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R Sormunen

Publications and source records attributed to R Sormunen.

At least 37 records · Page 2Linked to original sources
PubMed1996

Tenascin immunoreactivity as a prognostic marker in usual interstitial pneumonia.

In this investigation, tenascin (Tn) expression was studied in 51 cases of different types of fibrotic lung disorders originating for years 1981 to 1995. Our aim was to test if accumulation of Tn at the site of lung injury in usual interstitial pneumonia (UIP) could correlate with the prognosis. Lung biopsies taken from 28 patients with UIP, six with desquamative interstitial pneumonia (DIP), six with sarcoidosis, five with extrinsic allergic bronchioloalveolitis, five with bronchiolitis obliterans organizing pneumonia (BOOP), and one with nonspecific interstitial pneumonia were studied for the expression of Tn by using an immunohistochemical technique. In addition to Tn immunohistochemistry, selected cases were also studied by immunoelectron microscopy and Western blotting. For prognostic studies in UIP the clinical follow-up information was obtained from the patient records. The expression of Tn was increased in each type of fibrosis, especially in UIP. In immunoelectron microscopy the most prominent labeling in UIP was found in association with collagen fibers and within the type 2 pneumocytes. Every studied case of UIP showed reactivity for a polypeptide of M(r) approximately equal to 200,000 by Western blotting. In patients with UIP, increased Tn expression, especially under metaplastic bronchiolar-type epithelium, was associated with a shortened survival time. Immunoelectron microscopic findings support the idea that Tn in UIP is synthesized by the regenerating epithelial rather than interstitial cells in response to pulmonary interstitial inflammation.

Adult↗
PubMed1996

Non-erythroid spectrin (fodrin) in cutaneous tumours: diminished in cell membranes, increased in the cytoplasm.

The expression and distribution of non-erythroid spectrin (alpha-fodrin), a basic protein of the cell membrane skeleton, was investigated by immunohistochemical methods in 42 cutaneous tumours. The suprabasal keratinocytes of the normal epidermis showed plasma membrane-associated spectrin. The basal cells of the normal epidermis, seborrhoeic keratosis, and basal cell carcinoma, revealed both intracytoplasmic and membrane-bound spectrin. In squamous cell carcinoma, the expression of spectrin was heterogeneous and mostly intracytoplasmic. The dysplastic cells of solar keratosis expressed no spectrin at all. In various types of melanocytic naevi, intracytoplasmic and discontinuous membrane-bound spectrin was found in most tumour cells. Malignant melanomas showed a heterogeneous intracytoplasmic staining for spectrin, or were negative. The results indicate a diminished amount, or a total lack, of membrane-bound spectrin with increasing depolarization and proliferation of cells in solar keratosis and pigment cell tumours, but a partial preservation in polarized cells of basal cell carcinoma. The increase and heterogeneity, in cytoplasmic spectrin, of squamous cell carcinoma and malignant melanoma seemed to be associated with the less differentiated, invasive cells of these malignant tumours.

Basal Cell Carcinoma↗
PubMed1995

Enhanced apoptosis predicts shortened survival in non-small cell lung carcinoma.

This study was undertaken to determine the extent of apoptosis in lung carcinoma and to evaluate it as a prognostic marker. A series of 75 lung carcinomas (47 squamous cell carcinomas, 24 adenocarcinomas, 3 small cell carcinomas, and 1 large cell carcinoma) was analyzed for the extent of apoptosis by using the 3' end-labeling method of DNA in tissue sections. Apoptosis was correlated with the rate of cell proliferation, the immunohistochemically detectable p53 and bcl-2, the extent of tumor necrosis, and the survival data. The end-labeling method allowed a precise evaluation of the extent of apoptosis. In tumor tissue, the number of apoptotic bodies was roughly 2-fold greater than the number of apoptotic cells, whereas in nonneoplastic control tissues, the ratio was 1:1. The apoptotic indexes (percentages of apoptotic cells and bodies among tumor cells) were slightly higher in adenocarcinoma than in squamous cell carcinoma. There was no association between the extent of apoptosis and the expression of proliferating cell nuclear antigen or p53. On the other hand, tumor necrosis correlated significantly with proliferating cell nuclear antigen and p53 positivity (P = 0.00025 and 0.00087, respectively). Surprisingly, the extent of apoptosis was also found to be independent of the expression of bcl-2. Patients with apoptotic indexes greater than 1.5% had significantly shorter survival time than patients with apoptotic indexes equal to 1.50% or less (P < 0.01 by log rank). Aberrant p53 positivity also predicted a poor prognosis (P < 0.002 by log rank). By multivariate analysis, enhanced apoptosis showed a 1.9-fold risk (P = 0.04), and p53 positivity showed a 2.3-fold risk (P = 0.005) for a shortened survival. We conclude that both enhanced apoptosis and p53 positivity are independent prognostic markers in non-small cell lung carcinoma, predicting shortened survival time of the patients.

