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Biomedical subjects

M W Seiler

Publications and source records attributed to M W Seiler.

At least 19 recordsLinked to original sources
PubMed1992

Immunomorphometric studies of proteinuria in individual nephrons of rats.

BACKGROUND: Heterogeneity of proteinuria among nephrons has been directly shown by micropuncture analysis of experimental models. Since the number of nephrons per kidney that are accessible for micropuncture is very small, we have developed a new immunomorphometric method for directly studying proteinuria in a much larger number of individual nephrons. This new method is based on the luminal surfaces of thick ascending limb of the loop of Henle (TAL) cells collectively functioning as an immunoabsorbent column for anti-Tamm-Horsfall protein antibodies that enter the urinary filtrate of that nephron. EXPERIMENTAL DESIGN: The distribution of luminal IgG deposits formed in TALs after injection of anti-Tamm-Horsfall protein antibodies was studied in three models of experimental proteinuria in rats to define the relationship between the formation of luminal deposits and the overall level of albuminuria and to test the utility of this method in analyzing the heterogeneity of luminal deposits among nephrons in other models. RESULTS: A close relationship between the magnitude of albuminuria and the distances that luminal IgG deposits extended along the straight course of TALs in individual nephrons of rats injected with rabbit anti-Tamm-Horsfall protein antibodies was established in a model of proteinuria with a uniform pattern of glomerular hemodynamics, heterologous immune complex nephropathy in rats. In models with more heterogeneous glomerular hemodynamics, autologous immune complex nephropathy and aminonucleoside nephrosis, greater heterogeneity in luminal IgG deposit formation among nephrons was demonstrated. The distances that luminal IgG deposits extended along TALs was more variable in these models than in heterologous immune complex nephropathy rats with comparable levels of albuminuria. CONCLUSIONS: Variability in the distances that luminal IgG deposits extend along TALs reflects heterogeneity among nephrons. The luminal deposit technique provides a new means for direct analysis of variability of dysfunction in many individual nephrons not accessible to micropuncture.

Animals↗
PubMed1988

Extratubular Tamm-Horsfall protein deposits induced by ureteral obstruction in mice.

The effects of unilateral ureteral obstruction were studied in mice. Obstruction for 24 hr led to the formation of extratubular Tamm-Horsfall protein (TH) aggregates within the renal interstitium and at the base of distal convoluted tubular (DCT) cells. These DCT deposits were shown by ultrastructural analysis to be entirely extracellular. They had the fibrillar substructure characteristic of TH and had not been seen after urinary obstruction in other species. As a consequence of retrograde flow of urine to glomeruli, obstruction also caused TH aggregates to form within Bowman's spaces. These glomerular casts of TH were detected throughout the 3-week period of study after the release of unilateral obstruction. High serum titers of IgG antibodies to TH developed in mice intradermally immunized with TH but were not observed after obstruction alone. Circulating anti-TH antibodies combined with TH present on the basal surfaces of the thick ascending limb of the loop of Henle cells and DCT cells to form immune complexes in situ. Interstitial inflammation in the areas surrounding subepithelial tubular immune deposits was not present in the kidneys of immunized mice and was not selectively induced by temporary obstruction. However, foci of inflammation were seen in all obstructed kidneys. At later times, inflammatory foci in previously obstructed kidneys were associated with progressive scarring, primarily in polar regions. The location and severity of these changes within kidneys produced by obstruction in immunized mice did not differ from those in unimmunized mice. The titers of anti-TH antibodies in immunized mice were not enhanced or depressed as a consequence of unilateral ureteral obstruction. These studies demonstrate that complete obstruction of urinary flow in the mouse for periods as short as 24 hr may lead to progressive segmental renal scarring. These studies further indicate that increasing the quantities of extracellular TH by obstruction does not facilitate inflammatory responses to TH immune complexes formed in situ. While exposure of renal tissue to highly toxic components of extravasated urine may play a crucial role in inflammatory responses, autoimmunity to TH was not implicated as a contributing factor by the present studies in mice.

Animals↗
PubMed1986

Influence of renal transplantation in rats on glomerular and tubular immune complexes.

