Liver collagen synthesis and degradation in schistosomiasis.
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Animals↗
Biomedical subjects
M A Dunn
Publications and source records attributed to M A Dunn.
Chronic hepatitis B in patients with schistosomiasis mansoni.
A village, 20 miles north of Cairo, with a census population of 2010, was surveyed in 1976 by the Center of Disease Control (CDC) and the Egyptian Ministry of Health for hepatitis B surface antigen (HBsAg). Ninety individuals (47 males and 43 females were positive for HBsAg (a prevalence rate of 4.5%). Forty-two of the 47 males were the subject of this study. They were admitted to the Naval Medical Research Unit Hospital 2 years later. They all had active Schistosoma mansoni infection. Nineteen of the 42 were carrying HBsAg and the remaining 23 were negative for hepatitis antigen at this time of investigation. Histological examination of percutaneous liver biopsies showed chronic-active hepatitis in five of 17 HBsAg carriers including two with additional cirrhosis. Two others with clinical evidence of cirrhosis could not safely have biopsies taken. Two of these 19 persons died and three became incapacitated over 2 years of further observation. Of the 23 individuals who had transient HBsAg in 1976 and equally heavy S. mansoni infection, evaluation in 1978 showed chronic active hepatitis in one, and at re-evaluation 2 years later, one had become unable to work but none had died. Ten other individuals (military recruits) from different villages of the Nile Valley who had no schistosomiasis but were carriers of HBsAg, were symptom free and liver biopsy showed chronic active hepatitis in one individual and no morbidity or mortality in 2 years. Morbidity of chronic hepatitis B infection in S. mansoni infected persons appears to be unusually severe compared with hepatitis B infection in other populations.
Adolescent↗
Segmental splenectomy in schistosomiasis.
Segmental splenectomy was performed in 5 patients with hepatosplenic schistosomiasis mansoni and symptomatic splenomegaly. The aim was to preserve a functional remnant comprising 20-30 per cent of the bulk of a greatly enlarged spleen. The operative technique involved devascularization of anatomic segments and suture of an omental patch to the residual spleen. This procedure was simple, well tolerated and effective in relieving abdominal discomfort and cytopenias. The residual spleens showed normal uptake of 99Tc-sulphur colloid. If long term observation confirms the value of segmental splenectomy in hepatosplenic schistosomiasis, it may become appropriate therapy for those patients with symptomatic splenomegaly who do not require portal decompression.
Adolescent↗
Effects of fasting on muscle protein turnover, the composition of weight loss, and energy balance of obese and nonobese Zucker rats.
The effects of prolonged fasting on the composition of weight loss and the rates of muscle protein synthesis and degradation were compared in obese and nonobese (lean) rats. Lean rats weighting 400 g could survive 60 days of fasting whereas obese rats weighing 550 g could survive 60 days. Weight loss was similar in both phenotypes over the first 10 days of fasting (15 g/day), but the composition of weight loss differed. Obese rats lost nearly twice as much lipid but only one-fifth as much body protein as lean rats. The fasting metabolic rate [kilocalories/(day . kilograms 0.75)] was similar in both phenotypes. This finding indicates a slower decline in metabolic rate during fasting in obese rats, since maintenance requirements are greater in lean rats. In fed rats, the fractional rates of muscle protein synthesis (FRS) and breakdown (FRB) were slightly higher in obese rats. Fasting reduced muscle protein synthesis in both phenotypes. In obese rats, however, the FRS declined more slowly than in lean rats. On the other hand, FRB decreased in fasted obese rats but greatly increased in fasted lean rats. It was concluded that the better protein retention and slower decline in metabolic rate in fasted obese rats were related to their different regulation of muscle protein synthesis and breakdown during fasting.
Animals↗
Comparative amino acid and protein metabolism in obese and non-obese Zucker rats.
A mixture of [U-14C]amino acids was injected intraperitoneally into fed obese and non-obese Zucker rats that were either growing (8 weeks of age) or at maintenance (17 weeks of age). The metabolic fate of the dietary amino acid pool was determined from the distribution of 14C into carcass lean tissue, carcass lipid, CO2 and urine. In a second experiment, urinary and skeletal muscle 3-methylhistidine content was used to compare the rate of muscle protein breakdown between phenotypes at 8 weeks of age. The obese rat deposited a smaller proportion of its dietary amino acid pool in lean tissue compared with its non-obese control during growth and at maintenance. Obese rats incorporated a greater proportion of dietary amino acids into body lipid at both ages and metabolized a greater proportion of dietary amino acid carbon to CO2 during growth. At 8 weeks of age, the obese rat had a higher fractional rate of muscle protein breakdown and was less efficient at retaining amino acids that had been incorporated into muscle. These latter differences were major factors in producing the variation in dietary amino acid utilization and protein accretion between growing obese and non-obese rats. At maintenance, the variation in dietary amino acid utilization between phenotypes was due principally to the smaller body protein mass of the obese animals.
