Publications (5)38.72 Total impact
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Article: Role of alphavbeta6 integrin in acute biliary fibrosis.
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ABSTRACT: Acute biliary obstruction leads to periductal myofibroblasts and fibrosis, the origin of which is uncertain. Our study provides new information on this question in mice and humans. We show that bile duct obstruction induces a striking increase in cholangiocyte alphavbeta6 integrin and that expression of this integrin is directly linked to fibrogenesis through activation of transforming growth factor beta (TGF-beta). Administration of blocking antibody to alphavbeta6 significantly reduces the extent of acute fibrosis after bile duct ligation. Moreover, in beta6-null mice subjected to the injury, fibrosis is reduced by 50% relative to that seen in wild-type mice, whereas inflammation occurs to the same extent. The data indicate that alphavbeta6, rather than inflammation, is linked to fibrogenesis. It is known that alphavbeta6 binds latent TGF-beta and that binding results in release of active TGFbeta. Consistent with this, intracellular signaling from the TGFbeta receptor is increased after bile duct ligation in wild-type mice but not in beta6(-/-) mice, and a competitive inhibitor of the TGFbeta receptor type II blocks fibrosis to the same extent as antibody to alphavbeta6. In a survey of human liver disease, expression of alphavbeta6 is increased in acute, but not chronic, biliary injury and is localized to cholangiocyte-like cells. CONCLUSION: Cholangiocytes respond to acute bile duct obstruction with markedly increased expression of alphavbeta6 integrin, which is closely linked to periductal fibrogenesis. The findings provide a rationale for the use of inhibitors of alphavbeta6 integrin or TGFbeta for down-regulating fibrosis in the setting of acute or ongoing biliary injury.Hepatology 12/2007; 46(5):1404-12. · 11.66 Impact Factor -
Article: Role of αvβ6 integrin in acute biliary fibrosis
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ABSTRACT: Acute biliary obstruction leads to periductal myofibroblasts and fibrosis, the origin of which is uncertain. Our study provides new information on this question in mice and humans. We show that bile duct obstruction induces a striking increase in cholangiocyte vβ6 integrin and that expression of this integrin is directly linked to fibrogenesis through activation of transforming growth factor beta (TGF-β). Administration of blocking antibody to vβ6 significantly reduces the extent of acute fibrosis after bile duct ligation. Moreover, in β6-null mice subjected to the injury, fibrosis is reduced by 50% relative to that seen in wild-type mice, whereas inflammation occurs to the same extent. The data indicate that vβ6, rather than inflammation, is linked to fibrogenesis. It is known that vβ6 binds latent TGF-β and that binding results in release of active TGFβ. Consistent with this, intracellular signaling from the TGFβ receptor is increased after bile duct ligation in wild-type mice but not in β6−/− mice, and a competitive inhibitor of the TGFβ receptor type II blocks fibrosis to the same extent as antibody to vβ6. In a survey of human liver disease, expression of vβ6 is increased in acute, but not chronic, biliary injury and is localized to cholangiocyte-like cells. Conclusion: Cholangiocytes respond to acute bile duct obstruction with markedly increased expression of vβ6 integrin, which is closely linked to periductal fibrogenesis. The findings provide a rationale for the use of inhibitors of vβ6 integrin or TGFβ for down-regulating fibrosis in the setting of acute or ongoing biliary injury. (HEPATOLOGY 2007.)Hepatology 10/2007; 46(5):1404 - 1412. · 11.66 Impact Factor -
Article: Six decades of progress and change in hospital medicine, 1947-2007.
The Pharos of Alpha Omega Alpha-Honor Medical Society. Alpha Omega Alpha 02/2007; 70(1):10-5. -
Article: TWEAK induces liver progenitor cell proliferation.