Kidneys were transplanted from rats with immune complex nephritis to normal rats to determine the role of circulating antibodies to renal antigens in the maintenance of immune complexes. Glomerular subepithelial immune complexes in nine proteinuric donor rats, actively or passively immunized with proximal tubular antigen Fx1A (active and passive Heymann nephritis), were studied at the time of transplantation and two to four and one-half months after transplantation to normal unilaterally nephrectomized recipient rats. These subepithelial IgG deposits and proteinuria persisted throughout the four-month period after transplantation. Tubular subepithelial immune complexes in the kidneys of nine rats, actively immunized with a distal renal tubular antigen, Tamm-Horsfall protein, were studied at the time of transplantation when donors had high circulating IgG antibody titers to Tamm-Horsfall protein and at one to eight weeks after transplantation. The abundant granular and nodular immune complexes of rat IgG and Tamm-Horsfall protein at the base of tubular cells were very rapidly cleared during the first two weeks after transplantation and were virtually absent by four weeks. The rapid clearance of tubular immune complexes after transplantation of kidneys from actively immunized rats followed a time course similar to that after passive immunization with antisera to Tamm-Horsfall protein. These findings support the concept that high titers of circulating antibodies to Tamm-Horsfall protein are required to prevent the rapid clearance of tubular immune complexes, a process that is facilitated by conditions of antigen excess at the surface of tubular cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Annulate lamellae and single-pore complexes in human spermatogonia.

Electron microscopic examination of non-neoplastic human testes revealed cytoplasmic annulate lamellae (AL) in all cell types within the seminiferous epithelium. Short lamellar profiles with low numbers of pores were found in spermatogonia and spermatocytes, while larger stacks of AL were seen in spermatids and Sertoli cells. Stacks of lamellae were closely associated with redundant nuclear envelope during late spermiogenesis. Residual bodies shed by the developing spermatozoa contained large number of lamellar-pore complexes. One cryptorchid testis was also examined. In this case the seminiferous epithelium consisted only of Sertoli cells with rare spermatogonia. AL were found in both cell types, with a similar morphology to those of the non-neoplastic testes. This study demonstrates that AL are expressed in all stages of spermatogenesis.

Adult↗
PubMed1986

Studies of glomerular mesangial uptake and processing of macromolecules. I. Effect of polyvinyl alcohol-induced macrophages on uptake of iron dextran.

The influence of prior glomerular mesangial uptake of a macromolecule that induces the infiltration of macrophages (M phi) into the mesangium on the uptake of a second macromolecule by the mesangium was studied in inbred Lewis rats. Renal transplantation of kidneys from rats previously injected with polyvinyl alcohol (PVA) was performed to avoid the potential influences of ongoing uptake of PVA and altered host milieu on the glomerular uptake of iron dextran (ID), a macromolecule that localizes primarily in the intrinsic mesangial cells of unmodified rats. In contrast to that in the recipient's native kidney, the uptake of ID was markedly increased in the glomeruli in kidneys previously exposed to PVA. This enhanced uptake was the consequence of the phagocytic activity of mesangial M phi elicited by and containing PVA since the site of increased ID content was shown by ultrastructural studies to be within mesangial M phi. Isogeneic renal transplantation per se did not influence mesangial function since the glomerular uptake of ID in donor and recipient kidneys was the same when donors were normal rats. In addition to the enhanced uptake of ID into lysosomes by mesangial M phi these cells were also much more active in the further processing of ID to ferritin particles within the cytoplasm than were intrinsic mesangial cells. These studies demonstrate that M phi attracted to the mesangium by a stimulus such as PVA may have important effects on the consequences of additional challenges to the mesangium.

Animals↗
PubMed1986

Renal tubular immune complex formation in mice immunized with Tamm-Horsfall protein.

Mice were given injections of rat Tamm-Horsfall protein (TH) in order to study immune complex formation in the distal nephron. After immunization, all mice had high serum levels of antibodies to TH; immune deposits consisting of IgG antibodies to TH and TH formed at the base of cells of the thick ascending limb of the loop of Henle (ALH) and distal convoluted tubule. These basal complexes were maximal in number and size within the cortical ALH, where they often radiated toward the luminal surfaces. Although the highest anti-TH antibody titers were found in animals with the most extensive deposits, antibody levels were not directly proportional to IgG deposits or to the time after immunization. The larger immune deposits were visualized by light microscopy as PAS-positive deposits. The quantity of these deposits was proportional to the time after immunization and was directly related to anti-TH antibody levels. Electron microscopy showed that these immune deposits were present within the basal and lateral intercellular spaces of the cells of the ALH. The distribution and localization of TH within the normal mouse kidney was very similar to that in rats. However, the distribution of immune complexes within the distal nephron in mice differed from rats similarly treated with TH and indicates either species differences in the distribution and/or organization of TH associated with tubular cell surfaces or that the accessibility of distal tubules to antibodies is species-dependent.

Animals↗
PubMed1984

Pulmonary hamartoma. An ultrastructural study.