Aging↗
Hepatitis B in United States soldiers in Korea.
We studied US soldiers hospitalized in Korea during 1977 because of acute icteric hepatitis. The clinical characteristics of this illness were similar to those noted in previous studies of this population. In contrast to earlier reports, however, hepatitis B virus was shown to be the single most important cause. Of 139 patients with acute viral hepatitis, 76 (55%) had positive tests for hepatitis B surface antigen (HBsAg) and 63 (45%) were HBsAg-negative on a single determination by radioimmunoassay (AUSRIA II) approximately one week after the onset of symptoms. Nonparenteral transmission was the primary mechanism of hepatitis B infection in this sexually active population. Only one patient had evidence of parenteral drug use. Our increased recognition of hepatitis B virus in these patients can be explained entirely by increased sensitivity of the current radioimmunoassay methods for HBsAg. High rates of nonparenteral transmission of B virus within the populations of developing countries are well recognized. Our findings show that hepatitis B virus can be the major cause of nonparenterally acquired acute hepatitis among foreigners in contact with such a population.
Acute Disease↗
Liver collagenase in murine schistosomiasis.
Mice infected with Schistosoma mansoni represent a model for study of the most prevalent form of hepatic fibrosis in humans. In the present study, collagenase activity was measured in relation to collagen synthesis and accumulation in the livers of mice 6-11 wk after after infection. Total and latent collagenase and elastase activities and collagen synthesis were maximal 8 wk after infection and decreased thereafter, whereas collagen content progressively increased to the 11th wk. Maximal enzymatic activity coincided with the known peak of host cellular immune responses. Collagenase and elastase activities were isolated from liver homogenates. Isolated schistosome eggs did not contain collagenase or elastase activities. Collagenolytic activity had the characteristics of a tissue collagenase. These data show that marked increases in collagenase activity occur together with increased collagen synthesis in this animal model. Continued accumulation of liver collagen under these conditions suggests an imbalance between increased collagen synthesis and degradation.
Animals↗
Liver collagen synthesis in schistosomiasis mansoni.
We determined collagen synthetic rates and utilization of key amino acid precursors of collagen in slices of wedge liver biopsy specimens obtained at required surgery from 9 patients with hepatosplenic schistosomiasis and from 4 control patients. The liver specimens from the patients with schistosomiasis showed advanced fibrosis, with histologic evidence of schistosomiasis alone in four, and both schistosomiasis and chronic active hepatitis in five cases. Liver slices were incubated with radioactive proline, arginine and glutamine, using quantitative assay conditions validated earlier for murine schistosomiasis. Collagen peptide synthesis in slices from all nine fibrotic liver specimens was 4- to 25-fold greater than normal and correlated positively with liver collagen content, which was 2- to 5-fold greater than normal. Free proline, an amino acid that may contribute to regulation of collagen peptide synthesis, was increased in six of the nine fibrotic liver specimens, and proline was actively formed from arginine in liver slices from all specimens. These measurements of the initial steps of collagen biosynthesis in fibrotic human liver are quantitatively similar to those previously made of the same processes in experimental animals.
Adolescent↗
Liver collagen hydroxylation in murine schistosomiasis.
The activity of procollagen prolyl hydroxylase was measured in fibrotic liver obtained from mice with hepatosplenic schistosomiasis, an animal model of the most prevalent form of human liver fibrosis. Measurable activity of prolyl hydroxylase in fibrotic liver supernatants was 47-fold higher than that of normal liver. The effect of prolyl hydroxylase inhibition on collagen synthesis in fibrotic liver slices was studied, using 8,9-dihydroxy-7-methyl benzo[b]quinolizinium bromide (GPA 1734). This compound was shown in other systems to inhibit prolyl and lysyl hydroxylations by iron chelation at concentrations which did not affect total protein synthesis. The formation of nondialyzable labelled hydroxyproline was inhibited by GPA 1734, 40, 70 and 95% at 30, 50 and 100 micrometer, respectively. Incorporation of proline into total liver protein was unaffected at 30 and 50 micrometer, but was inhibited 20% at 100 micrometer GPA 1734. Underhydroxylated collagen synthesized by liver slices with GPA 1734 was extracted with neutral salt solution and was subsequently hydroxylated with partially-purified prolyl hydroxylase to the same extent as control material synthesized in the absence of GPA 1734.
2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗
Conversion of arginine to proline in murine schistosomiasis.
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Amino Acids↗
Liver collagen synthesis in murine schistosomiasis.
