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- Kohler, A., et al.
(författare)
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Portal hyperperfusion after major liver resection and associated sinusoidal damage is a therapeutic target to protect the remnant liver
- 2019
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Ingår i: American Journal of Physiology-Gastrointestinal and Liver Physiology. - : American Physiological Society. - 0193-1857 .- 1522-1547. ; 317:3
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Tidskriftsartikel (refereegranskat)abstract
- Extended liver resection results in loss of a large fraction of the hepatic vascular bed, thereby causing abrupt alterations in perfusion of the remnant liver. Mechanisms of hemodynamic adaptation and associated changes in oxygen metabolism after liver resection and the effect of mechanical portal blood flow reduction were assessed. A pig model (n = 16) of extended partial hepatectomy was established that included continuous observation for 24 h under general anesthesia. Pigs were randomly separated into two groups, one with a portal flow reduction of 70% compared with preoperative values, and the other as a control (n = 8, each). In controls, portal flow [mean (SD)] increased from 74 (8) mL.min(-1).100 preoperatively to 240 (48) mL.min(-1).100 g(-1) at 6 h after resection (P < 0.001). Hepatic arterial buffer response was abolished after resection. Oxygen uptake per unit liver mass increased from 4.0 (1.1) mL.min(-1) .100 g preoperatively to 7.7 (1.7) mL.min(-1) .100 g(-1) 8 h after resection (P = 0.004). Despite this increase in relative oxygen uptake, total hepatic oxygen consumption (Vo(2)) was not maintained, and markers of hypoxia and anaerobic metabolism were significantly increased in hepatocytes after resection. Reduced postoperative portal flow was associated with significantly decreased levels of aspartate aminotransferase and bilirubin and increased hepatic clearance of indocyanine green. In conclusion, major liver resection was associated with persistent portal hyperperfusion, loss of the hepatic arterial buffer response, decreased total hepatic (V) over doto(2) and with increased anaerobic metabolism. Portal flow modulation by partial portal vein occlusion attenuated liver injury after extended liver resection. NEW & NOTEWORTHY Because of continuous monitoring. the experiments allow precise observation of the influence of liver resection on systemic and local abdominal hemodynamic alterations and oxygen metabolism. Major liver resection is associated with significant and persistent portal hyperperfusion and loss of hepatic arterial buffer response. The correlation of portal hyperperfusion and parameters of liver injury and dysfunction offers a novel therapeutic option to attenuate liver injury after extended liver resection.
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- Liu, S. C., et al.
(författare)
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Effects of Trendelenburg position and increased airway pressure on hepatic regional blood flow of normal and resected liver
- 2020
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Ingår i: Journal of Applied Physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 128:3, s. 667-680
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Tidskriftsartikel (refereegranskat)abstract
- High portal venous blood flow (Qpv) may contribute to posthepatectomy liver failure. Both Trendelenburg position (TP) and elevated airway pressure (Paw) increase backpressure to venous return and may thereby reduce Qpv. The aim of this study was to evaluate the effects of TP and increased Paw on hepatosplanchnic hemodynamics before and after major liver resection. Arterial and venous blood pressures, Qpv, extrasplanchnic inferior vena cava (Qivc), superior mesenteric (Qsma), hepatic (Qha), and carotid artery blood flows (Qca) were measured in 14 anesthetized and mechanically ventilated pigs in supine and 30 degrees TP during end-expiratory hold at 5 cmH(2)O positive end-expiratory pressure (PEEP) and during inspiratory hold with Paw of 15, 20, 25, and 30 cmH(2)O. After major liver resection, the interventions were repeated in seven randomly selected animals. At baseline, TP increased right atrial pressure (Pra) and Qpv but not Qivc or Qsma. With increased Paw in the supine position, Pra increased and all regional blood flows decreased. TP during increasing Paw attenuated the decrease in Qpv, Qsma, and Qivc but not in Qha or Qca. After liver resection, the effects of TP during increasing Paw remained, albeit at higher portal vein pressures. However, TP alone did not increase IVC venous return. Increasing Paw in supine position reduces Qpv and all other regional flows, while the reduction in Qpv is attenuated in TP, suggesting partly preserved liver waterfall or decreased intrahepatic resistance. Liver resection, despite resulting in major intrahepatic blood flow changes, does not fundamentally influence the interaction of increasing Paw and TP on regional perfusion. NEW & NOTEWORTHY In Trendelenburg position (TP), liver blood flow is the only contributor to increased venous return measured in the inferior vena cava (IVC), which attenuates the decreased IVC venous return induced by increasing airway pressure. After liver resection, TP similarly attenuated effects of increasing airway pressure.
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- Joseph, A, et al.
(författare)
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Metabolic features of cancer cells impact immunosurveillance
- 2021
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Ingår i: Journal for immunotherapy of cancer. - : BMJ. - 2051-1426. ; 9:6
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Tidskriftsartikel (refereegranskat)abstract
- Tumors rewire their metabolism to achieve robust anabolism and resistance against therapeutic interventions like cisplatin treatment. For example, a prolonged exposure to cisplatin causes downregulation of pyridoxal kinase (PDXK), the enzyme that generates the active vitamin B6, and upregulation of poly ADP-ribose (PAR) polymerase-1 (PARP1) activity that requires a supply of nicotinamide (vitamin B3) adenine dinucleotide. We investigated the impact of the levels of PDXK and PAR on the local immunosurveillance (ie, density of the antigen presenting cells and adaptive immune response by CD8 T lymphocytes) in two different tumor types.MethodsTumors from patients with locally advanced cervical carcinoma (LACC) and non-small cell lung cancer (NSCLC) were stained for PAR, PDXK, dendritic cell lysosomal associated membrane glycoprotein (DC-LAMP) and CD8 T cell infiltration. Their correlations and prognostic impact were assessed. Cisplatin-resistant NSCLC cell clones isolated from Lewis-lung cancer (LLC) cells were evaluated for PAR levels by immunoblot. Parental (PARlow) and cisplatin-resistant (PARhigh) clones were subcutaneously injected into the flank of C57BL/6 mice. Tumors were harvested to evaluate their immune infiltration by flow cytometry.ResultsThe infiltration of tumors by CD8 T and DC-LAMP+ cells was associated with a favorable overall survival in patients with LACC (p=0.006 and p=0.008, respectively) and NSCLC (p<0.001 for both CD8 T and DC-LAMP cells). We observed a positive correlation between PDXK expression and the infiltration by DC-LAMP (R=0.44, p=0.02 in LACC, R=0.14, p=0.057 in NSCLC), and a negative correlation between PAR levels and CD8 T lymphocytes (R=−0.39, p=0.034 in LACC, R=−0.18, p=0.017 in NSCLC). PARP1 is constitutively hyperactivated in cisplatin-resistant LLC cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PARhigh). Tumors formed by such cancer cells injected into immunocompetent mice were scarcely infiltrated by CD8 T (p=0.028) and antigen presenting cells (p=0.086).ConclusionsOncometabolic features can impact local immunosurveillance, providing new functional links between cisplatin resistance and therapeutic failure.
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