The role of liver mesenchymal cell populations in porcine serum-induced rat liver fibrosis were studied morphologically and immunohistochemically. Five-week-old rats were intraperitoneally injected with porcine serum twice a week and examined at various intervals between 3 and 24 wk after the initial injection. At an early phase, numbers of fibroblasts and extracellular matrix increased in the walls of central veins and in portal and capsular connective tissues. In the walls of central veins, the number of "second-layer cells" (i.e., the fibroblasts located at the second layer of the wall) increased. Connective tissue septa, accompanying some fibroblasts, extended from these interstitial tissues into the hepatic parenchyma, and their foremost edges came into direct contact with the perisinusoidal stellate cells. The sinusoids adjacent to the newly formed septa collapsed and later disappeared; this process resulted in the formation of hepatic limiting plates along the septa. At a more advanced stage, the interstitial fibroblasts and septal cells-which were derived from interstitial fibroblasts and the stellate cells-increased and became multilayered, constructing three-dimensional cell networks. These networks, together with increased collagen fibrils and elastic fibers, constitute the fibrotic dense connective tissue. In the control rat, smooth muscle cells were positive on vimentin, desmin and smooth muscle-alpha-actin staining. The stellate cells, second-layer cells, capsular and portal fibroblasts were shown to be vimentin and desmin positive and smooth muscle-alpha-actin negative. In the fibrotic liver, septal(fibroblastic) cells were vimentin and desmin positive and smooth muscle-alpha-actin negative. We conclude that not only the perisinusoidal stellate cells but also the interstitial fibroblasts, including the second-layer cells, play substantial role in the development of porcine serum-induced septal fibrosis in rat liver.
of the liver capsule. The difference between normal and To investigate whether hepatic fibrosis induced by fibrotic rat liver in distribution of ED1-positive cells sugporcine serum in rats is caused by an immune reaction gests an involvement of macrophages in fibrogenesis to porcine serum, rats that were immunologically tolerand septum formation. In conclusion, our study showed ant exclusively to porcine serum were subjected to the a significant contribution by the immune response to repeated injection of porcine serum over a long period.porcine serum antigens leading to porcine serum-inThis porcine serum-tolerant group consisted of 15 duced rat hepatic fibrosis-processes in which macroWistar rats that had been injected intraperitoneally with phages may be important. This study may lead to an porcine serum twice a week from the first postnatal day understanding of the mechanism responsible for this for 18 weeks. The control group consisted of 16 Wistar form of experimental hepatic fibrosis. (HEPATOLOGY rats, aged 8 weeks, that were injected intraperitoneally 1996;23:811-817.) with porcine serum twice a week for 10 weeks. Livers were fixed and examined by light microscopy. The serum of each rat was subjected to indirect enzyme-linked Despite numerous studies on the development of heimmunosorbent assay (ELISA) to measure the level of antibody to porcine albumin. In addition, immunohisto-patic fibrosis, the mechanism remains unclear. Efforts chemical staining for ED1 was performed on untreated have been made to identify the cellular sources of extranormal and porcine serum-induced fibrotic rat livers cellular matrix proteins in normal and fibrotic livers. to examine the distribution of macrophages and their Observations suggest that hepatocytes play a key role precursors, the monocytes. All rats in the tolerant group in the production of interstitial collagen.1-6 However, showed an extremely low antibody level (x Å 68.27 other experiments have led to the conclusion that he- In humans, as well as in many experimental models, longed, repeated injections of porcine serum, if an immune response to porcine serum does not occur, the rats the chronic injury of hepatocytes usually leads to hedo not develop hepatic fibrosis. The porcine serum-tol-patic fibrosis and cirrhosis. It is postulated that mediaerant rats developed hepatic fibrosis after 4 weeks of tors from the damaged hepatocytes are involved in the CCl 4 treatment, indicating that injection of porcine se-structural changes associated with fibrosis, such as rum into neonatal rats did not cause anergy of fibrogen-capillarization, 15 or even in the process of fibrosis itself. esis, thereby preventing the animal from developing he-Gressner et al. 16 suggest that a cytosolic protein repatic fibrosis. In normal rat liver, ED1-positive cells, leased from the injured hepatocytes stimulates the prowhich include nearly all Kupffer cells, were located pre-liferation of hepatic stellate cells, which may be a preindominantly in the periportal area. In fibrotic rat liver, flam...
We re-evaluated three schemes of liver organization: the classic lobule, the portal lobule, and Rappaport's liver acinus. The lobular angioarchitecture of normal rat liver and the three-dimensional structure of pseudolubules found in rat livers with fibrosis induced by swine serum were compared with the classic lobule of the pig.
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