Collagen synthesis was measured in liver slices obtained from mice with hepatosplenic schistosomiasis. Enlarged fibrotic livers from these mice contained 20 times more collagen than normal. This model of hepatic fibrosis results from an inflammatory granulomatous host response to Schistosoma mansoni ova in portal tracts, rather than from direct lover cell injury as with carbon tetrachloride-induced liver fibrosis. Collagen synthesis, as measured by the formation of labeled protein-bound hydroxyproline, occurred in granulomas isolated from fibrotic livers. Labeled collagen that cochromatographed with type I collagen was extracted with neutral salt solution from liver slices incubated with labeled proline. The free proline pool of the liver was doubled in infected mice; coordinately, liver slices from these animals showed maximal collagen production when the concentration of free proline in the medium was raised to 0.4 mM, the same level measured in the fibrotic livers. Under such conditions, collagen synthesis was at a rate equivalent to the formation of 5.4 nmol of protein-bound hydroxyproline per g liver in 6 h. In comparative incubations in medium containing 0.2 mM proline, fibrotic liver slices produced 16-fold more collagen than normal slices. The proline analogue, L-azetidine 2-carboxylic acid, effectively inhibited synthesis of labeled collagen by fibrotic liver slices. These studies show the synthesis of collagen in a reproducible animal model of the most prevalent form of human liver fibrosis. Difinitition of the controlling factors in this system is of interest for the general problem of fibrosis produced by immunological responses.
Animals↗
Hypersplenism in advanced breast cancer: report of a patient treated with splenectomy.
A patient with widespread metastatic breast cancer had thrombocytopenia and severe anemia due to splenic hyperfunction, confirmed by chromium51-labeled red cell survival and sequestration studies. Marked splenic enlargement was produced by metastatic tumor. After she failed to respond to steroids, her hematologic status was improved by splenectomy, and has been stable for 16 months. Hypersplenism may be suspected as a cause of severe hemolytic anemia in advanced carcinoma. If the patient's general status is otherwise compatible with long comfortable survival, appropriate diagnostic studies and consideration of splenectomy are warranted.
Anemia↗
Pre-erythrocytic rodent malaria, Plasmodium berghei--prevention of development in the ethionine fatty liver.
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Adenosine↗
Proline trapping in granulomas, the site of collagen biosynthesis in murine schistosomiasis.
Proline, a critical substrate for collagen synthesis, is increased in liver undergoing fibrosis. In mice with schistosomiasis, the incorporation of proline into collagen occurs within liver granulomas. To study the interaction of liver cells and granulomas in the development of fibrosis, we assayed the enzymes that catalyze the formation and degradation of proline in isolated granulomas and liver. Two sequential enzymes involved in the formation of proline from arginine are ornithine-delta-aminotransferase and delta-pyrroline-5-carboxylate (P5C) reductase. Activities of both these enzymes in granulomas were approximately 10% of those in liver, expressed on the basis of DNA content. The enzymes involved in degradation of proline are proline oxidase and P5C dehydrogenase; both are present in liver cells. In isolated granulomas, activity of proline oxidase was minimal, and P5C dehydrogenase activity was absent. These findings suggest that the metabolism of proline within granulomas differs greatly from that in liver cells. Earlier studies showed that exogenous proline enters granulomas and is rapidly incorporated into collagen. The combined findings raise the possibility that granulomas serve as a proline trap. Proline can enter this compartment and can be incorporated into collagen; however, proline within granulomas cannot readily be diverted into other pathways by degradation.
Animals↗
Urea synthesis after protein feeding reflects hepatic mass in rats.
Urea synthesis is an exclusive biosynthetic function of the liver. Since the exact relationship between urea synthesis in vivo and functional liver mass remains unclear, we established an animal model using oral protein loading and measurement of resultant urea synthesis in rats. We studied rats subjected to sham operation, 40% hepatectomy, 66% hepatectomy, portacaval shunt and CCl4-induced cirrhosis. Urea synthesis was calculated as the sum of urinary urea excretion and accumulation of urea in body water during the 6-hr period after oral administration of a casein protein load equivalent to 20 gm per kg body weight. Peak urea synthesis rate in the sham-operated group of rats was 142 +/- 11 mumoles per hr per gm wet liver weight (mean +/- 1 S.D.), 473 +/- 34 mumoles per hr per gm liver protein and 80 +/- 5 mumoles per hr per mg liver DNA. This rate closely matched those of the other groups for each type of liver mass measurement. Marked reduction (p less than 0.01) of urea synthesis on a DNA basis was noted only in the CCl4-cirrhotic livers, related to the significantly higher (p less than 0.01) DNA content of the cirrhotic livers. Similarly, increased (p less than 0.05) liver protein content of the sham-operated rats when compared with the other groups was reflected in slightly lower urea synthesis rates expressed on the basis of liver protein (p less than 0.05) when compared to that of all other groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