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Immunohistochemical study of histological sections and immunochemical study in supernatants of primary cultures demonstrated a marked increase of the factor production in the regions of the background changes outside foci of carcinoma invasive growth. There was no difference in the type of expression of TGFbeta-I and TGFbeta-II receptors in morphologically different regions of the tumour. TGFbeta-I is considered as a principal factor that mediates hyperplastic reaction of the stroma in prostatic adenocarcinoma outside the zones of invasive growth. Formation of reactive stroma, in the authors' opinion, plays the role of a defensive mechanism hindering invasion of tumour cells into the connective tissue and its progression.

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Influence of methylprednisolone (MP) and cyclosporine A (CsA) on the extracellular matrix and growth factors was studied on the model of rapid nephrotoxic nephritis (RNN) and puromycin-aminonucleoside nephrosis (PAN). MP decreased accumulation of type IV collagen in RNN and increased the content of laminine in both models. CsA decreased deposits of type IV collagen but increased accumulation of fibronectin in both models. CsA reduced the content of a free form of oPRP in both models but MP did so in RNN only. CsA and MP decreased the level of active PRP in both models but MP did so in RNN only. CsA and MP decreased the level of active TPR-beta and increased the content of latent forms but CsA was more active in PAN. In experimental models of inflammatory RNN and non-inflammatory CPAN nephropathy CsA raised fibronectin production, MP increased deposition of laminine. CsA in both models suppressed production of basic fibrogenic factor TPR-beta while MP inhibited this in RNN only.

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Primary culture of prostatic adenocarcinoma is obtained from surgical material after radical prostatectomy. Typing of the obtained culture with antibodies to vimentin and cytokeratins has shown that the proportion of basic cell components--stromal and epithelial--in vitro correlates with such in the initial tumor tissue. In cultivation in different media active migration and proliferation of all cell types in the presence of embryonal serum and suppression of the stromal component in the medium where the serum was replaced for bovine hypophysis extract were observed. A comparative immunohistochemical analysis registered a release into culture of alpha SMA-positive myofibroblasts and active expression of TGF beta-1 in the medium containing serum. Design of dynamic mixed cell systems may serve a convenient model for investigation of stromal-epithelial interactions and their changes in cancer progression.

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Acute and chronic stages of NTN are followed by infiltration of glomeruli with monocytes/macrophages having different location (lumen of capillaries in the acute stage and mesangial zone in the chronic one). TNF-alpha is one of the key factors of the NTN acute stage damaging glomerular structures and initiating production of matrix form of the main factor of the fibroblast growth and transforming growth factor beta. Accumulation of these cytokines in the matrix facilitated monocyte penetration in the mesangium zone in chronization. Interaction of the matrix-associated cytokines regulates proliferative and fibrogenic activity of the mesangial cells as well as production of TNF-alpha by monocytes/macrophages. A decrease of TNF-alpha level during a chronic stage of NTN results in a decrease of the mesangial cell ability to produce matrix-associated cytokines.

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An acute stage of both immune (nephrotoxic nephritis) and non-immune (puromycin-aminonucleoside nephrosis) damage is characterized by an affected area infiltration with mononuclear leucocytes which produce cytokines that control mesangial cells proliferation and their production of the extracellular matrix components. This mononuclear infiltration is very intensive in the immune kidney damage and rather weak in the non-immune damage. Accumulation of the extracellular matrix in a chronic stage of puromycin-aminonucleoside nephrosis is very slight against the background of a weak mononuclear infiltration of the kidney glomeruli. Nephrotoxic nephritis is characterized by intensive infiltration of a glomerulus with mononuclear leukocytes and this results in high proliferation of mesangial cells and an extracellular matrix accumulation with appearance of an atypical interstitial collagen of types I and III. The absence or excessive number of mononuclear leukocytes in the affected area may result in metabolism disturbances of the extracellular matrix components with an increasing risk of glomerulosclerosis.

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The interaction of IL-1 and TNF alpha in the autolous phase of anti-GBM nephritis was studied. The influx of mononuclear leukocytes into the glomerulus and high cytokine levels induced a decrease in mesangial cell proliferation and an increase in extracellular matrix production. The methylprednisolone suppression of mononuclear leukocyte infiltration caused the autocine cytokine secretion of mesangial cells. Cyclophosphamide decreased cytokine production, but did not affect mononuclear leukocyte infiltration. The absence of mononuclear leukocytes in the site of the injury induced by imbalance between the synthesis and degradation of extracellular matrix components. The uncontrolled metabolism of the extracellular matrix may be induced glomerulosclerosis.