Aged↗
PubMed1995

Cloning of a novel bacteria-binding receptor structurally related to scavenger receptors and expressed in a subset of macrophages.

A novel murine plasma membrane protein has been identified in subpopulations of macrophages. It has an intracellular N-terminal domain, a transmembrane domain, and an extracellular region with a short spacer, an 89 Gly-Xaa-Yaa repeat-containing collagenous domain, and a C-terminal cysteine-rich domain. In situ hybridization and immunohistochemical staining have localized the protein to a subset of macrophages in the marginal zone of the spleen and the medullary cord of lymph nodes. No expression was observed in macrophages of liver or lung. Transfected COS cells synthesized a native trimeric plasma membrane protein that bound labeled bacteria and acetylated LDL, but not yeast or Ficoll. The results suggest that the novel protein is a macrophage-specific membrane receptor with a role in host defense, as it shows postnatal expression in macrophages, which are considered responsible for the binding of bacterial antigens and phagocytosis.

Amino Acid Sequence↗
PubMed1995

Defective maturation of a viral glycoprotein and partial loss of the Golgi stack structure during in vitro myogenesis.

In the present study, the functional and structural reorganization of the Golgi compartment shortly after the fusion of rat L6 myoblasts into multinucleated muscle cells was examined. When we followed the maturation and the transport of a bulk flow marker protein, the vesicular stomatitis virus G glycoprotein, in the fused cells, we found that only about half of the newly synthesized G protein acquired endo H resistance within the Golgi prior to its transport to the cell surface. The other half of the G protein remained endo H-sensitive and was retarded intracellularly. Our immunofluorescence and cell fractionation data indicated that this maturation defect did not result from the inefficient transport of the G protein into the Golgi, but rather from the functional impairment of the Golgi compartment in the fused cells. In accordance with this view, electron microscopy revealed that the majority of the Golgi-derived elements in the fused cells were structurally abnormal and consisted of large tubulovesicular "Golgi clusters." Our results support the view that reorganization of the Golgi complex during myogenesis involves at least a partial loss of both Golgi structure and function.

Animals↗
PubMed1995

Ultrastructural changes during continuous retrograde warm and mild hypothermic blood cardioplegia for coronary bypass operations.

Ultrastructural changes in myocardial tissue were studied in 21 patients undergoing elective aorta-coronary bypass operation. The patients were randomized into two groups, with 10 of them receiving continuous retrograde warm and 11 continuous retrograde mild hypothermic blood cardioplegia. Biopsy specimens for electron microscopy were taken from the apical part of the left ventricle before and at the end of the aortic crossclamp period and after reperfusion of the myocardium. The ultrastructural changes were analyzed with use of a semiquantitative scoring system and classified as mild, moderate, or severe. Slight ultrastructural changes were found in both groups even before the aortic crossclamp period. At the end of the aortic crossclamp period the most prominent ultrastructural changes were mitochondrial swelling, damage of capillary endothelium, and clearing of the nucleoplasm or margination of chromatin, but some enlargement in intercalated discs was also discernible. Reperfusion of the myocardium for 15 minutes somewhat further increased the overall score of the ultrastructural changes. Two patients in the warm cardioplegia group had a perioperative myocardial infarction, and this may be one reason for the higher postoperative creatine kinase MB efflux in this patient group. Despite this finding, no major differences in the ultrastructural changes between the two cardioplegia groups could be observed. We conclude that only mild to moderate and principally reversible ultrastructural changes occur in myocardium during continuous retrograde warm and mild hypothermic blood cardioplegia for coronary bypass operation.

