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Biomedical subjects

M Wettstein

Publications and source records attributed to M Wettstein.

At least 19 recordsLinked to original sources
PubMed1999

[Hepatopulmonary syndrome].

ANAMNESIS: We report about a 60-year-old woman with hepatopulmonary syndrome. The patient suffered from progressive dyspnea and liver cirrhosis following viral hepatitis C, acquired through blood transfusion 30 years ago. EXAMINATION RESULTS: Remarkable were clinical signs of chronic liver disease (cutaneous spider naevi, palmar erythema) and signs of chronic respiratory failure (clubbing) with platypnea. Arterial pO2 was 33 mm Hg under 41 O2/min nasal oxygen supplement and improved to 74 mm Hg under 81 O2/min. Arterial pO2 deteriorated in upright position (orthodeoxia). Contrast enhanced two-dimensional transthoracic echocardiography showed a delayed microbubble opacification in the left heart chambers (without atrial or ventricular septal defect), suggesting pulmonary vascular dilatations. Perfusion scan with macroaggregated albumin labelled with technetium-99m showed uptake over thyroid, kidneys, liver, and spleen suggesting an abnormal passage through the pulmonary vascular bed. The radiological examination with chest radiography and high resolution computer tomography revealed no signs of interstitial lung disease. The pulmonary artery angiography showed neither anatomical shunts nor malformations. DIAGNOSIS: The final diagnosis was hepatopulmonary syndrome Type 1. TREATMENT/FOLLOW-UP: The patient underwent liver transplantation with following good function of the liver graft. After 6 months the patient presented in a much better general condition, but with persisting severe hypoxemia whereas the spider naevi disappeared completely. One year after the liver transplantation in the perfusion scan the uptake over thyroid, kidneys, liver, and spleen was absent. The orthodeoxia and hypoxemia improved evidently. From that we conclude that the pulmonary vascular dilatations diminished after liver transplantation.

Diagnosis, Differential↗
PubMed1999

Regulation of the multidrug resistance protein 2 in the rat liver by lipopolysaccharide and dexamethasone.

BACKGROUND & AIMS: Endotoxin lipopolysaccharide (LPS) induces cholestasis and down-regulates the multidrug resistance protein 2 (MRP2). This study intends to characterize the short-term effects of LPS on MRP2. METHODS: The effects of LPS and dexamethasone on excretion of bromosulphalein (BSP), MRP2 messenger RNA (mRNA) levels, and subcellular MRP2 localization were studied by means of liver perfusion, Northern blots, and confocal microscopy. RESULTS: LPS treatment for 3-12 hours decreased biliary BSP excretion (10 micromol/L) by 40%. Hyposmolarity stimulated BSP excretion to control levels 3 hours after LPS injection, but was ineffective after 12 hours or in saline-treated controls. LPS led to a strong decrease of MRP2 mRNA after 12 hours, but not during the first 6 hours. LPS induced the appearance of MRP2 in intracellular vesicles in the immediate vicinity of the canaliculi within 3 hours, and these vesicles were remote from the canaliculi after 6 and 12 hours. The MRP2-containing vesicles did not stain for dipeptidylpeptidase IV (DPPIV). Dexamethasone counteracted the LPS effects on MRP2 mRNA levels, subcellular distribution, and BSP excretion. CONCLUSIONS: LPS induces cholestasis due to an early retrieval of MRP2 from the canalicular membrane, whereas down-regulation of MRP2 mRNA is a later event. LPS-induced MRP2 retrieval from the canalicular membrane is not associated with the retrieval of DPPIV, suggestive for selectivity of the process.

Animals↗
PubMed1999

Regulation of bile salt export pump mRNA levels by dexamethasone and osmolarity in cultured rat hepatocytes.