Three so-called pulmonary hamartomas were studied by electron microscopy. Histologically, the hamartomas included one case with mainly mature cartilage (chondroma), one with loose myxoid fibrous tissue and rare areas of mature cartilage, and one with only loose myxoid fibrous tissue. Ultrastructurally, a common feature in all three cases was the presence of stellate, undifferentiated mesenchymal cells. These cells were sparse in the chondroma, and abundant in the other two cases. Areas of transition between undifferentiated mesenchyme and cartilage were present in two cases (the chondroma and the myxoid fibrous tumor with areas of mature cartilage). Unusual stellate smooth muscle cells were present in areas of loose myxoid tissue. The epithelial components revealed continuity and morphologic identity to terminal bronchiolar and alveolar epithelium. A distinct basement membrane was always present. These observations support the concept that pulmonary hamartomas represent a histologic spectrum of benign mesenchymal neoplasms, which originate in peribronchial connective tissue and incorporate respiratory epithelium as they expand.

Aged↗
PubMed1984

Abnormal cilia in a breast carcinoma. An ultrastructural study.

Epithelial cells bearing multiple cilia of the motile type were observed in an infiltrating ductal carcinoma of the postmenopausal breast. These cilia displayed a number of abnormalities, the most striking of which was the widespread occurrence of supernumerary single microtubules. While the presence of occasional cells with a single primary cilium is a common finding in a great variety of tumors, including breast neoplasms, the occurrence of cells with multiple abnormal cilia in malignant mammary epithelium is most intriguing and, to our knowledge, has not been documented before.

Breast Neoplasms↗
PubMed1983

Uptake of polyvinyl alcohol by macrophages in the glomerular mesangium of rats. Histologic and functional studies.

Rats received daily subcutaneous injections of the synthetic polysaccharide polyvinyl alcohol (PVA) for 1-28 days. The amount of PVA localized in the glomerular mesangium increased progressively during this time. By 28 days, all glomeruli showed extensive intracellular mesangial sequestrations of PVA, causing marked widening of mesangial areas, while the peripheral capillary loops were unaltered. Overall glomerular hypercellularity was mild to moderate, occurring mainly in areas of PVA deposition. Follow-up studies after 6, 12, 26, and 40 weeks revealed partial reduction of glomerular PVA masses. The PVA deposits were frequently associated with nonspecific esterase (NSE)-positive cells. The number of NSE-positive cells per glomerular tuft section increased from 0.1 in controls, to 2.1, 4.0, and 4.5 after 3, 14, and 28 days of PVA treatment, respectively. Similarly, glomerular counts for Ia-antigen-bearing cells rose from 2.1 in controls to 4.8 on Day 3 and showed further increases at later time periods with confluent staining of clusters of Ia-positive cells. In glomeruli, Ia-bearing cells were mainly noted in PVA-positive mesangial areas. These results indicate that PVA is taken up in the glomerulus primarily by cells that are NSE- and Ia-antigen-positive, suggesting that these cells are activated blood-borne monocyte-macrophages that sequester this polysaccharide. Clearance studies revealed that the glomerular filtration rate and effective renal plasma flow remained normal after 4 weeks of PVA injections. PVA-treated rats showed only mild elevations of urinary protein excretion. These findings indicate that confinement of marked structural and cellular alterations to the mesangium, even including the presence of infiltrating monocyte-macrophages, is compatible with absent or minimal dysfunction of the glomerular ultrafilter.

Animals↗
PubMed1983

Role of macrophages in the glomerular mesangial uptake of polyvinyl alcohol in rats.

Glomerular mesangial cell populations were characterized through sequential morphologic studies after injection of polyvinyl alcohol (PVA), a synthetic polysaccharide previously shown to accumulate in the mesangium. Renal tissue was obtained from groups of rats, 1 day to 28 days after initial subcutaneous injection of PVA, and studied by transmission electron microscopy and fluorescence microscopy using monoclonal antibodies to rat Ia. PVA was initially present in areas of attenuated mesangial matrix. Subsequently, only a small fraction of PVA was associated with "classical" mesangial cells. By 3 days, variable degrees of glomerular hypercellularity were noted, and PVA appeared within phagocytic vacuoles of immature macrophages in the mesangium and in occasional endocytic vacuoles of endothelial and mesangial cells. At later time points, increasing quantities of PVA were found within the large confluent phagolysosomes of more mature mesangial macrophages. By 2 weeks, features of epithelioid transformation were evident. By 3 and 4 weeks many glomeruli contained several mesangial microgranulomas, i.e., collections of epithelioid cells of variable degree of maturation, including giant cells. An increase in Ia-positive cells in glomeruli corresponded closely to the increase in numbers of cells with ultrastructural characteristics of macrophages and epithelioid cells within mesangial regions. These studies demonstrate a primary role for macrophages in the uptake of PVA, a process ultimately leading to granuloma formation in the mesangium.