Aged↗
PubMed1995

The polarity of the membrane skeleton in retinal pigment epithelial cells of developing chicken embryos and in primary culture.

We studied the morphogenesis and the membrane skeleton in the retinal pigment epithelium during chicken embryogenesis and in culture, by using immunofluorescence and electron microscopy. During embryogenesis two distinct membrane skeletal structures were formed, an apical and a basolateral one. The former was seen in the apical surface already in the 10-day-old embryos. It was comprised of ankyrin and alpha-fodrin and showed a codistribution with Na+,K(+)-ATPase and an as yet uncharacterized cadherin-like molecule. The basolateral membrane skeleton was seen in the lateral walls already in the 10-day-old embryos, and later, between the 13th and 17th embryonic days, it also appeared at the basal membrane, coincidentally with the formation of the basal infoldings. It consisted of ankyrin and alpha-fodrin, but did not codistribute with any of the integral membrane proteins studied (Na+,K(+)-ATPase and cadherins). In culture, the retinal pigment epithelial cells retained their polarized morphology. Compared with the situation in vivo, however, there was a distinct translocation of the membrane skeletal components fodrin and ankyrin from the apical surface to the lateral walls, accompanied by a similar redistribution of Na+,K(+)-ATPase and the cadherin-like molecule. The results suggest that (1) there is, in the retinal pigment epithelium, an apical Na+,K(+)-ATPase-membrane skeleton structure stabilized by contacts between the retinal pigment epithelium and the neural retina, possibly mediated by a cadherin-like molecule, and that (2) there is another fodrin/ankyrin-based membrane skeleton in the basolateral walls that is important for the maintenance of the extensive folding of these surface areas.

Animals↗
PubMed1995

Spectrin in the leading lamella of cultured chicken fibroblasts.

The leading lamella is a highly dynamic cell compartment of locomoting fibroblasts. Based on its well-characterized internal cytoskeletal architecture, the leading lamella can be divided into three structurally distinct zones. Much less is known about the membrane components of the leading lamella. In this study, we looked at the distribution of spectrin, the major component of the subplasmalemmal membrane skeleton, in the leading lamella and its relation to the subdivision of the lamellar space in cultured fibroblasts. In immunofluorescence microscopy, a general, plasma membrane-associated staining of spectrin was observed especially in the more central regions of detergent-extracted cells. In the leading lamella, spectrin was seen particularly along the lamellar edge and as small protrusions, or nodes, along the lamellar periphery. A weaker staining was observed in the more proximal regions of the lamella. In wet-cleaved cells also, spectrin was observed along the leading edge and in the protrusions of the lamella. In double immunofluorescence microscopy, a close colocalization of spectrin and actin was seen in the lamellar region. In immunoelectron microscopy of whole-mount preparations, spectrin was also found to be in close association with the actin meshwork in the most peripheral zone of the lamella and it was also associated with the actin-containing microspikes. A weaker labeling for spectrin was observed along the filaments in the proximal regions of the lamella. The node-like accumulations of spectrin seen along the lamellar edge were reactive to antibodies raised against talin and paxillin, suggesting that they represent evolving focal adhesions. The results show that spectrin is particularly present along the leading edge of the leading lamella. It is also present in the active protrusion sites of translocating cells, probably representing evolving adhesion sites. The role of spectrin should therefore be considered when studying the mechanisms of events associated with the locomotive behavior of fibroblasts.

Animals↗
PubMed1994

Lysyl hydroxylase, a collagen processing enzyme, exemplifies a novel class of luminally-oriented peripheral membrane proteins in the endoplasmic reticulum.

Lysyl hydroxylase (LH), an enzyme required early during collagen biosynthesis, appears to be exceptional among proteins that are thought to be residents of the endoplasmic reticulum (ER). It is a homodimer and does not contain either of the two previously characterized ER-specific retention motifs (KDEL or the double lysine motif) in its primary structure. We now show that LH, nevertheless, resides in the lumen of the ER. In immunofluorescence experiments, LH co-localizes with a KDEL-containing protein, protein disulfide isomerase (PDI), and also co-sediments with it after fractionation of subcellular organelles by sucrose density gradient centrifugation. In addition, LH seems to be stress-inducible. In one respect, however, LH differs from PDI and other known luminal proteins in the organelle. It is found in situ only in association with the ER membranes. Our cell fractionation and Triton X-114 phase separation experiments suggest that it binds to the membranes via weak electrostatic interactions. LH can thus be regarded as a first luminally-oriented "peripheral membrane" protein which has been characterized in the ER. The results suggest a novel possibility by which ER lumen can acquire its specific protein components from the bulk flow.

