Journal of Pathology and Translational Medicine

Original Articles

Extracellular Matrix and Astrocytic Response during Regeneration following Cryogenic Injury in Adult Rat Cerebral Cortex.: Soo Im Choi, Woo Ick Yang, Tae Seung Kim; Korean J Pathol. 1996;30(6):473-486.

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Abstract PDF: Astrocytes are the most numerous cellular elements in the cerebrum, and they normally have a very slow turnover rate. But during regeneration after injury, they proliferate markedly resulting in astrogliosis. The extracellular matrix in the central nervous system is present in the vessel walls and in the external glia limitans as a basal lamina. The presence of an intact extracellular matrix framework is important in regeneration after injury. Understanding the properties of astrocytic proliferation will be helpful to find out new treatment for functional recovery in the central nervous system. In this study, after cryogenic injury was performed on the cerebral cortex in rats, changes in astrocytes and the extracellular matrix were observed using light microscopy, immunohistochemical stain for glial fibrillary acidic protein(GFAP), proliferating cell nuclear antigen(PCNA), fibronectin, laminin, and type IV collagen, autoradiography and electron microscopy. The results were as follows; 1) The coagulative necrosis, which followed cryogenic injury on the cerebral cortex was healed, forming a new pia mater above the lesion. 2) Some of the PCNA positive cells were astrocytes and some of the GFAP positive cells showed a positive reaction to PCNA. 3) Proliferating astrocytes labelled by autoradiography or immunohistochemical stain for PCNA reached maximal numbers 3days after the injury and they were no longer found 2 weeks after injury. 4) In autoradiography with immunohistochemical stain for GFAP, about 1% of GFAP positive astrocytes were labelled by autoradiography and in double immunohistochemical stain for PCNA and GFAP, about 8-16% of GFAP positive astrocytes were also stained by PCNA. 5) In immunohistochemical stain for fibronectin, laminin and type IV collagen, laminin and type IV collagen were present in the newly formed blood vessel walls and fibronectin showed a diffuse positive reaction within the lesion. The new pia mater was formed within 2 weeks after the injury. 6) On electron microscopic examination, basal lamina material was found in the vessel wall 1 week after the injury and at 2 weeks, a nearly complete and continuous basal lamina was formed although the thickness was uneven. According to these findings, astrocytes in the cerebral cortex of adult rats proliferate very early in the regenerative period after cryogenic injury. At 2 weeks after the injury, this regeneration ceases and the damaged basal lamina of pia mater and vessel wall were reconstituted.

Immunohistochemical Localization of Extracellular Matrix Components in Diabetic Nephropathy.: Seung Sam Paik, Moon Hyang Park; Korean J Pathol. 1997;31(5):427-435.

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Abstract PDF: Normal human glomerular basement membrane (GBM) and mesangial matrix (MM) contain several different basement membrane components in varying degrees. The characteristic morphological and ultrastructural changes in patients with diabetic nephropathy are the thickening of the GBM and the expansion of the MM. In order to investigate the changes of extracellular matrix components in diabetes, the immunohistochemical localization was performed in 17 cases with different degrees using antisera to human collagen types I, III, IV, VI, fibronectin, and laminin. The following results were obtained: 1. The reactivity for collagen IV was increased in expanded MM in the diffuse glomerulosclerosis (GS). With the progression to the nodule formation, collagen IV was prominently decreased in the peripheral area of the nodules. 2. Collagen VI was increased in GBM and MM in the diffuse GS, it was especially prominent in the expanded MM. With the progression to nodule formation, collagen VI was prominently increased in the periphery of the nodules. 3. Interstitial collagen I and III were not stained in many of the cases with the diffuse GS. With the progression to nodule formation, these were slightly expressed. A lamellar pattern of positive reaction was noted at the periphery of the late nodular lesions. 4. Fibronectin was increased in GBM & MM in the diffuse GS, it was especially intense in the MM. With the progression to the nodule formation, the reactivity of antibody to the fibronectin was decreased. 5. Laminin was weakly stained along the GBM & trace in the MM, but was not changed in the nodular GS. In summary, the expanded mesangial matrix in the diffuse GS showed a markedly increased staining for collagen IV, fibronectin and collagen VI. Less intense linear staining for collagen VI, fibronectin, laminin, collagen IV and collagen III was noted along the GBM. In the nodular GS, the composition of the early nodules resembled that of the diffuse GS. However, the late nodular lesion of the nodular GS revealed decreased reactivity for collagen IV and fibronectin at the periphery of the nodule, where collagen VI and interstitial collagen I and III were increased in laminated pattern.