The major canalicular bile salt export pump (Bsep) of mammalian liver is downregulated by endotoxin. This study reports on the effects of dexamethasone and osmolarity on Bsep mRNA expression in cultured rat hepatocytes and its functional relevance in rat liver. Expression of Bsep mRNA in rat hepatocytes 24 and 48 h after isolation was dependent on the presence of dexamethasone (100 nM) in the culture medium. Bsep was functionally active at the pseudocanalicular membrane in cells cultured for 4 days in medium containing dexamethasone. Hypoosmolarity (205 mosmol/l) led to an induction of Bsep mRNA levels, whereas expression was decreased by hyperosmolarity (405 mosmol/l). Also the decay of Bsep mRNA following dexamethasone withdrawal was osmosensitive. In rat liver, dexamethasone counteracted the lipopolysaccharide (LPS)-induced down-regulation of Bsep mRNA levels after 12 hours and abolished the LPS-induced inhibition of taurocholate excretion. These results indicate that glucocorticoids are strong inducers of Bsep in liver. Furthermore, Bsep mRNA levels are osmosensitively regulated. The data suggest a longterm control of Bsep mRNA by osmolarity in addition to the short-term effects on canalicular bile acid excretion, which were reported recently.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Betaine as an osmolyte in rat liver: metabolism and cell-to-cell interactions.

Betaine was recently identified as an osmolyte in rat liver macrophages (Kupffer cells [KCs]) and sinusoidal endothelial cells (SECs). Betaine interferes with KC functions, such as phagocytosis, cytokine, and prostaglandin syntheses. As betaine is derived from choline, the present study was undertaken to evaluate osmosensitivity and cell heterogeneity of choline metabolism in rat liver. In the perfused rat liver after in vivo prelabeling with [14C]-choline, hypoosmotic stress induced a radioactivity release into the perfusate which was identified as [14C]-betaine by high-performance liquid chromatography (HPLC) analysis and which was inhibited by the anion exchanger inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid. Choline metabolism was studied in cultured liver parenchymal cells, (PCs), KCs, and SECs. Choline was taken up by all but betaine formation from choline was only detectable in PCs and not in KCs and SECs. Betaine formation in PCs was not stimulated by hyperosmolarity; rather, betaine has a role as an osmolyte in KCs and SECs but is of minor importance in PCs, as evidenced by only minor hyperosmolarity-induced betaine uptake. Thus, liver PCs can produce and release betaine derived from choline, and, thereby, possibly supply the osmolyte important for KC and SEC cell function. This may be another example for cell-to-cell interaction in the liver.

Animals↗
PubMed1997

Osmoregulated taurine transport in H4IIE hepatoma cells and perfused rat liver.

The effects of aniso-osmotic exposure on taurine transport were studied in H4IIE rat hepatoma cells. Hyperosmotic (405 mosmol/l) exposure of H4IIE cells stimulated Na+-dependent taurine uptake and led to an increase in taurine transporter (TAUT) mRNA levels, whereas hypo-osmotic (205 mosmol/l) exposure diminished both taurine uptake and TAUT mRNA levels when compared with normo-osmotic (305 mosmol/l) control incubations. Taurine uptake increased 30-40-fold upon raising the ambient osmolarity from 205 to 405 mosmol/l. When H4IIE cells and perfused livers were preloaded with taurine, hypo-osmotic cell swelling led to a rapid release of taurine from the cells. The taurine efflux, but not taurine uptake, was sensitive to 4,4'-di-isothiocyanatostilbene-2,2'-disulphonic acid (DIDS), suggestive of an involvement of DIDS-sensitive channels in mediating volume-regulatory taurine efflux. Whereas in both H4IIE rat hepatoma cells and primary hepatocytes TAUT mRNA levels were strongly dependent upon ambient osmolarity, mRNAs for other osmolyte transporters, i.e. the betaine transporter BGT-1 and the Na+/myo-inositol transporter SMIT, were not detectable. In line with this, myo-inositol uptake by H4IIE hepatoma cells was low and was not stimulated by hyperosmolarity. However, despite the absence of BGT-1 mRNA, a slight osmosensitive uptake of betaine was observed, but the rate was less than 10% of that of taurine transport. This study identifies a constitutively expressed and osmosensitive TAUT in H4IIE cells and the use of taurine as a main osmolyte, whereas betaine and myo-inositol play little or no role in the osmolyte strategy in these cells. This is in contrast with rat liver macrophages, in which betaine has been shown to be a major osmolyte.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1997

Cytoprotection by the osmolytes betaine and taurine in ischemia-reoxygenation injury in the perfused rat liver.