Animals↗
PubMed1983

Influence of altered glomerular permeability on renal tubular immune complex formation and clearance.

Proteinuria was induced in rats to determine whether intravenously injected antibodies to a distal tubular antigen would bind to the luminal surfaces of distal tubular cells in vivo. Rats with proteinuria induced by an intravenous injection of sheep antisera to Fx1A (passive Heymann model) were injected 10 days later with rabbit antisera to Tamm-Horsfall protein. Linear rabbit IgG deposits along the luminal cell surfaces in the initial portion of the thick ascending limb of the loop of Henle (ALH) were demonstrated by immunofluorescence microscopy at 4 hours and were maximal 1 to 3 days after injection of antibodies to Tamm-Horsfall protein. The distance that these immune deposits extended along the ALH was directly proportional to the magnitude of proteinuria. Light microscopy showed periodic acid-Schiff-positive luminal deposits and an increased number of mitoses confined to the early ALH. Ultrastructural studies revealed continuous very electron-dense deposits initially covering the luminal surfaces of ALH cells. During the clearance phase, these deposits were surrounded and separated from ALH cell surfaces by a less electron-dense fibrillar material with the ultrastructural characteristics of Tamm-Horsfall protein. The mechanism of immune complex formation in the present study appears to involve the in situ combination of rabbit antibodies to Tamm-Horsfall protein in the glomerular filtrate with a tubular surface membrane antigen, Tamm-Horsfall protein.

Albuminuria↗
PubMed1982

Formation and clearance of tubulointerstitial immune complexes in kidney of rats immunized with heterologous antisera to Tamm-Horsfall protein.

Tubulointerstitial immune complex nephritis was produced by passive immunization of rats with antisera to rat Tamm-Horsfall protein (TH), a surface membrane glycoprotein of the cells of the thick ascending limb of Henle's loop. Circulating anti-TH antibodies were deposited in the kidney after an intravenous injection of rabbit antisera to TH. These anti-TH antibodies combined with TH at the base of tubular cells in the thick ascending limb of Henle's loop and formed granular immune complexes in situ in the space between basal cell surface membranes and tubular basement membranes. Immune complexes were also selectively formed in this site during perfusion of isolated kidneys with antisera to TH. Tubular immune complexes containing immunoglobulin, complement, and TH were maximal during the first week after an intravenous injection while high circulating anti-TH antibody titers were present. As the antibody titers subsequently fell to undetectable levels, tubular immune complexes were rapidly cleared and were virtually absent 4 weeks after the injection. During this clearance phase, rabbit IgG and rat TH were detected in the renal interstitium and in renal hilar lymph nodes. The rapid clearance of subepithelial TH immune complexes contrasts with the prolonged persistance of both glomerular subepithelial immune complexes and basement membrane deposits formed after injection of heterologous antisera to other renal components. The process of rapid clearance of tubulointerstitial immune complexes may allow rapid reversibility of immune injury in tubulointerstitial nephritis.

Animals↗
PubMed1982

Mechanism of glomerulotubular balance in the setting of heterogeneous glomerular injury. Preservation of a close functional linkage between individual nephrons and surrounding microvasculature.

