Jan W. Steiner

A randomized, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma

Background CRTH2 is a G‐protein‐coupled receptor that mediates the activation of Th2 lymphocytes, eosinophils and basophils in response to prostaglandin D2 and may be involved in the pathogenesis of airway inflammation and dysfunction in asthma.

The ductular cell reaction of rat liver in extrahepatic cholestasis. I. Proliferated biliary epithelial cells.

Abstract The ductular cell reaction in the liver of rats during the second to sixth weeks following ligation of the common bile duct is in part an organized proliferation of ductular (biliary epithelial) cells. The cells show an invariable tendency to surround lumina. Thin ( I 2μ ) sections exmined in the light microscope assist in the understanding of the behavior of ductular cells since the lumina of the penultimate bile-conduction channels can be more clearly visualized than in routine sections. Biliary epithelial cells from proliferated ductules in rats killed two to six weeks after the ligation, show by electron microscopy a persistence of some of the changes noted as occurring during the first 14 days of their proliferation, a paucity of microvilli, edema of microvilli, an increase of the endoplasmic reticulum, and an increase of free ribosomes. Additional abnormalities develop in ductular cells after day 14 of cholestasis. The Golgi zones multiply and become prominent. Smooth-surfaced vesicles increase in number. Some cells become increasingly electron-opaque, and have been designated as ‘dark’ cells. Other cells may acquire a unique one-centriole type of cilia which have an abnormal 7 + 1 doublet filament arrangement. The functional effectiveness of these cilia could not be assessed, owing to the absence of information about any other comparable cilia with a known motility. It was suggested that the prominent ER and RNP granules may signify an increased protein production by proliferating cells rather than evidence of elaboration of a protein-rich secretion. The prominence of Golgi zones and of smooth-surfaced vesicles was interpreted as possible evidence of secretory activity involving water and electrolytes. ‘Dark’ biliary epithelial cells may form as a result of a sudden discharge of such secretion into ductular lumina.

Glycogen depletion in the newborn rat liver an electron microscopic and electron histochemical study

In the rat, the hepatic glycogen store extant at birth is almost completely mobilized in the first 12 hours of life. The close-meshed reticulum of smooth membranes (SER) which has been associated with glycogenolysis in the adult rat liver cell is virtually absent throughout the period of glycogen mobilization in the newborn. This finding is strongly supported by glycogen digestion procedures since the hyaloplasm of the digested specimens completely lacks any trace of a network of smooth membranes. We have concluded that the SER plays no role in the mobilization of glycogen in these liver cells. Many cytolysomes containing glycogen (glycogenosomes) were found 6 hours following birth. Acid phosphatase was localized within the glycogenosomes establishing their lysosomal nature. Digestion of the hyaloplasmic glycogen sometimes failed to remove the glycogen within glycogenosomes. We have concluded that lysosomal enzymes contribute, at least in some measure, to glycogen catabolism in these cells.

Experimental Extrahepatic Biliary Obstruction: Fine Structural Changes of Liver Cell Mitochondria

Summary This paper records observations of disturbances of mitochondrial morphology in parenchymal liver cells of rats after ligation of the common bile duct. The changes observed include an apparent increase in number of mitochondria in some areas of cells, focal disturbances of the size and density of the matrix of mitochondria, and changes in the relative and absolute length of the cristae mitochondriales. These observations could not be related to any specific type of cell degeneration as seen in the light microscope. No explanation can be offered at present f or their occurrence beyond a general statement that they represent, at an electron microscopic level of observation, evidence of cell injury.

Observations on the fine structure of rat liver cells in extrahepatic cholestasis.