Amino Acid Sequence↗
PubMed1994

Segmental mediolytic arteritis--electronmicroscopic and immunohistochemical study.

We examined specimens of human gastroepiploic artery aneurysm from a patient having several visceral aneurysms using electronmicroscopic and immunohistochemical techniques. The histopathological and ultrastructural findings confirmed the diagnosis of segmental mediolytic arteritis. Arterial smooth muscle cells from the gastroepiploic artery contained cytoplasmic vacuoles, media was thin and the internal elastic membrane showed distortion. X-ray microanalysis revealed calcium deposits in the medial extracellular space. Antigenic determinants of human immunoglobulins, fibrinogen, complement C3a and factor VIII were demonstrated in the injured artery wall, suggesting that immunocomplexes deposited in the artery wall may be associated with local injury. These findings support the role of autoimmune disorders in the pathogenesis of segmental mediolytic arteritis.

Aged↗
PubMed1994

Dissection of the molecular consequences of a double mutation causing a human lysosomal disease.

Aspartylglucosaminidase (AGA) is a lysosomal enzyme, the deficiency in which leads to human storage disease aspartylglucosaminuria (AGU). AGUFin is the most common AGU mutation in the world and is found in 98% of AGU alleles in Finland, where the population displays enrichment of the disease allele. The AGUFin allele actually contains a double mutation, both individual mutations resulting in amino acid substitutions: Arg-161-->Gln and Cys-163-->Ser. The separate consequences of these two amino acid substitutions for the intracellular processing of the AGA polypeptides were analyzed using a stable expression of mutant polypeptides in Chinese hamster ovary (CHO) cells. The synthesized polypeptides were monitored by metabolic labeling, followed by immunoprecipitation, immunofluorescence, and immunoelectron microscopy. The Arg-161-->Gln substitution did not affect the intracellular processing or transport of AGA and the fully active enzyme was correctly targeted to lysosomes. The Cys-163-->Ser substitution prevented the early proteolytic cleavage required for the activation of the precursor AGA polypeptide and the inactive enzyme was accumulated in the endoplasmic reticulum (ER). The precursors of the translation products of the AGUFin double mutant and the Cys-163-->Ser mutant were also observed in the culture medium. When cells expressing the normal AGA or AGUFin double mutation were treated with DTT to prevent the formation of disulfide bonds, both normal and mutated AGA polypeptides remained in the inactive precursor form and were not secreted into the medium. These results indicate that correct initial folding is essential for the proteolytic activation of AGA.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1994

Fodrin and actin in the normal, metaplastic, and dysplastic respiratory epithelium and in lung carcinoma.

Distribution of actin and fodrin, a nonerythroid analogue of spectrin, was studied in cytocentrifuge preparations and in tissue sections of normal and pathologic respiratory epithelium by using immunofluorescence and immunoelectron microscopy. In ciliated epithelial cells and in goblet cells of normal bronchial epithelium, fodrin and actin were located in the apical parts and along the lateral walls of the cells. In basal cells, fodrin and actin were also seen diffusely in the cytoplasm. Immunoelectron microscopy showed fodrin in close association with the basal bodies and rootlets of the cilia and microvilli in the ciliated cells. In alveolar epithelium, fodrin and actin were located at the apical membrane in type I pneumocytes and along the apical and lateral membranes in type II pneumocytes. In type II pneumocytes, fodrin was also seen in close association with the secretory vacuoles. In metaplastic and dysplastic bronchial epithelium, a diffuse cytoplasmic and a circumferential, membrane-associated staining for fodrin and actin was seen. In all types of carcinomas, fodrin was seen along the lateral walls and diffusely in the cytoplasm. The staining was more intense than in the normal cells. In immunoblotting of the normal bronchial epithelium, and peripheral lung and lung carcinomas, a single 240 kD band was recognized with antibodies to fodrin. The results show distinct differences in the distribution of fodrin in the various cell types of the respiratory epithelium. In ciliated cells, the close relationship with cytoskeleton suggests a role of fodrin in the establishment of the elaborate structural architecture of the apical compartment. In type II pneumocytes, on the other hand, fodrin probably plays a role in secretion of the surfactant. In basal cells, the diffuse distribution of fodrin probably reflects the high proliferative capacity of this cell compartment. Interestingly, a similar distribution was also seen in premalignant and malignant cells.