Medium osmolarity sensitively regulates Kupffer cell functions like phagocytosis and prostaglandin (PG) and cytokine production. Betaine and taurine, recently identified as osmolytes in liver cells, interfere with these effects. Because Kupffer cell activation is an important pathogenic mechanism in ischemia-reoxygenation injury, the influence of osmolarity and osmolytes was investigated in a rat liver perfusion model of warm ischemia. Livers were perfused with different medium osmolarities for 60 to 90 minutes in the absence of oxygen, followed by another 90 minutes of reoxygenation. Lactate dehydrogenase (LDH) leakage into the effluent perfusate during the hypoxic and the reoxygenation period was eight- to 10-fold higher with a medium osmolarity of 385 mosmol/L than in normo-osmolarity, and further decreased with hypo-osmolar perfusion buffer. Betaine and taurine addition to the perfusate in near physiological concentrations decreased hypoxia-reoxygenation-induced LDH leakage, aspartate transaminase (AST) leakage, and perfusion pressure increase in hyperosmolar and normo-osmolar perfusions. Stimulation of PGD2, PGE2, thromboxane B2 (TXB2), and tumor necrosis factor alpha (TNF-alpha) release, as well as induction of carbon uptake by the liver during reoxygenation, were suppressed by betaine and taurine, pointing to an interference of these osmolytes with Kupffer cell function. In contrast, endothelial cell function as assessed by hyaluronic acid (HA) uptake was not influenced. It is concluded that warm ischemia-reoxygenation injury in rat liver is aggravated by hyperosmolarity and attenuated by hypo-osmolarity. The osmolytes betaine and taurine have a protective effect, presumably by inhibition of Kupffer cell activation.

Animals↗
PubMed1997

[Gastrointestinal hemorrhage and diverticula of the jejunum--presentation of a case report and review of the literature].

Gastrointestinal bleeding due to jejunal diverticulosis is an uncommon emergency condition that has been encountered recently in one patient. The case of this patient treated with an emergency laparotomy and a segmentary small bowel resection is here presented. The clinical significance, proper diagnostic evaluation, and treatment of the hemorrhagic complication of jejunal diverticular disease are reviewed.

Aged↗
PubMed1996

Regulation of taurocholate excretion by a hypo-osmolarity-activated signal transduction pathway in rat liver.

BACKGROUND & AIMS: Hypo-osmotic cell swelling increases the capacity of taurocholate excretion into bile in the perfused rat liver. The aim of this study was to clarify the mechanisms linking cell swelling to bile acid secretion. METHODS: The influence of hypo-osmotic cell swelling on intracellular signal transduction and bile acid secretion was studied in isolated rat hepatocytes and the perfused rat liver. RESULTS: In rat livers perfused with hypo-osmotic buffer (225 mOsm/L), the maximum velocity of taurocholate excretion into bile is increased by 135% within 10-20 minutes. To unravel signaling events mediating this effect, the activities of the mitogen-activated protein kinases, extracellular-signal-regulated kinase (Erk)-1 and Erk-2, were measured after hypo-osmotic treatment in cultured rat hepatocytes. A rapid parallel activation of Erk-1 and Erk-2 was observed within 1 minute, which became maximal after 10 minutes and returned to the basal level within 60 minutes. The hypo-osmolarity-induced Erk activation and the increase in bile flow after hypo-osmotic liver perfusion were completely abolished by inhibitors of signal transduction at the level of G proteins and tyrosine kinases but remained unaffected by the inhibition of the protein kinase C. CONCLUSIONS: A G protein-and tyrosine kinase-dependent but protein kinase C-independent activation of mitogen-activated protein kinases is involved in the regulation of taurocholate excretion by liver cell hydration changes.

Animals↗
PubMed1996

Identification of betaine as an osmolyte in rat liver macrophages (Kupffer cells).

