The Effectiveness of Oral Tin Mesoporphyrin Prophylaxis in Reducing Bilirubin Production after an Oral Heme Load in a Transgenic Mouse Model
Department of Pediatrics , Stanford University, Palo Alto, California, United States Biology of the Neonate
(Impact Factor: 1.74).
02/2006; 89(3):139-46. DOI: 10.1159/000088717
Neonatal jaundice is commonly encountered and rarely associated with morbidity and mortality. Nonetheless, infants with glucose-6-phosphate dehydrogenase deficiency often have hemolysis (a heme load) caused by an environmental oxidant trigger, thus increasing their risk for serious morbidity. The use of tin mesoporphyrin (SnMP) has been proposed for interdicting the development of severe hyperbilirubinemia in a variety of conditions.
We studied the in vivo effects of prophylactic oral SnMP on heme oxygenase (HO) activity and bilirubin production, as indexed by the excretion rate of carbon monoxide (VeCO), following a subsequent oral heme load.
Adult mice were exposed serially to heme and assessed for in vivo bilirubin production rates, HO-1 transcription and protein, and HO activity. The effect of prophylaxis with a single oral dose of SnMP prior to an oral heme load was assessed by measuring VeCOand tissue HO activities.
After serial heme exposures, VeCO, HO-1 transcription and protein, and liver and spleen HO activities increased incrementally. After pretreatment with oral SnMP, bilirubin production decreased in response to an oral heme load. Also, heme-mediated increases in liver, spleen, and intestine HO activities were significantly dampened.
A single oral dose of SnMP results in durable inhibition of bilirubin production and HO activity for at least 24 h in a mouse model of oral heme loading. Further studies are needed to fully elucidate the duration of this protection against hyperbilirubinemia due to a delayed heme load and any long-term consequences of prophylaxis with SnMP on HO-1 transcription and HO-1 protein.
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- "Tin mesoporphyrin IX (SnMP, Rockfeller University, New York, NY, USA), an inducer of HO protein synthesis , is considered a potent inhibitor of the activity of both preformed and newly synthesized enzyme [21,22]. SnMP was administered via intra-peritoneal injection at a dose of 8 mg/kg body weight. "
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ABSTRACT: Up-regulation of HO-1 by genetic manipulation or pharmacological pre-treatment has been reported to provide benefits in several animal models of myocardial infarction (MI). However, its efficacy following MI initiation (as in clinical reality) remains to be tested. Therefore, this study investigated whether HO-1 over-expression, by cobalt protoporphyrin (CoPP) administered after LAD ligation, is still able to improve functional and structural changes in left ventricle (LV) in a rat model of 4-week MI.
A total of 144 adult male Wistar rats were subjected to either left anterior coronary artery ligation or sham-operation. The effect of CoPP treatment (5 mg/kg i.p. at the end of the surgical session and, then, once a week for 4 weeks) was evaluated on the basis of survival, electro- and echocardiography, plasma levels of B-type natriuretic peptide (BNP), endothelin-1 and prostaglandin E2, coronary microvascular reactivity, MI size, LV wall thickness and vascularity. Besides, the expression of HO-1 and connexin-43 in different LV territories was assessed by western blot analysis and immunohistochemistry, respectively.
CoPP induced an increased expression of HO-1 protein with >16 h delay. CoPP treatment significantly reduced mortality, MI size, BNP concentration, ECG alterations, LV dysfunction, microvascular constriction, capillary rarefaction and restored connexin-43 expression as compared to untreated MI. These functional and structural changes were paralleled by increased HO-1 expression in all LV territories. HO activity inhibition by tin-mesoporphyrin abolished the differences between CoPP-treated and untreated MI animals.
This is the first report demonstrating the putative role of pharmacological induction of HO-1 following coronary occlusion to benefit infarcted and remote territories, leading to better cardiac function in a 4-week MI outcome.
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ABSTRACT: De ziekte van Crigler-Najjar is een ernstige, weinig voorkomende vorm van geelzucht. Kenmerk van de ziekte is ophoping in het lichaam van ongeconjugeerd bilirubine (UCB), een afbraakproduct van rode bloedcellen. Ophoping van UCB kan leiden tot neurologische schade. De gebruikelijke behandeling van de ziekte is fototherapie, waarbij de patiënt dagelijks vele uren onder een soort zonnebank moet doorbrengen. Dit tast het sociale leven van de patiënt erg aan. Bovendien wordt de behandeling met het stijgen van de leeftijd minder effectief. Promovendus Anja Hafkamp deed onderzoek naar een nieuwe behandeling van deze ziekte. Doel was UCB in de darmen te “vangen” door middel van vet. Dit voorkomt heropname van UCB vanuit de darm in het lichaam. Door oraal toe te dienen medicatie werd de vetuitscheiding en daarmee de UCB uitscheiding via de ontlasting bevorderd. Bij patiënten met de ziekte van Crigler-Najjar waren de effecten relatief beperkt. Echter, een subgroep van de patiënten reageerde wél op de behandeling. Nader onderzoek moet duidelijk maken wat de verschillen veroorzaakt. Hafkamp verwacht dat deze nieuwe behandelmethode in de toekomst toegepast kan worden.
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ABSTRACT: The gastrointestinal tract is lined by a simple epithelium that undergoes constant renewal involving cell division, differentiation and cell death. In addition, the epithelial lining separates the hostile processes of digestion and absorption that occur in the intestinal lumen from the aseptic environment of the internal milieu by defensive mechanisms that protect the epithelium from being breached. Central to these defensive processes is the synthesis of heme and its catabolism by heme oxygenase (HO). Dietary heme is also an important source of iron for the body which is taken up intact by the enterocyte. This review describes the recent literature on the diverse properties of heme/HO in the intestine tract. The roles of heme/HO in the regulation of the cell cycle/apoptosis, detoxification of xenobiotics, oxidative stress, inflammation, development of colon cancer, heme-iron absorption and intestinal motility are specifically examined.
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