anhepatic period, although the ex-act mechanisms of such upregulation are unknown. It has been shown that physiological disturbance, pro-inflammatory cytokines and growth hormones can be responsible for such changes [20,28,29] and these disturbances can be found in liver transplantation [30,31] . Clearly, the transcriptional change of this gene is not necessarily indicating its translational activity.…”

Section: Discussionmentioning

confidence: 99%

“…A tethered infusion system (Instech Solomon, Plymouth Meeting, Pa., USA) was established to allow animal to move freely during experiments. A single bolus dose of propofol (clinical used emulsion formula, 10 mg/kg) was injected slowly via the right deep jugular vein for over 60 s. Blood samples of 100 l were taken from the cannula at 2, 4,6,8,10,15,20,30,45, 60 min after injection and the lost blood volume was replaced with the same volume of acetate Ringer's solution. The animals were allowed to recover for the experiments.…”

Section: Pharmacokinetic Parameter Determinationmentioning

confidence: 99%

Pharmacokinetics of Propofol and Extrahepatic UGT1A6 Gene Expression in Anhepatic Rats

Lü²,

Xia³

et al. 2009

Pharmacology

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Objective: The metabolic enzyme of UDP-glucuronosyltransferase 1A6 (UGT1A6) has been considered to metabolize propofol intra- or extrahepatically. The aim of the present study was to investigate the pharmacokinetics of propofol and UGT1A6 mRNA expression in extrahepatic organs before and during the anhepatic status in rats. Methods: Male Sprague-Dawley rats were injected with propofol (10 mg/kg) intravenously and a blood sample was taken at 2–60 min after injection. The hepatic hilum was occluded under laparotomy and then the propofol injection and blood sampling were repeated as above 24 h later. The plasma concentrations of propofol were analyzed and UGT1A6 mRNA expression in the kidney, small intestine, lung and brain from other cohort rats at 30 and 60 min of anhepatic status were semiqualified by RT-PCR. Results: T_1/2_α,T_1/2_β and V_d of propofol were not changed significantly before and during the anhepatic status. The area under curve, derived from a time-dependent concentration response curve, was significantly increased whereas plasma clearance rate was decreased significantly in the anhepatic period when compared to that in the control period, respectively. UGT1A6 mRNA expression in extrahepatic organs was significantly increased at 30 or 60 min of the anhepatic status when compared to those in the control status. Conclusion: The pharmacokinetics of propofol during the prehepatic and anhepatic status are largely similar, which is associated with the upregulation of extrahepatic UGT1A6 gene. The marginal accumulation of propofol during anhepatic period is likely to be due to both the limited function of this metabolic pathway and physiological disturbance induced by hepatic hilum occlusion.

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Time Course of Intraoperative Cytokine Levels in Liver Transplant Recipients

Cited by 18 publications

References 9 publications

Proinflammatory and Anti-Inflammatory Cytokine Balance in Patients With Cirrhotic Hepatitis During Live-Donor Liver Transplant

Proinflammatory and Anti-Inflammatory Cytokine Balance in Patients With Cirrhotic Hepatitis During Live-Donor Liver Transplant

Toll-like receptor 4 and myeloid differentiation factor 88 provide mechanistic insights into the cause and effects of interleukin-6 activation in mouse liver regeneration

Pharmacokinetics of Propofol and Extrahepatic UGT1A6 Gene Expression in Anhepatic Rats

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