With 12 Figures in the Text (Received June 16th, 1962) The more recent light microscopic studies of the lesions which occur in the liver of rats after ligation of the common bile duct dwelt mainly upon the changes in the biliary system which are the most prominent features of these lesions (CAMERON and 0AKLEY 1932; CAMERO~ and MUZAFFER HASAN 1958; Koc~W]~SER, MEY]~R, u and POPPER 1952; Ri~TT~ER and STOFEI~ 1960; STEIN~ and MARTINEZ 1961; TRAMS and SY~O~IDIS 1957). Electron microscopists have also paid much attention to the changes which occur in the bile eanalieuli (GoLDFISCttER, ARIAS, ESSNER and NOVIKOFI~ 1962; KALIFAT, CARRUTH]~RS and STEIN]~R 1962; ROUILLER 1956; SCHAFFN]~R and PO]~PER 1959) and in the bile ductules and the ducts of Hering (CARRUTHERS and STEIN~R 1961 ; STEINER and CARRUTHERS 1962 ; STEI~E~, CARRU~HERS and KALIFAT 1962), but attention had also been given to the vascular granulation tissue which forms a mantle around the newly-formed ductular channels (CARRUTHERS, KALI]~AT and STEIN~, 1962, STEINER and CAR~CTHERS 1961; STEINE~, CAR~CTHERS and KALIFAT 1962). Considerable discussion has been also devoted to the nature and pathogenesis of the focal, coagulative and cytolytie necroses which occur in the parenchyma of the liver (CAMEROn and Hou 1962). Much less attention has been paid to the more widespread degenerative alterations which affect single hepatocytes, scattered here and there throughout the liver, perhaps because they are less prominent, and more subtle. We know from the work of CA~E~ON and OAKL~,Y (1932), STEINW~ and MAR~INWZ (1961) and TRAMS and SYMEOI~IDIS (1957) that these degenerative changes make their appearance as early as one hour after ligation of the common bile duet, and that they persist to a variable degree throughout the remaining life of the animal. The change consists of a loss of cytoplasmic basophilia with glycogen depletion, mild fat ty metamorphosis and cytoplasmic vacuolation, together with enlargement of the nuclei, and prominence of nucleoli. Mitotic activity is found in cells adjacent to portal tracts. Electron microscopic studies have demonstrated an increase of pericanalicular lysosomes (GOLDFISCHER, ARIAS, ESS~ER and NOVIKOFF 1962), and the development of cytoplasmic vacuoles, some of which are

Die Feinstruktur des Mesangiums im Nierenglomerulum von Hund und Maus

SummaryThe mesangium of the glomerulus of dogs and mice was examined. Basement membranes and their branches in the mesangial region were described. Stress was laid upon the intercapillary location of mesangial cells which are always separated by endothelial cells from capillary lumina and upon their cytoarchitectural features: irregularly-shaped nuclei, a dense and homogeneously, finely granular cytoplasm with centrally distributed organelles and peripherally placed filaments, a well developed endoplasmic reticulum with abundant numbers of RNP granules, peripherally placed cytoplasmic densities comparable to attachment bodies of smooth muscle cells, as well as cytoplasmic protrusions into endothelial cells (Intrakapillarhöckerchen).Based upon the above findings and upon a comparison of smoth muscle cells of arteries with mesangial cells located close to and distant from the “vascular pole” (Gefäßpol), the conclusion was reached that mesangial cells differ essentially from endothelial cells and from fibroblasts and that they bear a marked resemblance to smooth muscle cells.An attempt was made to relate the structure of mesangial cells to their function.

The ductular cell reaction of rat liver in extrahepatic cholestasis: II. The proliferation of connective tissue☆

Abstract Fibrosis is an invariable accompaniment of the ductular cell reaction following ligation of the common bile duct of rats. Inflammatory cells aggregate around the proliferating ductules and may penetrate between their lining cells. Others are found in close apposition to aberrant microvilli of parenchymal liver cells which are in contact with the peri-ductular connective tissue. Only neutrophils undergo necrobiosis and they are phagocytosed by numerous macrophages. The stimulus to fibrogenesis and the cause of the inflammation are unknown. It is suggested that a phlogistic nonlipid material is excreted into ductules and gains access to the connective tissue where its chemotactic effects can be assessed morphologically. The migration of monocytes and their conversion into phagocytic macrophages are thought of as a response to the presence of degenerating neutrophils. Four types of capillary channels are found in the ductular cell reaction: fenestrated and nonfenestrated blood capillaries, lymphatics and stranded parenchymal sinusoids.

Vascular alterations in the liver of rats with extrahepatic biliary obstruction. An electron and fluorescent microscopic study.

