Effects of Hepatic Zonal Oxygen Levels on Hepatocyte Stress Responses

Broughan, Thomas A.; Naukam, Rebecca; Tan, Chibing; Wiele, C. Justin Van De; Refai, Hazem H.; Teague, T. Kent

doi:10.1016/j.jss.2007.04.014

Cited by 21 publications

(18 citation statements)

References 37 publications

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“…The individual hepatocyte is predominantly exposed to ca. 2% oxygen while intravascular oxygen levels vary dependent on localization (venous vs portal) and range between 8% to 16%[72,73]. It is well established that the portal zone 1 is exposed to ca.…”

Section: How To Dissect Sp From Hypoxia-mediated Liver Pathologies?mentioning

confidence: 99%

Does pressure cause liver cirrhosis? The sinusoidal pressure hypothesis

Mueller¹

2016

WJG

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Independent of their etiology, all chronic liver diseases ultimately lead to liver cirrhosis, which is a major health problem worldwide. The underlying molecular mechanisms are still poorly understood and no efficient treatment strategies are available. This paper introduces the sinusoidal pressure hypothesis (SPH), which identifies an elevated sinusoidal pressure (SP) as cause of fibrosis. SPH has been mainly derived from recent studies on liver stiffness. So far, pressure changes have been exclusively seen as a consequence of cirrhosis. According to the SPH, however, an elevated SP is the major upstream event that initiates fibrosis via biomechanic signaling by stretching of perisinusoidal cells such as hepatic stellate cells or fibroblasts (SPH part I: initiation). Fibrosis progression is determined by the degree and time of elevated SP. The SPH predicts that the degree of extracellular matrix eventually matches SP with critical thresholds > 12 mmHg and > 4 wk. Elevated arterial flow and final arterialization of the cirrhotic liver represents the self-perpetuating key event exposing the low-pressure-organ to pathologically high pressures (SPH part II: perpetuation). It also defines the “point of no return” where fibrosis progression becomes irreversible. The SPH is able to explain the macroscopic changes of cirrhotic livers and the uniform fibrotic response to various etiologies. It also opens up new views on the role of fat and disease mechanisms in other organs. The novel concept will hopefully stimulate the search for new treatment strategies.

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Section: How To Dissect Sp From Hypoxia-mediated Liver Pathologies?mentioning

confidence: 99%

Does pressure cause liver cirrhosis? The sinusoidal pressure hypothesis

Mueller¹

2016

WJG

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“…Oxygen delivery also plays an important role in other hepatic process, such as hepatic redox state. It was also observed that reduced intrahepatic oxygen levels in zone 3 are associated with enhanced susceptibility of these cells to anoxia-induced damage [4]. These findings indicate that hepatocytes oxygen availability prior to the occurrence of stress can dramatically affect the outcome.…”

Section: Introductionmentioning

confidence: 82%

“…Due to the liver structure and metabolism, the blood composition significantly alters during the passage through the sinusoids, leading to the formation of periportal-to-perivenous concentration gradients of substrates, products and hormones [3]. Oxygen partial pressure in the periportal blood (zone 1) is about 60–65 mm Hg (84–91 µmol/L, 9–11% oxygen) and falls as blood percolates throw the liver lobules towards the perivenuous (zone 3), where the oxygen partial pressure is about 30–35 mm Hg (42–49 µmol/L, 5–7% oxygen) [3], [4]. Oxygen regulates metabolic zonation in normal liver and under pathological condition serves as a modulator of liver diseases [3].…”

Section: Introductionmentioning

confidence: 99%

Non-alcoholic fatty liver disease, to struggle with the strangle: Oxygen availability in fatty livers

2017

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Nonalcoholic fatty liver diseases (NAFLD) is one of the most common chronic liver disease in Western countries. Oxygen is a central component of the cellular microenvironment, which participate in the regulation of cell survival, differentiation, functions and energy metabolism. Accordingly, sufficient oxygen supply is an important factor for tissue durability, mainly in highly metabolic tissues, such as the liver. Accumulating evidence from the past few decades provides strong support for the existence of interruptions in oxygen availability in fatty livers. This outcome may be the consequence of both, impaired systemic microcirculation and cellular membrane modifications which occur under steatotic conditions. This review summarizes current knowledge regarding the main factors which can affect oxygen supply in fatty liver.

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“…Whereas zone 1 (periportal) hepatocytes are relatively tolerant to hypoxia, zone 3 (perivenous) hepatocytes are particularly susceptible to low oxygen tension and suffer worse injury 10 . Liver cubes in culture have a diffusion capacity that mimics the in vivo hepatic lobular organization.…”

Section: Discussionmentioning

confidence: 99%

Novel in vitro model for studying hepatic ischemia-reperfusion injury using liver cubes

DuBray

Conzen

Upadhya

et al. 2012

Surgery

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Background While inflow occlusion techniques have given surgeons the ability to carry out increasingly complex liver resections, ischemia-reperfusion (IR) injury continues to be a source of morbidity. Efforts to ameliorate IR injury have been hindered in absence of adequate pre-clinical models. The goal of the present study was to develop a simple, efficient, and cost-effective means of studying hepatic IR injury. Methods Liver cubes were procured from normal (C57BL/6) mice. Following hepatectomy, 4 mm punch biopsies were taken for individual placement in culture wells containing hepatocyte media. Experimental cubes underwent hypoxia for 60 minutes, while controls remained normoxic. Supernatants were collected from individual wells following 0, 6 and 12 hours of rediffusion for transaminase and cytokine measurement. Histologic examination was performed on individual cubes. Results Extensive histologic injury was seen in the experimental cubes compared to controls with greater staining for activated caspase-3 and TUNEL at 6 and 24 hours, respectively. Changes consistent with ischemic injury occurred more centrally in liver cubes whereas markers for rediffusion injury were appreciated along the periphery. Transaminases were significantly higher at 6 hours following rediffusion in experimental cubes compared to controls, p = 0.02. TNF-α and IL-1β were significantly higher in the media of experimental cubes compared to controls at 12 hours rediffusion, p = 0.05 and 0.03 respectively. Conclusions In vitro IR of cubes produces a significant injury whose pattern is reflective of hepatic lobular architecture. This novel technique may open new avenues for uncoupling the mechanisms of IR while facilitating rapid screening of potential therapies.

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Effects of Hepatic Zonal Oxygen Levels on Hepatocyte Stress Responses

Cited by 21 publications

References 37 publications

Does pressure cause liver cirrhosis? The sinusoidal pressure hypothesis

Does pressure cause liver cirrhosis? The sinusoidal pressure hypothesis

Non-alcoholic fatty liver disease, to struggle with the strangle: Oxygen availability in fatty livers

Novel in vitro model for studying hepatic ischemia-reperfusion injury using liver cubes

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