Sequential Changes of Extracellular Matrix mRNA in Anti-GBM Antibody Induced Crescentic Glomerulonephritis in the Rabbit.: Moon Hyang Park, Unn Wha Lee, In Sup Han, Rho Won Chun, Jung Woo Noh; Korean J Pathol. 1998;32(9):627-637.

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Abstract: Progressive renal fibrosis is considered to be the final common pathway leading to chronic renal insufficiency, however, the mechanism regarding renal fibrosis in renal injury is not well understood. Recently, several kinds of cytokines have been known to be related to fibrosis after renal injury. The interaction between elements regulating fibrogenesis would be better understood by looking at the effect of TGF-beta1 on the synthesis and accumulation of extracellular matrix, especially collagenous proteins. Crescentic glomerulonephritis (CGN) was induced in New Zealand White rabbits by administration of guinea pig anti-GBM IgG after sensitization with guinea pig IgG; and their kidneys were analyzed for the development of crescents and fibrosis through sequential renal biopsies. Serum creatinine levels in a time course progressively increased until day 15. We semi-quantitatively assayed the levels of the expression of alpha1(I) collagen mRNA and TGF-beta1 mRNA factored for GAPDH mRNA using RT-PCR. We observed a progressive interstitial fibrosis and the expression of collagen I both in the cortex and medulla. The effect of repeated renal biopsy itself on pathology and on the expression of alpha1(I) collagen mRNA and TGF-beta1 mRNA in a time course were not significant, but a very mild increase of the expression of alpha1(I) collagen mRNA was noted at day 15. Histology showed a progressive crescent formation and interstitial fibrosis in a time course that roughly paralleled the expression of alpha1(I) collagen mRNA in both cortex and medulla. TGF-beta1 mRNA was hardly expressed at day 0 in cortex as well as in medulla. It was elevated from day 1, peaked at day 7, and then decreased. In medulla, TGF-beta1 mRNA was noticeably expressed at day 1, peaked at day 4, and then decreased. The expression of alpha1(I) collagen mRNA was seen even before inducing CGN. It was gradually and continuously increased until day 15 both in cortex and medulla. These results suggest that the expression of TGF-beta1 mRNA precedes that of alpha1(I) collagen mRNA in the early stage of CGN and has a central role for provoking the accumulation the collagen I, the most representative interstitial extracellular matrix, in the rabbit model CGN induced by anti-GBM antibody. We conclude that the measurement of the expression of TGF-beta1 mRNA and/or alpha1(I) collagen mRNA in a biopsy sample can be a useful predictor for renal outcome.

Expression of Transforming Growth Factor-beta1 and Its Effects on the Extracellular Matrix Formation and Angiogenesis in Gastric Carcinoma.: Young Hee Choi, Young Euy Park; Korean J Pathol. 1998;32(9):647-654.