BACKGROUND & AIMS: Anisosmotic cell volume changes were identified recently as a critical factor in the regulation of eicosanoid formation in stimulated liver macrophages (Kupffer cells). Therefore, the aim of this study was to investigate whether osmolytes are involved in the control of Kupffer cell function. METHODS: Cultured rat liver macrophages (Kupffer cells) were studied with respect to their functional adaptation to hyperosmotic environments. RESULTS: Hyperosmotic exposure of lipopolysaccharide-stimulated Kupffer cells led to sevenfold stimulation of prostaglandin E2 formation caused by a strong induction of cyclooxygenase 2. Hyperosmotic exposure was accompanied by approximately a 10-fold increase of Na(+)-dependent betaine uptake and betaine transporter-messenger RNA levels. Conversely, hypoosmotic exposure decreased betaine uptake and stimulated betaine release from Kupffer cells and the perfused rat liver. Addition of betaine (1 mmol/L) to hyperosmotically exposed Kupffer cells abolished the strong induction of cyclooxygenase 2 and the increase of prostaglandin E2 formation. CONCLUSIONS: This study identifies the use of an osmolyte strategy in liver macrophages. Betaine serves as an osmolyte in Kupffer cells, whose transport is induced in response to increases of ambient osmolarity. Regulation of this transporter as well as betaine availability may represent a novel regulation site for Kupffer cell function.

Animals↗
PubMed1996

Secretin-induced plasma bicarbonate decrease as a simple indicator of exocrine pancreatic function.

During a secretin-cerulein test for exocrine pancreatic function, venous acid-base analysis was performed before and 30 and 45 min after the intravenous injection of secretin (1 clinical unit/kg body weight). A decrease in plasma bicarbonate was observed in persons with normal exocrine pancreatic function as defined by normal bicarbonate and enzyme secretion in the secretin-cerulein test (n = 39). Bicarbonate values were 94.8 +/- 3.6% (mean +/- SD) of the initial concentration after 30 min and 92.9 +/- 3.9% after 45 min. In contrast, there was no statistically significant decrease in plasma bicarbonate in patients with global pancreatic exocrine deficiency (n = 15). In normal exocrine pancreatic function, the maximal plasma bicarbonate decrease was 2.17 +/- 1.12 mM (mean +/- SD; n = 39). In patients with global exocrine deficiency, however, a maximal plasma bicarbonate decrease of 0.54 +/- 0.68 mM (n = 15) was obtained. The difference was highly significant (p < 0.001). In patients with partial exocrine deficiency (isolated decrease in bicarbonate secretion or reduced excretion of a single enzyme), values were also significantly lower (1.44 +/- 1.40 mM; n = 14; p < 0.05). The maximal plasma bicarbonate decrease correlated with the bicarbonate secretion into the duodenal juice (r = 0.62, p < 0.001). If a maximal plasma bicarbonate decrease > or = 0.9 mM was considered normal, determination of plasma bicarbonate following secretin administration allowed us to detect the presence of global exocrine deficiency with a sensitivity of 87% and a specificity of 87%. The secretin-induced plasma bicarbonate decrease may therefore be used as a new simple tubeless test to evaluate exocrine pancreatic function.

Acid-Base Equilibrium↗
PubMed1996

The role of birth injury and the consequences of inadequately treated hypogonadism in longstanding panhypopituitarism.

We describe a middle-aged profoundly hypogonadal man with panhypopituitarism since infancy who was treated only with glucocorticoid and thyroid replacement. A magnetic resonance imaging study (MRI) revealed absence of pituitary stalk and ectopic neurohypophysis consistent with traumatic transection, probably resulting from a traumatic birth. The hormonal consequences of this stalk lesion were recognized but inadequately treated for 45 years resulting in avoidable endocrine and psychosocial defects. Androgen replacement was started at age 45 with good initial results. The unique hormonal replacement issues at this age are discussed.

Birth Injuries↗
PubMed1995

Betaine is an osmolyte in RAW 264.7 mouse macrophages.

Hyperosmotic (405 mosmol/l) exposure of RAW 264.7 mouse macrophages led to a stimulation of betaine uptake and an increase in betaine transporter (BGT-1) mRNA levels. Conversely, hypoosmotic (205 mosmol/l) exposure decreased betaine uptake and diminished BGT-1 mRNA levels. Betaine uptake was Na(+)-dependent and was inhibited by about 90% by GABA, whereas inhibition by methylaminoisobutyrate and myoinositol was less than 15%. Addition of betaine strongly diminished BGT-1 mRNA levels in cells exposed to normoosmotic or hyperosmotic media. When mouse macrophages were preloaded with betaine, lowering of the extracellular osmolarity was followed by a rapid betaine efflux from the cells. This study identifies a constitutively expressed and osmosensitive betaine transporter in RAW 264.7 macrophages and the use of betaine as an osmolyte in these cells.

