DOE003 2010-5-12 10:22
骨橋蛋白可作為酒精性肝中毒之治療目標
作者：Thomas R. Collins
出處：WebMD醫學新聞
April 28, 2010(奧地利維也納) — 西班牙研究的新資料認為，骨橋蛋白(osteopontin)或其基因，可能值得作為酒精性肝中毒患者的治療目標。
西班牙巴塞隆納大學博士候選人Oriol Morales在歐洲肝臟研究協會(EASL)第45屆年會中向與會聽眾表示，我們可以辨識出骨橋蛋白，這些病患中，多數人的「上調表達基因(upregulated genes)」之一，相較於正常肝臟，過度表現值為58.5。
他們研究了44個酒精性肝炎病患，研究者發現，酒精性肝炎病患的骨橋蛋白血清值幾乎是健康對照組的5倍，是C型肝炎患者的4倍(兩組的P均< .001 )。
他們也發現，嚴重酒精性肝炎患者的骨橋蛋白血清值，是較不嚴重患者的2倍(P= .038)。
骨橋蛋白是骨骼和牙齒的細胞外基質中重要的蛋白質，可以透過多個受體刺激細胞活性。
以前的研究已經建立骨橋蛋白和肝臟的關聯，一篇研究顯示，慢性損傷的肝臟中骨橋蛋白表現增加，另一篇研究顯示，缺乏骨橋蛋白基因的老鼠較少發生肝臟損傷，但是未曾探討和酒精性肝炎的關聯。
研究者也發現，富含乙醇的飲食使野生型老鼠比骨橋蛋白基因剔除鼠產生更多的肝臟損傷。
給予富含乙醇飲食的野生雌鼠，代表肝臟損傷的丙胺酸轉胺酶(ALT)高達缺乏骨橋蛋白基因之老鼠的4倍，野生雄鼠的ALT值達2倍(兩組的P均< .05)。
Morales先生表示，結果認為，缺乏骨橋蛋白的老鼠可以免於乙醇引起的細胞損傷。
研究者也發現，骨橋蛋白基因表現誘發了纖維化基因的表現。
Morales先生表示，骨橋蛋白在未來的治療中佔有一席之地，整合之後，這些結果認為，骨橋蛋白可以作為酒精性肝炎病患的治療目標。
該場會議的主持人、EASL副秘書長、英國倫敦帝國學院肝臟科教授Mark Thursz醫師指出，骨橋蛋白已經被提出用於其他疾病之治療，包括類風濕性關節炎。
Thursz醫師表示，它在作為治療目標這方面已經有一些幫助，很難說還在研究階段，很像「雞生蛋、蛋生雞」的問題，它的數值增加是因為有發炎、還是因為它引起發炎？
他表示，該研究提出一些證據支持這實際上強化了發炎的觀念，因此，藉由將它視為目標，可以有新的治療介入方式用於酒精性肝炎病患。
他指出，這類疾病治療之任何進展是相當需要的，這類疾病的重症病患死亡率仍高達30%。
Thursz醫師表示，目前，我們只有類固醇，類固醇的問題之一是，病患會有感染風險，坦白說，那是有點亂槍打鳥的方法，你只是壓抑了所有的免疫和發炎反應。我們知道，這類病患很容易發生感染，若給他們類固醇，情況會惡化。
該研究並未接受商業補助，Morales先生和 Thursz醫師都宣告沒有相關財務關係。
歐洲肝臟研究協會(EASL)第45屆年會，發表於2010年4月16日。
Osteopontin a Possible Therapeutic Target in Alcoholic Hepatitis
By Thomas R. Collins
Medscape Medical News
April 28, 2010 (Vienna, Austria) — New data from a Spanish research team suggest that the protein osteopontin, or its gene, might be a worthwhile target in therapy for patients with alcoholic hepatitis.
"We were able to identify osteopontin?.?.?. as one of the most upregulated genes in these patients, with a 58.5 value of overexpression vs normal livers," Oriol Morales, a PhD candidate at the University of Barcelona in Spain, told meeting attendees here at the European Association for the Study of the Liver (EASL) 45th Annual Meeting.
In their study of 44 patients with alcoholic hepatitis, the researchers found that osteopontin serum levels were about 5 times greater in alcoholic hepatitis patients than in healthy control subjects and about 4 times greater than in patients with hepatitis?C virus infection (P?< .001 in both cases).
They also found that osteopontin serum levels in patients with severe alcoholic hepatitis were double those of patients with less severe disease (P?= .038).
Osteopontin is a protein that is a prominent part of the extracellular matrices of bones and teeth. It is known for its ability to stimulate cell activity through multiple receptors.
Previous studies have established a relation between osteopontin and the liver. One showed that osteopontin expression in the liver was increased in chronically damaged livers. Another showed that mice lacking the osteopontin gene developed less hepatic injury. But a link to alcoholic hepatitis had not been explored.
The researchers also found that an ethanol-rich diet produced far more liver injury in wild-type mice than in osteopontin-knockout mice.
Female wild-type mice on an ethanol-rich diet had 4 times as much alanine aminotransferase (ALT), indicating liver injury, than mice lacking the osteopontin gene. Male wild-type mice had twice the ALT levels (P?< .05 in both cases).
"The results suggest that osteopontin-deficient mice could be protected from the cellular injury caused by ethanol," Mr. Morales said.
The researchers also found that osteopontin gene expression triggered the expression of profibrogenic genes.
Osteopontin could figure prominently in future treatment, Mr. Morales said. "Taken together, these results suggest that osteopontin could be a potential therapeutic target in patients with alcoholic hepatitis."
Mark Thursz, MD, professor of hepatology at Imperial College London in the United Kingdom, vice-secretary of EASL, and a moderator of the session, noted that osteopontin has already been drawing interest as a therapy for other illnesses, including rheumatoid arthritis.
"There is already some interest in it as a target for therapy," Dr. Thursz said. "It's difficult to say at this stage [of research]. There's this chicken and egg situation. Has it gone up because there's inflammation, or is it actually a cause of the inflammation?"
He said the study "gives some credence to the idea that this actually amplifies the inflammation and, therefore, by targeting it, you may have another therapeutic intervention in alcoholic hepatitis."
Any progress in treating the disease is sorely needed, he added, pointing out that there is a 30% mortality rate among patients with severe forms of the disease.
"At the moment all we have is steroids," Dr. Thursz said. "And one of the problems you have with steroids is you then put the patient at risk of infection. It's a very, sort of, blunderbus approach, frankly. You're just suppressing all the immune and inflammatory responses. We know patients with this disorder are susceptible to infection anyway, and then you make it worse by giving them steroids."
The study received no commercial financial support. Mr. Morales and Dr. Thursz have disclosed no relevant financial relationships.
European Association for the Study of the Liver (EASL) 45th Annual Meeting. Presented April?16, 2010.