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Abstract: Malignant cells in culture express elevated levels of transforming growth factor-beta1 (TGF-beta1) mRNA and secrete an abundant amount of the TGF-beta1 protein. An attempt was made to define the role of the TGF-beta1 secreted from tumor cells, as a possible humoral factor which functions in a paracrine manner to stimulate the production of collagen and angiogenesis in gastric carcinoma. The expression of the TGF-beta1 by immunohistochemical stain (n=70) in gastric adenocarcinoma tissues was studied. Angiogenesis was evaluated by immunohistochemical staining of tumor vessels, using polyclonal antibody to factor VIII related antigen and counting the three most active areas of neovascularization. The extracellular matrix was counted as area density by using an image analyzer following Masson-Trichrome staining. The prominent reactivity for TGF-beta1 was associated with invasion depth (r=0.2, p<0.05), increased number of microvessel (r=0.49, p<0.05) and increased area density of extracellular matrix (r=0.36, p<0.05), respectively. In summary, TGF-beta1 may have a role in tumor invasion and metastasis by increased angiogenesis and deposits of extracellular matrix.

Immunohistochemical Study on Tenascin Expression in IgA Nephropathy.: Ho Jung Kim, Hye Jin Park, Ok Kyung Kim, Sun Hee Sung; Korean J Pathol. 2000;34(1):68-76.

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Abstract PDF: Glomerulosclerosis is a common outcome in various progressive glomerular diseases, and results from accumulation of extracellular matrices. Depending on the disease progression the extracellular matrices show quantitative and qualitative alterations. Tenascin is a significant extracellular matrix glycoprotein that expresses in normal and pathologic tissue of varying organs including kidney. We performed immunohistochemical staining for tenascin using 30 cases of renal biopsy specimens diagnosed as IgA nephropathy to study the alteration of tenascin expression in IgA nephropathy according to the histologic grading. The results were as follows; 1. The more high histologic grade, the more increase of tenascin was found in the glomerulus. 2. Tenascin was increased in proportion to the mesangial matrix. 3. The staining of tenascin was more intense in glomerular sclerotic area and was increased in proportion to the progression of sclerosis. 4. Cellular crescents showed strong positivity for tenascin. 5. Tenascin was increased in proportion to the degree of interstitial fibrosis in renal cortex. In conclusion, tenascin is an important extracellular matrix component which is significantly increased in both glomerulus and cortical interstitium according to the progress of the disease in IgA nephropathy.

Expression of Platelet-Derived Growth Factor and Extracellular Matrix in IgA Nephropathy.: Hwal Woong Kim, Kyoung Cheol Moon, So Yeon Park, Hyun Soon Lee; Korean J Pathol. 2000;34(6):446-455.

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Abstract PDF: Glomerulosclerosis represents a pathological hallmark of progressive glomerular injury. Mesangial cell proliferation and accumulation of extracellular matrix (ECM) proteins in the mesangial area frequently precede the formation of glomerulosclerosis. To understand the role of platelet-derived growth factor (PDGF) and ECM in the development of glomerulosclerosis, we examined the expression of type IV collagen, laminin, fibronectin, and PDGF in 45 renal biopsies diagnosed with IgA nephropathy (IgAN) using a standard peroxidase antiperoxidase (PAP) technique. Normal control specimens were obtained from four nephrectomy specimens diagnosed with renal cell carcinoma. As compared with normal controls, type IV collagen increased in 68%, fibronectin in 73%, laminin in 51%, and PDGF in 36% of patients with IgA nephropathy. The staining intensity of PDGF, type IV collagen, and fibronectin increased significantly in cases with moderate to severe mesangial cell proliferation than cases without. In the areas of glomerulosclerosis, the staining intensity of type IV collagen, laminin, and PDGF decreased, whereas that of fibronectin increased. These results suggest that mesangial cell proliferation in relation to increased PDGF expression in IgAN could stimulate the expression of type IV collagen, laminin and fibronectin leading to mesangial expansion. They also suggest that ECM decreased in advanced glomerulosclerosis. Deposition of fibronectin, which originates mainly from the blood stream, increases during the course of progressive glomerulosclerosis, whereas other ECM components decrease in advanced glomeruloslresosis.