Aminoisobutyric Acids↗
PubMed1995

Hyperosmolarity stimulates prostaglandin synthesis and cyclooxygenase-2 expression in activated rat liver macrophages.

The effect of aniso-osmotic exposure on the level of inducible cyclooxygenase (Cox-2) and on prostanoid synthesis was studied in cultured rat liver macrophages (Kupffer cells). In lipopolysaccharide (LPS)- or phorbol 12-myristate 13-acetate-stimulated Kupffer cells, hyperosmotic (355 mosmol/l) exposure, due to addition of NaCl or impermeant sugars, markedly increased prostaglandin (PG) E2, D2 and thromboxane B2 synthesis in a time- and osmolarity-dependent manner. Increased prostanoid production was observed about 8 h after exposure to LPS in hyperosmotic medium compared to Kupffer cells treated with LPS under normotonic (305 mosmol/l) conditions. A similar stimulatory effect of hyperosmolarity on PGE2 production was also seen when arachidonate was added exogenously. Hyperosmotic stimulation of PGE2 production was accompanied by a strong induction of Cox-2 mRNA levels and an increase in immunoreactive Cox-2, whereas the levels of immunoreactive phospholipase A2 and cyclooxygenase-1 did not change significantly. Dexamethasone, indomethacin and the selective Cox-2 inhibitor, NS-398, abolished the hypertonicity-induced stimulation of PGE2 formation; dexamethasone also prevented the increase in Cox-2 mRNA and protein. The increase of immunoreactive Cox-2 lasted for about 24 h and was also blocked by actinomycin D or cycloheximide, but not by brefeldin A. Tunicamycin or treatment with endoglucosidase H reduced the molecular mass of hypertonicity-induced Cox-2 by 5 kDa. Tunicamycin treatment also suppressed the hypertonicity-induced stimulation of PGE2 production. The hyperosmolarity/LPS-induced stimulation of prostaglandin formation was partly sensitive to protein kinase C inhibition but was not accompanied by an increase in the cytosolic free Ca2+ concentration. The data suggest that osmolarity may be a critical factor in the regulation of Cox-2 expression and prostanoid production in activated rat liver macrophages.

Adenosine Triphosphate↗
PubMed1995

Metabolism of cysteinyl leukotrienes in the perfused rat liver: the influence of endotoxin pretreatment and the cellular hydration state.

The influence of endotoxin on the hepatic metabolism and elimination of 3H-leukotriene C4 (LTC4) and 3H-leukotriene E4 was studied in the single-pass perfused rat liver. Endotoxin (4 mg/kg body mass) was injected intraperitoneally 8 to 10 hours before livers were isolated for perfusion. Tritiated leukotriene C4 and leukotriene E4 (10 nmol/L) were infused for 5 minutes, and metabolites in bile were determined by high-pressure liquid chromatography. In livers without endotoxin pretreatment, single-pass uptake of LTC4 was 77.3% +/- 3.2%, and 73.8% +/- 1.8% of the radioactivity taken up was excreted into the bile within 80 minutes. In endotoxin-pretreated livers, LTC4 uptake was 62.8% +/- 3.5% and only 31.2% +/- 1.5% of the radioactivity taken up was eliminated into the bile within 80 minutes. Bile flow was reduced to 0.20 +/- 0.07 microL/min, compared with 1.18 +/- 0.18 microL/g/min in untreated livers. Biliary excretion of infused 3H-LTE4 was also reduced in endotoxin-pretreated livers (31.5% +/- 6.1% compared with 61.4% +/- 3.3% without endotoxin pretreatment), whereas uptake was not significantly different. The effect of cellular hydration state on leukotriene processing was also investigated. Anisoosmotic cell volume changes did not influence uptake and biliary excretion of 3H-LTC4 and its metabolism in control livers. In endotoxin-pretreated livers, however, cell swelling induced by hypotonic perfusion media (225 mOsm/L) or by 3 mmol/L glutamine increased biliary elimination of the radioactivity taken up by 68% and 54%, respectively. Bile flow was also stimulated (0.31 +/- 0.09 microL/g/min and 0.46 +/- 0.01 microL/g/min, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