Actins↗
PubMed1994

Intracellular sites involved in the biogenesis of bile canaliculi in hepatic cells.

Studies in hepatoma cells and hepatocytes have revealed that the biogenesis of bile canalicular membrane involves microvilli-lined vesicles (MLV), which are formed in well differentiated cells. The vesicles grow as a function of time and are presumably vectorially transported to cell surface contact sites of attached cells. We demonstrate that a fluorescent head group-labeled lipid analog, N-(lissamine rhodamine B sulfonyl)phosphatidylethanolamine (N-Rh-PE), after its exogenous insertion into the plasma membrane of HepG2 cells at 4 degrees C, accumulates in these microvilli-lined vesicles at 37 degrees C. This shows that the MLV are a target for plasma membrane-derived lipids. Furthermore, also the Golgi apparatus is involved in the formation of the vesicles. After initial accumulation of the fluorescent sphingolipid precursor, 6-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]hexanoic acid (C6-NBD)-ceramide in the Golgi apparatus at 37 degrees C, prolonged incubation at 37 degrees C results in the appearance of NBD fluorescence in the microvilli-lined vesicles. The transport route for the Golgi-derived material to the developing bile canalicular vesicle is not an indirect pathway, i.e. involving transcytosis via the basolateral plasma membrane. This could be demonstrated by including bovine serum albumin (BSA) in the incubation media, a lipid scavenger that will remove any C6-NBD-lipids exposed at the basolateral membrane. At these conditions, lipid trafficking between the Golgi complex and MLV still occurred. We further demonstrate that the targeting from the Golgi apparatus to the bile canaliculus is also operational in isolated human hepatocytes. The latter results suggests that the Golgi complex is involved in both the formation of bile canaliculi and in bile secretion in fully differentiated cells.

Bile Canaliculi↗
PubMed1993

Alpha-spectrin in detergent-extracted whole-mount cytoskeletons of chicken embryo heart fibroblasts.

The distribution of alpha-spectrin, and its relation to other cytoskeletal structures and to the plasma membrane, was studied in detergent-extracted whole-mount cytoskeletons of chicken embryo heart fibroblasts by using immunogold labelling and electron microscopy (IEM). The cell surface was labelled with gold-conjugated wheat germ agglutinin (WGA-gold), microtubules with anti-tubulin antibodies, and spectrin by using antibodies raised to chicken erythrocyte alpha-spectrin. Additionally, the effect of fixation and drying on the labelling pattern was evaluated. In electron microscopy, a three-dimensional filamentous network was observed in detergent-extracted whole-mount preparations. Filaments of diameter 7-10 nm and 15 nm, microtubules of diameter 30 nm, and filament bundles (40-50 nm in diameter) were seen. In IEM, alpha-spectrin was seen on the surface of the cytoskeletal network, especially along the thick filament bundles. In some cells, a distinct membrane skeleton which was labelled with alpha-spectrin antibodies, was seen in close association with the cytoskeletal network. The cells which were labelled first with WGA-gold, and then permeabilized, fixed and labelled with alpha-spectrin, showed a co-localization of the WGA binding sites and alpha-spectrin along the surface of the filament bundles. Reversing the order of the staining, such that fixation was done before WGA labelling and permeabilization, led to a greatly diminished labelling for alpha-spectrin and less pronounced co-localization of spectrin and WGA. Comparison of the conventional critical point drying method with Peldri II, a novel drying agent, indicated a better stability of the cellular structures under the electron beam when Peldri II was used.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Binding of the alpha-fodrin SH3 domain to the leading lamellae of locomoting chicken fibroblasts.