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The therapeutic effects of the phenolic antioxidants alpha-tocopherol, potassium phenosan and ionol were investigated in rats with nephrotoxic nephritis (NN). The antioxidants were given to the animals during the first 15 days of NN in the maximal doses being 50 mg/kg, 10 mg/kg and 60 mg/kg, respectively. alpha-Tocopherol and ionol were given to the rats 14 days and 3 days, respectively before NN was induced. The biochemical and histological evidence suggests that the antioxidants studied had no effect on NN. In contrast, methylprednisolone, given for 15 days in dose of 4 mg/kg exerted a pronounced therapeutic effect in the autologous phase of NN. Concurrent treatment of the rats with both methylprednisolone and potassium phenosan did not enhance a therapeutic hormonal effect.

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Cyclophosphamide (CP) and methylprednisolone (MP) were tried on rats with experimental nephrotoxic serum nephritis and mice with experimental acute serum nephritis. Pathological processes were analyzed simultaneously in vivo and in vitro. CP reduced the antibody impairment and stimulated glomerular infiltration by mononuclear leukocytes whose mediator spectrum was oriented to repair. MP failed to stop the impairment and aggravated the infiltration. The resultant chaotic accumulation of the extracellular matrix raised the risk of sclerosis. CP showed the advantages in experiment demonstrable also in the clinical setting.

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Late heterologous and autologous stages of nephrotoxic serum nephritis were studied against the background of MP-induced immunological suppression and PP effect on arachidonic acid metabolism. MP prevented mononuclear infiltration of the renal glomerulus and the development of severe morphological lesions in the autologous stage, while cell culture and mononuclear leukocyte number drastically decreased. PP did not significantly influence the autologous stage of the nephritis though resulted in marked proliferation in both renal glomerulus and mesangial cell culture during the heterologous stage. In spite of more pronounced proliferative activity of mesangial cells interleukin-I level was lower than in animals with nephritis untreated with PP. The enhancement of the proliferative reaction is obviously related, apart from interleukin-I, to the effect of other growth factors.

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To specify the role of mononuclear (MN) leukocytes in the development of mesangial cell proliferation, which is one of the main manifestations of glomerulonephritis, cell cultures of renal glomeruli of rats with nephrotoxic serum (NTS) nephritis were examined for the intensity of mesangial cell proliferation, the MN-leukocyte count, and for IL-1 production. The amount of mesangial cells and the intensity of their proliferation in the cultures of glomerular cells from rats with NTS nephritis were much higher than in intact rat cultures. At the same time the glomerular cultures from rats with NTS nephritis demonstrated an increase in the MN leukocyte count together with enhancement of IL-1 production. The treatment with prednisolone averted accumulation of MN leukocytes by the glomerular cultures and noticeably reduced mesangial cell proliferation. The supernatant liquid of cultures of peripheral blood MN leukocytes from patients with active nephritis suppressed human fibroblast proliferation, exerting no such action on mesangial cell culture. During the treatment with prednisolone, the supernatant liquid produced a reverse effect on fibroblast and mesangial cell cultures, which was associated with the clinical improvement of the health status. It is assumed that mesangial cell proliferation seen in nephritis may be related to infiltration of the glomeruli by MN leukocytes and to elevated production by them of IL-1 and that the therapeutic action of prednisolone may be determined by suppression of these processes.

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Late heterologous and autologous stages of serum nephritis together with glomerular cells in culture are studied biochemically, morphologically and immunohistochemically for the assessment of the role of mononuclear leucocyte mediator system. The heterologous stage of the nephrotoxic nephritis is associated with the increase of Interleukin-I and TxA2 production. Role of Interleukin-I in the autologous stage is less pronounced in spite of proliferative activity of cultured mesangial cells. The effect of suppressive factors prevails in the glomerulus.

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Heterologous serum glomerulonephritis (GN) was induced in CBA and C57BL mice. CBA mice developed diffuse proliferative GN. Glomerular changes in C57BL mice corresponded to the mesangial GN with proliferation of glomerular mesangial cells and mesangial infiltration with mononuclear phagocytes. Single administration of cyclophosphamide (CP) at the time of immunization exerted different effect on the development of the two morphological variants of GN. In CBA mice CP treatment resulted in disappearance of the immune complexes deposits with no influence on the cell reactions. In C57BL mice CP completely inhibited the development of the glomerular morphological changes. The lack of morphological similarity is most likely connected with the immunological differences in the histocompatibility complex (H-2).

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A retrospective analysis was made of the efficacy of oral treatment with cytostatics (azathioprin, batriden, cyclophosphamide) in 109 patients with chronic glomerulonephritis (CGN) (with a known morphologic appearance in 94 patients) and with excessive doses of cyclophosphamide i. v. in 32 patients with CGN depending on the nephritis standing, its clinical pattern and morphologic variant. The best results were recorded with nephritis lasting up to 2 years in patients suffering from the nephrotic pattern of CGN or at the stage of the nephrotic syndrome formation in patients with latent CGN, in membranoproliferative, membranous and membranocapillary versions of CGN, during pulse therapy, and in patients with focal segmental glomerulohyalinosis. No remissions were observed in mixed CGN. The experimental data are also provided concerning the influence of a single oral cyclophosphamide administration on the morphologic signs of nephritis in GBA and C57BL mice.

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