Autologous immune complex nephropathy (AICN), an experimental model for human membranous glomerulopathy, is characterized by marked heterogeneity in function from glomerulus to glomerulus. However, the fraction of the filtered load of fluid reabsorbed by the proximal tubule remains nearly constant from nephron to nephron, despite wide variation in single nephron glomerular filtration rate (SNGFR). To define the physiological mechanisms responsible for this marked variation in SNGFR values within a given kidney and for the remarkable preservation of glomerulotubular balance, the various determinants of fluid exchange across glomerular and peritubular capillary networks were evaluated in Munich-Wistar rats with AICN. For comparison, similar measurements were obtained in rats with the functionally more homogeneous lesion of heterologous immune complex nephropathy. In AICN rats studied approximately 5 mo after injection of renal tubule epithelial antigen (Fx1A), a high degree of glomerulus-proximal tubule balance was found, despite marked variations in SNGFR values within a single kidney. These changes were associated with marked heterogeneity in immunoglobulin and complement deposition within and among glomeruli. Although mean capillary hydraulic pressure and Bowman's space hydraulic pressure ranged widely from glomerulus to glomerulus, the mean glomerular transcapillary hydraulic pressure difference was remarkably uniform among these functionally diverse glomeruli and could not, therefore, be implicated as the cause of the dispersion in SNGFR values. The two remaining determinants of SNGFR, namely, glomerular plasma flow rate (Q(A)) and ultrafiltration coefficient (K(f)), varied markedly from glomerulus to glomerulus, but always in direct proportion to SNGFR, and proved to be responsible for the marked variation in SNGFR. The mean net peritubular capillary reabsorptive force ( P(r)) correlated closely with the absolute rate of fluid reabsorption in adjacent proximal tubules (APR) in AICN. Of the factors determining P(r), peritubular capillary hydraulic pressure was essentially constant in a given AICN kidney, whereas peritubular capillary plasma protein concentration and oncotic pressure varied directly with APR and largely accounted for the observed tight correlation between P(r) and APR. ON THE BASIS OF THESE OBSERVED CORRELATIONS, WE SUGGEST THAT THE CLOSE QUANTITATIVE COUPLING BETWEEN SNGFR AND APR IN INDIVIDUAL NEPHRONS IN AICN IS DUE TO THE FUNCTIONAL RESPONSE OF INDIVIDUAL GLOMERULI: those with the most pronounced declines in SNGFR are characterized by the most pronounced declines in Q(A) and K(f). The resultant low peritubular capillary oncotic pressure favors a decline in APR, thus favoring nearly perfect glomerulotubular balance. In glomeruli with higher SNGFR values, Q(A) and K(f) values are also higher. These changes in K(f) once again are capable of establishing the conditions in downstream peritubular capillaries, this time favoring augmented APR (i.e., high intracapillary oncotic pressure), again leading to nearly perfect glomerulotubular balance.

Animals↗
PubMed1982

Ribosome-lamellae complexes in a symptomatic insulinoma. An ultrastructural study.

Ribosome-lamellae complexes (RLCs) were identified in approximately 20% of the tumor cells from a functional insulinoma studied by electron microscopy. Whereas these peculiar cytoplasmic inclusions are commonly seen in hairy cell leukemia (HCL) and can be present in a few cells in other hematologic disorders, to our knowledge they have never been documented in insulinoma. In fact, they are exceedingly rare in epithelial tumors. A review of the literature uncovered only two instances, one in an adenoma of the adrenal cortex, and one in a paraganglioma. In these two cases and in the insulinoma reported here, RPCs tend to be longer, have fewer lamellae, and occur in greater numbers per single cell than in HCL. Although the nature and significance of RLCs remain poorly understood, the fact that all three epithelial neoplasms in which they have been observed belong to the endocrine system is noteworthy.

Adenoma, Islet Cell↗
PubMed1981

Ultrastructural markers of colonic adenocarcinoma.

A mixed population of 96 adenocarcinomas was examined by electron microscopy to establish the presence of organ specific features. This resulted in the identification of fine structural characteristics, occurring consistently in colorectal adenocarcinomas but not in other epithelial tumors. The colorectal "ultrastructural profile" consists of microvilli with dense cores of microfilaments extending as long rootlets into a clear zone of apical cytoplasm, apical electron dense bodies, and abundant glycocalyceal bodies. Of these features, the long rootlets constitute the best morphologic marker for large intestinal type adenocarcinoma. Using these characteristics in another series of 58 adenocarcinomas studied in a double-blind manner, it was possible to distinguish colorectal adenocarcinomas from other carcinomas on ultrastructural grounds alone.

Adenocarcinoma↗
PubMed1981

Ultrastructural studies of tubulointerstitial immune complex nephritis in rats immunized with Tamm-Horsfall protein.

Rats immunized with Tamm-Horsfall protein, a surface membrane glycoprotein of cells of the ascending thick limb of Henle's loop, develop autoantibodies to Tamm-Horsfall protein and a tubulointerstitial nephritis selectively involving the thick ascending limb of Henle's loop. The localization of the immune deposits formed in this model was studied by transmission electron microscopy. The frequency, size, and distribution of electron-dense deposits closely paralleled that of granular and nodular deposits of rat IgG, C3, and Tamm-Horsfall protein at the base of the cells of the ascending thick limb of Henle's loop. The earliest electron-dense deposits were present in the extracellular space between basal infoldings of cell membranes and the tubular basement membranes. In the more advanced lesions, the larger electron-dense deposits were also present within the tubular basement membranes and between tubular cell membranes displacing tubular structures. Selective mononuclear cell infiltration around these tubules with deposits in this model of tubulointerstitial nephritis suggests that antibodies to Tamm-Horsfall protein cross tubular basement membranes and form immune complexes in situ by combining with the Tamm-Horsfall protein molecules of basal cell surface membranes.

Animals↗