Fodrin (nonerythroid spectrin) is a membrane skeletal protein that plays an important role in the establishment and maintenance of the cell shape and polarity. We have identified in alpha-fodrin an src homology 3 (SH3)-related region, a small domain that is present in a large number of proteins that are involved in signal transduction, cell polarization and membrane-cytoskeleton interactions. In this study we have explored the function of the alpha-fodrin SH3 by incubating fixed and permeabilized cultured chicken fibroblasts with the alpha-fodrin SH3 peptide, expressed in bacteria as a fusion protein with glutathione S-transferase. Immunofluorescence and immunoelectron microscopy showed that alpha-fodrin SH3 binds to the cytoplasmic face of the plasma membrane in the leading lamellae and the pseudopodial lobes of the spreading and locomoting cells. No, or only minimal, binding was seen in immotile cells, or in the stationary trailing ends of the locomoting cells. SH3 binding was also seen in cytochalasin-D-treated cells, suggesting that actin filaments are not responsible for the binding. These findings suggest that alpha-fodrin SH3 interacts with plasma membrane components that are present in the leading lamellae exclusively or are modulated in a manner specific to the leading lamellae.

Amino Acid Sequence↗
PubMed1993

Bile canaliculus formation in cultured HEPG2 cells.

BACKGROUND: The plasma membrane of hepatocytes can be divided in sinusoidal, lateral and apical membrane, each with functionally and structurally distinct features. The apical domain consists of the bile canalicular structures. The morphogenesis and the polarization of hepatocytes is still poorly known. EXPERIMENTAL DESIGN: We used HepG2 cells, a hepatoma cell line to study the formation of the bile canaliculi in the apical part of the cells. The cells were synchronized by using nocodazole. The formation of the bile canaliculi was monitored by using immunofluorescence microscopy, confocal laser scanning microscopy, and immunoelectron microscopy. Antibodies to alpha-fodrin and villin were used. Actin was visualized with rhodamine phalloidin. RESULTS: Confocal laser scanning microscopy showed accumulations of actin, villin and fodrin at the cell membranes 8 to 12 hours after the release of the nocodazole block. These sites probably represent areas destined to develop into bile canaliculi. Later, immature bile canaliculi were discerned that were located asymmetrically between adjacent cells. Transmission electron microscopy of serial sections showed that they were always connected with the surface of the cell. Mature bile canaliculi appeared between adjacent cells 48 hours after the release of the nocodazole block. They were round, vesicle-like structures lined with microvilli and sealed by tight junctions and desmosomes. They were usually seen between two juxtaposed cells, and often several cells contributed to their formation. Typically, mature bile canaliculi were delineated by a subplasmalemmal filamentous meshwork of fodrin and actin, resembling a terminal web of enterocytes. Actin and villin were also found in microvillar cores. CONCLUSIONS: The results show that (i) bile canaliculi are formed de novo between two or more juxtaposed cells; (ii) canalicular-formation is accompanied by a distinct accumulation of the membrane skeletal and microvillar proteins fodrin, actin and villin at the apical surfaces of the cells, suggesting that they play an important role in bile canaliculus morphogenesis, and that (iii) apical membrane differentiation in the cells contributing to the formation of a single canaliculus is an asymmetric process.

Bile Canaliculi↗
PubMed1992

Human aspartylglucosaminidase. A biochemical and immunocytochemical characterization of the enzyme in normal and aspartylglucosaminuria fibroblasts.

Aspartylglucosaminidase (AGA, EC 3.5.1.26) is an essential enzyme in the degradation of asparagine-linked glycoproteins. In man, deficient activity of this enzyme leads to aspartylglucosaminuria (AGU), a recessively inherited lysosomal storage disease. Here we used affinity-purified polyclonal antibodies against the native AGA and its denatured subunits to establish the molecular structure and intracellular location of the enzyme in normal and AGU fibroblasts. Inactivation of the enzyme was found to coincide with the dissociation of the heterodimeric enzyme complex into subunits. Although the subunits were not linked by covalent forces, the intrapolypeptide disulphide bridges were found to be essential for the normal function of AGA. AGA was localized into lysosomes in control fibroblasts by both immunofluorescence microscopy and immuno-electron microscopy, whereas in AGU cells the location of antigen was different, suggesting that, owing to the mutation, a missing disulphide bridge, most of the enzyme molecules get retarded in the cis-Golgi region and most probably face intracellular degradation.

Aspartylglucosaminuria↗