Abstract In the 6 weeks which follow the induction of total extrahepatic cholestasis in rats, vascular lesions develop in capillaries, lymphatics, and sinusoids in the granulation tissue around the newformed ductules and in the adjacent peripheral parts of lobules. The lesions correspond in distribution to the biliary necroses which are found in rats after ligation of the common bile duct. The principal change is a disturbance of endothelial and Kupffer cell hydration, which leads to a narrowing vascular of lumina and is followed by stasis, hyperplasia, and hypertrophy of Kupffer cells and by secondary alterations of parenchymal liver cells. We have suggested that the necrosis may be the result of the ischaemia, perhaps in association with regurgitation of bile constituents into the interior of hepatocytes because of disturbance of the selective permeability of their cell membranes. The development of a prominent endoplasmic reticulum in Kupffer cells after ligation of the common bile duct, was related to the presence of a material staining positively with rabbit anti-rat gamma globulin both in the Kupffer cells and in biliary epithelial cells. Further investigations are required to probe the nature of this material, and its significance in the evolution of the biliary necroses.

Disturbances of hydration of cells of rat liver in extrahepatic cholestasis

Livers of rats were examined during a period of 39 days after ligation of the common bile duct. A widespread disturbance of cell hydration was noted. There was oedema of some of the microvilli of biliary epithelial cells in ductules, and of some of the microvilli of parenchymal liver cells. In other cases, a condensation or oedema affected the hyaloplasm of entire biliary epithelial, endothelial or Kupffer cells. Retrograde intrabiliary injections of colloidal mercuric sulphide showed that these particles came in contact not only with cell surfaces lining biliary lumina, but that they also penetrated between biliary epithelial cells, and traversed their basement membranes to reach the lumina of capillaries and sinusoids. The particles also were found within biliary ductular cells and hepatocytes. These observations led us to suggest that bile constituents with detergent and protein denaturing properties may escape by these routes, and so cause the alterations in hydration. It has also been suggested that the mode of regurgitation of bile in extrahepatic cholestasis is by diffusion across natural barriers rather than by rupture of the bile conduction pathways. Die Leber von Ratten wurde bis 39 Tage nach einer Unterbindung des Gallenganges elektronenmikroskopisch untersucht. Dabei konnte eine ausgesprochene Veränderung des Wassergehaltes der Zellen beobachtet werden. Einige der Mikrovilli der Gallengangsepithelien und manche Mikrovilli der Leberzellen waren ödematös geschwollen; in anderen Fällen hatte Kondensierung oder Ödem, das Hyaloplasma einer ganzen Gallengangsepithelzelle, Endothelzelle oder Kupfferschen Sternzelle erfaßt. Retrograde Injektion von kolloidalem Quecksilbersulfid in den Gallengang zeigte, daß diese Partikel nicht nur mit der Oberfläche der die Gänge auskleidenden Epithelzellen in Berührung kommen, sie dringen vielmehr auch zwischen die Epithelzellen ein, durchqueren die Basalmembran, um schließlich die Lichtung der Capillaren und der Sinusoide zu erreichen. Auch in den Zellen der Ductuli und den Leberzellen selbst wurden Partikel gefunden. Auf Grund dieser Beobachtungen erscheint die Annahme berechtigt, daß Gallenbestandteile mit der Fähigkeit, detergent zu wirken und Eiweiß zu denaturieren, auf diesem Wege austreten und so die Veränderungen im Wassergehalt der Zellen verursachen könnten. Dies würde mit der Anschauung übereinstimmen, nach der die Galle bei extrahepatisch bedingter Cholostase eher infolge einer Diffusion durch die natürlichen Barrieren, als infolge einer Ruptur aus den Gängen austrete.

Die Feinstruktur der Basalmembran der Grlomerulumcapillaren bei akuter Glomerulonephritis

Die elektronenmikroskopisch sichtbaren Veränderungen der Glomerulumcapillaren bei akuter Glomerulonephritis des Menschen wurden untersucht. Als charakteristische Befunde wurden folgende Basalmembranveränderungen hervorgehoben: allgemeine Verdickung, großflächige Anlagerung eines feingranulären Materials von verschiedener Dichte auf der Endothelseite, Anlagerung eines ähnlichen Materials in pilzförmigen Vorwölbungen auf der Deckzellseite der Basalmembran. Es wurde erörtert, inwieweit diese morphologischen Erscheinungen Ausdruck eines immunologischen Prozesses sein können. This paper deals with the fine structural changes of the glomerular capillaries in acute glomerulo-nephritis. The following changes were encountered in connection with the basement membrane: generalized thickening; deposition of a finely granular material of varying density along the endothelial side of the basement membrane; deposition of a similar material in the form of mushroom-shaped protrusions on the epithelial side of the basement membrane. The nature of the deposited material was discussed and the possibility was considered that it may represent an immune precipitate.