Expression of Transforming Growth Factor-beta1 in Cyclosporine-Induced Nephropathy in Rats.: Yu Na Kang, Kwan Kyu Park, Mee Yul Hwang, Kun Young Kwon, Sang Sook Lee, Eun Sook Chang, Hyun Chul Kim; Korean J Pathol. 2000;34(9):642-651.

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Abstract PDF: Cyclosporine nephropathy was induced by intraperitoneal injection of cyclosporine 25 mg/kg in Sprague-Dawley rats daily for 1, 4, 8, and 12 weeks to clarify the relationship between cyclosporine nephropathy and the expression of TGF-beta1 with extracellular matrix deposition. On light microscopic examination, the kidneys in the 12 week cyclosporine-treated rats showed focal or striped fibrosis, vacuolization of tubular cells, and injury of endothelial cells. Immunohistochemically, TGF-beta1 protein was strongly expressed in the cyclosporine-treated rat kidneys, especially in the glomerular endothelial cells, interstitial endothelial cells, tubular epithelial cells, and parietal cells in the Bowman's capsule of the glomerulus as well as the periglomerular arterioles. The amount of TGF-beta1 expression was correlated with the morphological change in the cyclosporine-treated rats. Extracellular matrix, such as fibronectin and collagen IV, was also expressed in the endothelial cells of the glomerulus and the interstitium. It can be concluded, therefore that TGF-beta1 protein is probably involved in the early stage of fibrogenesis in cyclosporine nephropathy. It can be postulated that cyclosporine nephropathy results from the accumulation of extracellular matrix associated with the increase of TGF-beta1 transcription. Therefore, these results could be used in reducing fibrosis in cyclosporine nephropathy.

Immunohistochemical Study on Expression of Extracellular Matrix Components in Glomerular Diseases.: Sun Hee Sung, In Joon Choi; Korean J Pathol. 1994;28(3):288-296.

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Abstract: Most glomerular lesions are associated with qualitative and quantitative alterations of the extracellular matrix components, having relation to progressive glomerular sclerosis. We aimed to investigate the characteristic alteraltions in distribution of extracellular matrix components, such as fibronectin, laminin, collagen type III and IV in human glomerular diseases by immunohistochemical method. The materials included are 3 nephrectomy as normal control, 51 renal biopsies and I autopsy; 3 normal, 5 minimal change disease, 5 minimal change disease with minimal mesangial lgA deposit, 5 benign recurrent hematuria, 10 focal segmental glomerulosclerosis, 15 lgA nephropathy, 10 membranoproliferative glomerulonephritis, 2 diffuse mesangial sclerosis of infancy. Type IV collagen and laminin were present normally in the mesangium, GBM, TBM and interstitial vessels, and were increased at the portion of increased mesangial matrix, of sclerosis and thickened GBM in cases of lgA nephropathy, membranoproliferative glomerulonephritis, focal segmental glomrulosclerosis and diffuse mesangial sclerosis in the proportion to the glomerular damage. Type III collagen was absent in the normal glomeruli, but was detectable focally and segmentally in cases of membranoproliferative glomerulonephritis, IgA nephropathy and focal segmental glomerulosclerosis at the sclerotic portion. Fibronectin was normally detectable mainly in the mesangium, and partly and incompletely in GBM, and was increased at the portion of increased mesangial matrix, sclerosis and thickened GBM in cases of focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, IgA nephropathy and diffuse mesangial sclerosis, but was diminshed at the old slcerotic portion or global sclerosis. The expression of these antibodies in cases of minimal change disease, minimal change disease with minimal mesangial IgA deposit, benign recurrent hematuria was not different, quantitatively and qualitatively, from that of normal glomeruli. These findings suggest that progressive glomerular sclerosis was due to the increase of extraceuular matrix components such as type IV collagen, laminin, fibronectin and new appearance of type III collagen, and the expression was in proportion to the degree of sclerosis, but had no relation to the disease entity.

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