根据发表在临床研究杂志上的一项新研究，研究人员已经确

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Potential Target Identified to Reduce Liver Damage, Prevent Cancer
Jennifer Barrett, Associate Editor
Publish Date: Monday, September 17, 2018

Researchers have identified a potential point of intervention that could prevent the progression of liver damage to cancer, according to a new study published in the Journal of Clinical Investigation.

A triggering receptor expressed on myeloid cells-1, also known as TREM-1, activates inflammation short-term following an insult, such as a laceration, or in response to external invaders, such as bacteria. However, for the first time, researchers have found that, when activated by chronic offending agents such as hepatitis and obesity, TREM-1 can contribute to a destructive level of inflammation that results in liver damage and possibly cancer.

According to the researchers, this transformation can occur in 5 to 50 years, and could be reversible up to the point of cirrhosis if the offending agent is stopped. The findings suggest that potentially targeting this receptor on Kupffer cells, the liver’s resident macrophages, could return TREM-1 activation to normal levels to reduce damage.

“Right now we have a treatment for hepatitis C, for example, which is very efficient, if we treat it before too much damage is done,” study author Anatolij Horuzsko, PhD, reproductive immunologist in the Georgia Cancer Center and Department of Medicine at the Medical College of Georgia at Augusta University, said in a press release. “But we don’t have treatment for alcohol- or obesity-related damage.”

To examine TREM-1 activity in the face of chronic liver disease, the researchers created a mouse model using carbon tetrachloride. They observed that TREM-1 activation increased and remained high on a larger number of Kupffer cells, as well as other immune cells circulating the body.

Deleting TREM-1 from the model reduced inflammation, injury, and subsequent fibrosis, according to the study. When returned to the mice, TREM-1 caused inflammation and related damage to rapidly increase again. Additionally, the researchers determined that TREM-1 recruits other pro-inflammatory cells from the bone marrow of the liver, which further multiplies inflammation, liver cell damage, and death.

As such, TREM-1 activity sets off a cascade of damaging effects. Damage-associated molecular patterns released when liver cells die further activate TREM-1 on the macrophages. When this happens, the macrophages activate stellate cells, leading to collagen production.

“Efficiency goes down and it causes additional damage to liver cells that already have been damaged by something like hepatitis or obesity,” Dr Horuzsko said in the press release.

TREM-1 models also showed high levels of enyzmes alanine aminotransferase and aspartate aminotransferase, both indicators of liver injury. However, without TREM-1 expression, rates went up only short-term before returning to pre-injury levels.

“TREM-1 is a molecule that can be very dangerous and is normally very controlled in the body,” Dr Horuzsko said. He noted that, in hepatitis B for example, high levels of TREM-1 expression on stellate cells is considered an indicator of poor prognosis.

“The balance in our body is very, very tightly regulated and important. Alcohol, obesity, and hepatitis viruses all change the balance,” he concluded.

Reference

New target could prevent progression of liver damage to cancer [news release]. https://jagwire.augusta.edu/archives/55991. Accessed August 29, 2018.

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确定潜在目标以减少肝脏损害，预防癌症
Jennifer Barrett，副主编
发布日期：2018年9月17日，星期一

根据发表在临床研究杂志上的一项新研究，研究人员已经确定了可能阻止肝脏损害癌症进展的潜在干预点。

在骨髓细胞-1（也称为TREM-1）上表达的触发受体在损伤（例如撕裂）或响应外部入侵物（例如细菌）后短期激活炎症。然而，研究人员首次发现，当由慢性有害物质如肝炎和肥胖症激活时，TREM-1可导致破坏性的炎症水平，导致肝脏损害并可能导致癌症。

根据研究人员的说法，这种转变可以在5到50年内发生，并且如果停止使用违规药物，这种转变可能是可逆的，直至肝硬化。研究结果表明，在肝脏常驻巨噬细胞Kupffer细胞上潜在靶向这种受体，可使TREM-1活化恢复到正常水平，从而减少损伤。

“目前我们已经接受了丙型肝炎的治疗，例如，如果我们在造成太大损害之前对其进行治疗，效果非常高，”研究作者，佐治亚州癌症中心和医学系的生殖免疫学家Anatolij Horuzsko博士说。佐治亚州奥古斯塔大学医学院在一份新闻稿中说。 “但我们没有针对酒精或肥胖相关的伤害进行治疗。”

为了检查面对慢性肝病的TREM-1活性，研究人员使用四氯化碳创建了一个小鼠模型。他们观察到TREM-1活化在大量Kupffer细胞以及其他体内循环的免疫细胞中增加并保持高水平。

该研究表明，从模型中删除TREM-1减少了炎症，损伤和随后的纤维化。当返回小鼠时，TREM-1引起炎症并且相关损伤再次迅速增加。此外，研究人员确定TREM-1从肝脏骨髓中募集其他促炎细胞，进一步增加炎症，肝细胞损伤和死亡。

因此，TREM-1活动引发了一系列破坏性影响。肝细胞死亡后释放的损伤相关分子模式进一步激活巨噬细胞上的TREM-1。当发生这种情况时，巨噬细胞会激活星状细胞，从而导致胶原蛋白的产生。

Horuzsko博士在新闻发布会上表示，“效率下降，对已经因肝炎或肥胖等疾病已经受损的肝细胞造成额外损害。”

TREM-1模型还显示高水平的enyzmes丙氨酸氨基转移酶和天冬氨酸氨基转移酶，这两者都是肝损伤的指标。然而，如果没有TREM-1表达，在恢复到伤前水平之前，费率只会短期上升。

“TREM-1是一种非常危险的分子，通常在体内非常受控制，”Horuzsko博士说。他指出，例如，在乙型肝炎中，星状细胞上高水平的TREM-1表达被认为是预后不良的指标。

“我们身体的平衡是非常非常严格的，也是非常重要的。酒精，肥胖和肝炎病毒都改变了平衡，“他总结道。

参考

新靶点可以预防肝脏对癌症的损害[新闻发布]。 https://jagwire.augusta.edu/archives/55991。访问于2018年8月29日。