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ABSTRACT: Progenitor ("oval") cell expansion accompanies many forms of liver injury, including alcohol toxicity and submassive parenchymal necrosis as well as experimental injury models featuring blocked hepatocyte replication. Oval cells can potentially become either hepatocytes or biliary epithelial cells and may be critical to liver regeneration, particularly when hepatocyte replication is impaired. The regulation of oval cell proliferation is incompletely understood. Herein we present evidence that a TNF family member called TWEAK (TNF-like weak inducer of apoptosis) stimulates oval cell proliferation in mouse liver through its receptor Fn14. TWEAK has no effect on mature hepatocytes and thus appears to be selective for oval cells. Transgenic mice overexpressing TWEAK in hepatocytes exhibit periportal oval cell hyperplasia. A similar phenotype was obtained in adult wild-type mice, but not Fn14-null mice, by administering TWEAK-expressing adenovirus. Oval cell expansion induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) was significantly reduced in Fn14-null mice as well as in adult wild-type mice with a blocking anti-TWEAK mAb. Importantly, TWEAK stimulated the proliferation of an oval cell culture model. Finally, we show increased Fn14 expression in chronic hepatitis C and other human liver diseases relative to its expression in normal liver, which suggests a role for the TWEAK/Fn14 pathway in human liver injury. We conclude that TWEAK has a selective mitogenic effect for liver oval cells that distinguishes it from other previously described growth factors.Journal of Clinical Investigation 10/2005; 115(9):2330-40. · 15.39 Impact Factor -
Chapter: Hereditary Coproporphyria
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ABSTRACT: Hereditary coproporphyria (HCP) is an acute (hepatic) porphyria in which the acute symptoms are neurovisceral and occur in discrete episodes. Attacks typically start in the abdomen with low-grade pain that slowly increases over a period of days (not hours) with nausea progressing to vomiting. In some individuals, the pain is predominantly in the back or extremities. When an acute attack is untreated, a motor neuropathy may develop over a period of days or a few weeks. The neuropathy first appears as weakness proximally in the arms and legs, then progresses distally to involve the hands and feet. Some individuals experience respiratory insufficiency due to loss of innervation of the diaphragm and muscles of respiration. Acute attacks are associated commonly with use of certain medications, caloric deprivation, and changes in female reproductive hormones. About 20% of those with an acute attack also experience photosensitivity associated with bullae and skin fragility. The most sensitive and specific biochemical screening test for any one of the acute porphyrias (including HCP) during an acute attack is a striking increase in urinary porphobilinogen (PBG). Quantitative analysis of porphyrins in both urine and feces is essential to distinguish between the different acute porphyrias and establish the diagnosis of HCP. Identification of a heterozygous mutation in CPOX (encoding the enzyme coproporphyringen-III oxidase) confirms the diagnosis and enables family studies. Treatment of manifestations: Acute attacks are treated by discontinuation of any medications thought to induce attacks, management of dehydration and/or hyponatremia, administration of carbohydrate, and infusion of hematin. Treatment of symptoms and complications should be with medications known to be safe in acute porphyria (see www.drugs-porphyria.org). A minority of affected individuals experience repeat acute attacks, in which case management strategies include suppression of ovulation in females, prophylactic use of hematin, and liver transplantation when attacks and neurologic complications persist despite multiple courses of hematin. Prevention of primary manifestations: Agents or circumstances that may trigger an acute attack (including use of oral contraception in women) are avoided. Suppression of menses using a GnRH agonist (leuprolide, nafarelin, and others) may help CPOX heterozygotes who experience monthly exacerbations. Prevention of secondary complications: In CPOX heterozygotes undergoing surgery, intravenous glucose is provided in the perioperative period and non-barbiturate agents are used for induction of anesthesia. Agents/circumstances to avoid: Fasting, use of female reproductive hormones, and certain drugs including barbiturates and phenytoin. Evaluation of relatives at risk: If the family-specific CPOX mutation is known, clarification of the genetic status of relatives at risk allows early diagnosis of heterozygotes and education regarding risk factors for an acute attack. HCP is inherited in an autosomal dominant manner with reduced penetrance. Most individuals with HCP have an affected parent; the proportion with a de novo mutation is unknown. Each child of an individual with HCP has a 50% chance of inheriting the CPOX mutation. Because of reduced penetrance, many individuals with a CPOX mutation have no signs or symptoms of HCP. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in an affected family member is known. However, because the prenatal detection of a CPOX mutation does not predict the presence or severity of symptoms, the authors’ opinion is that prenatal testing is not warranted unless pregnancy termination is being considered.
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2007
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University of California, San Francisco
- Division of Hospital Medicine
San Francisco, CA, USA
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