Ultrastructural zonal heterogeneity of hepatocytes and mitochondria within the hepatic acinus during liver regeneration after partial hepatectomy

BACKGROUND INFORMATION: Partial hepatectomy (70%) induces cell proliferation until the original mass of the liver is restored. In the first 24 h after partial hepatectomy, drastic changes in the metabolism of the remaining liver have been shown to occur. To evaluate changes in hepatocyte ultrastructure within the hepatic acinus during the liver regenerative process, we investigated, by light and electron microscopy observations on specimens taken 0 h, 24 h and 96 h after partial hepatectomy, the hepatocyte structure and ultrastructure in the periportal and pericentral area of the hepatic acinus, with a particular emphasis on mitochondria ultrastructure. Moreover, some biochemical events that could affect the mitochondria ultrastructure and function were investigated. RESULTS: We found that, 24 h after partial hepatectomy, mitochondria with altered ultrastructure were preferentially localized in the periportal area. Periportal hepatocytes showed also an increase in the number of peroxisomes, free ribosomes, lysosomes and autophagosomes. Altered mitochondria showed swelling, an ultrastructural index of increased membrane permeability, a reduction in the number of cristae, and a rarefied, often vacuoled, matrix. Consistently, an increase in the mitochondrial oxidized/reduced glutathione ratio was found as well as calcium release from mitochondria in a manner inhibited by cyclosporin A. Interestingly, light and electron microscopy analysis showed that the hepatocytes in the periportal area were the cells with the major structural attributes to proliferate. At 96 h after partial hepatectomy, the preferential zonation of altered mitochondria was lost and the normal mitochondrial membrane permeability properties were restored. CONCLUSIONS: We suggest that 24 h after partial hepatectomy, a preferential zonation of altered mitochondria in the periportal hepatocytes could be involved in the changes of metabolic and functional heterogeneity of the hepatocytes within the hepatic acinus during the regenerative process.     

Perfusion heterogeneity in the pulmonary acinus

There is little information on the distribution of acinarperfusion because it is difficult to resolve blood flow within such small regions. We hypothesized that the known heterogeneity of arteriolar blood flow and capillary blood flow would result in heterogeneous acinar perfusion. To test this hypothesis, the passage offluorescent dye boluses through the subpleural microcirculation ofisolated dog lobes was videotaped by using fluorescence microscopy. Asthe videotapes were replayed, dye-dilution curves were recorded fromeach of the tributary branches of Y-shaped venules that drained anacinus. From the dye curves, we calculated the mean appearance time ofeach curve. The difference in mean appearance times between venulartributary branches was small in most cases. In 43% of the observedvenular branch pairs, the dye curves were essentially superimposable(the mean appearance-time difference was <5%); and in another 42%,the mean appearance-time difference between curves was 5-10%.From these results, we conclude that acinar perfusion is unexpectedlyhomogeneous.

     

Diffusional screening in the human pulmonary acinus.

In the mammalian lung acini, O(2) diffuses into quasi-static air toward the alveolar membrane, where the gas exchange with blood takes place. The O(2) flux is then influenced by the O(2) diffusivity, the membrane permeability, and the acinus geometric complexity. This phenomenon has been recently studied in an abstract geometric model of the acinus, the Hilbert acinus (Sapoval B, Filoche M, and Weibel ER, Proc Natl Acad Sci USA 99: 10411, 2002). This is extended here to a more realistic geometry originated from the morphological model of Kitaoka et al. (Kitaoka K, Tamura S, and Takaki R, J Appl Physiol 88: 2260-2268, 2000). Two-dimensional numerical simulations of the steady-state diffusion equation with mixed boundary conditions are used to quantify the process. The alveolar O(2) concentration, or partial pressure, and the O(2) flux are computed and show that diffusional screening exists at rest. These results confirm that smaller acini are more efficient, as suggested for the Hilbert acini.     

Gas mixing in the airways of dog lungs during high-frequency ventilation

Washout of insoluble inert test gases of different diffusivity (He and SF6 or He and Ar) from dog lungs was studied during high-frequency ventilation (HFV). Test gas equilibrium and subsequent washout were performed with HFV, succeeding measurements being performed at different stroke volumes (1.5-2.5 ml/kg body wt), oscillation frequencies (10-30 Hz), and with different lung volumes (32-74 ml X kg-1). Test gas concentrations were continuously measured by a mass spectrometer. The time course of washout could be described as the sum of two exponentials. There were no consistent differences in the time courses of washout between He and SF6 or between He and Ar. It is concluded that gas mixing in the airways during HFV is not significantly limited by diffusion, and this is suggested to apply during HFV to steady-state transport of respiratory gases (e.g., O2 and CO2) as well as to the transient state of inert gas washout.     

A three-dimensional model of the human pulmonary acinus.

A three-dimensional (3-D) model of the human pulmonary acinus, a gas exchange unit, is constructed with a labyrinthine algorithm generating branching ducts that fill a given space completely. Branching down to the third respiratory bronchioles is generated with the proposed algorithm. A subacinus, a region supplied by the last respiratory bronchiole, is approximated to be a set of cubic cells with a side dimension of 0.5 mm. The labyrinthine algorithm is used to determine a pathway through all cells only once, except at branching points with the smallest path lengths. In choosing each step of a pathway, random variables are used. Resulting labyrinths have equal mean path lengths and equal surface areas of inner walls. An alveolus can be generated by attaching alveolar septa, 0.25 mm long and 0.1 mm wide, to the inner walls. Total alveolar surface area and numbers of alveolar ducts, alveolar sacs, and alveoli in our 3-D acinar model are in good accordance with those reported in the literature.     

Performance characteristics of a model secreting acinus

An acinus is the principal secretion unit of an exocrine gland. This paper sets up a mathematical model of an acinus and examines the effect on the output of varying the operating parameters, both of the secretion mechanism and the fluid properties. Particular reference is made to acini of the pancreas. The question of whether the effects of cystic fibrosis on the pancreas can be attributed to the increased viscosity of the exudate is also considered. The work identifies key parameters, and their quantitative ranges, which would need to be examined experimentally in order to resolve this question.