A novel method for determining hepatic sinusoidal oxygen permeability in the isolated perfused rat liver using [15O]O2.

Measurement of hepatic sinusoidal permeability of oxygen and other substrates may help elucidate the mechanisms responsible for impaired liver function in cirrhosis. However studies of sinusoidal oxygen permeability in normal liver and various disease states have been limited due to the considerable technical difficulties involved in the use of standard techniques. We have developed a new method for measuring sinusoidal oxygen permeability in the isolated perfused rat liver that overcomes the difficulties of previous methods by using [(15)O]O(2) and an in-line fluid monitor. This method uses data obtained from impulse response curves of radiolabelled red cells, albumin and oxygen that are fitted mathematically using the axial dispersion model to yield rate constants that describe oxygen transit through the liver. We have demonstrated the utility and reproducibility of this method by comparing multiple injections and permeability determinations in the same preparation. This approach could be used in isolated perfused organs to study oxygen permeability in a range of disease states.

The effect of oxygen supplementation on the arterial ketone body ratio in human cirrhosis.

BACKGROUND/AIMS: Data from studies in experimental models have suggested that the impairment of mitochondrial function and altered redox state that occur in cirrhosis may be due to impaired hepatic oxygenation. Since interventions that improve oxygen delivery to hepatocytes may improve mitochondrial functions, we studied the effects of oxygen supplementation on the arterial ketone body ratio (AKBR) in normal volunteers and patients with cirrhosis. METHODS: After a 2-hour fast, ketone bodies were measured in arterial blood taken from patients and controls while breathing room air and then after breathing oxygen via a face mask at 12 liters/min for 60 min. RESULTS: The AKBR was reduced in cirrhotic patients compared with controls, 0.74 +/- 0.23 and 1.51 +/- 0.4, respectively (p = 0.002). Oxygen supplementation significantly improved the AKBR in cirrhotic patients, from 0.74 +/- 0.23 to 1.04 +/- 0.28 (p = 0.001) but did not affect the AKBR in controls. CONCLUSION: These findings suggest that reduced hepatocyte oxygenation contributes to impaired hepatic mitochondrial function in cirrhosis. Strategies at increasing hepatic oxygen delivery may improve hepatic mitochondrial function in patients with chronic liver disease.

Hepatic Kupffer cell phagocytotic function in rats with erythrocytic-stage malaria.

BACKGROUND: In the erythrocytic phase of malaria, Kupffer cells show marked hypertrophy and hyperplasia and are filled with malarial pigment. However, phagocytic function in this state has not been well characterized. The aim of the present study was to use mouse Plasmodium berghei to infect rats with malaria and study the phagocytic function and morphology of Kupffer cells. METHODS: We used a recirculating isolated perfused rat liver (IPRL) to quantitate Kupffer cell phagocytic clearance of radiolabeled albumin-latex over 120 min in high parasitemia (53 +/- 6%; n = 7) and low parasitemia (approximately 1%; n = 4) malaria-infected rats and littermate controls (n = 7 and n = 4, respectively). In a further group of high-parasitemic rats, perfusion was ceased after 7 min and liver radioactivity also measured. Electron microscopy was performed after perfusions. RESULTS: In high-parasitemia malaria rats, clearance of radiolabeled latex from IPRL perfusate over 120 min was significantly (P < 0.01) faster than in controls, with a lower area under the curve (0.19 +/- 0.02 vs 0.43 +/- 0.07 /mL per min, respectively) and shorter half-life (t1/2k; 2.4 +/- 0.6 vs 10.0 +/- 2.3 min, respectively). Low-parasitemia rats were identical to controls. After 7 min perfusion in high-parasitemic rats (n = 4), total radioactivity in liver homogenates was higher than in controls (n = 4; 33.1 +/- 6.2 vs 18.4 +/- 1.9% of injected radiolabel; P < 0.05). Electron microscopy showed latex in Kupffer cells, more abundantly seen in high-parasitemic animals. CONCLUSIONS: Total Kupffer cell phagocytic activity of the liver is markedly increased in rats with a high parasitemic load of malarial P. berghei infection. This is presumed to reflect an upregulation of scavenger activity phagocytosing erythrocytes and their breakdown products.