Scar wars: Repairing the liver
肝臟瘢痕修復
Scarring of the liver was once thought to be an irreversible situation, but a new and exciting field of experimental drugs may put an end to this dogma.
肝臟瘢痕曾一度被認為是不可逆轉的，但是一項新型激動人心的實驗藥物有望打破這種傳統觀念。
The liver is a large smooth organ that carries out many essential functions. It stores and releases nutrients, aids digestion and breaks down unwanted substances. Unfortunately, numerous chronic diseases damage the liver and when they continue for a long time they cause scarring — a condition called fibrosis.
肝臟是一種具有許多重要功能的巨大平滑器官。它儲存和釋放營養物質，促進消化，分解多餘的物質。然而，許多慢性疾病都會損傷肝臟，長期損害會導致瘢痕形成，即肝臟纖維化。
The most common causes are hepatitis viruses, long-term heavy drinking and fatty liver disease associated with obesity and diabetes. This scarring is caused by a buildup of fibrous collagen proteins which begin to replace healthy tissue.
最常見的病因是肝炎病毒、長期酗酒，以及肥胖和糖尿病相關的脂肪肝疾病。纖維膠原蛋白聚集，開始替代健康組織，引起肝臟瘢痕形成。
If the fibrosis keeps worsening, the liver can progress to a state known as cirrhosis. At this stage, excessive scarring hampers the liver's blood flow and stops it being able to do its job. Unchecked cirrhosis can lead directly to liver failure, and puts patients at high risk for liver cancer. Cirrhosis currently kills a million people worldwide each year. The good news is that the liver has its own mechanisms that degrade scar tissue,and this discovery has spurred a new wave of research into developing drugs which can halt the progression of fibrosis, or speed up healing once the underlying disease has been treated.
如果纖維化持續惡化，肝臟會發展為肝硬化。在此階段，大量瘢痕形成會阻斷肝臟血流，使其無法正常工作。如果不及時診斷治療，則可能直接導致肝臟衰竭，增加肝癌風險。目前，全世界範圍內，肝硬化每年的致死人數為100萬人。所幸，肝臟具有降解瘢痕組織的自身機制，這一發現激發了新一輪的研發可阻止纖維化進展，或治療潛在疾病後加速癒合的藥物熱潮。
The best way to reduce fibrosis is to avoid it altogether by removing the risk factors associated with the disease, but now scientists are examining the biology of the scar-causing cells as potential targets for therapeutic interventions. Scars are generated by cells called myofibroblasts.When these cells become activated, they proliferate, migrate to injury sites and secrete collagen into the extracellular matrix. As these collagen fibres accumulate, they become cross-linked into a mesh which stiffens the tissue and blocks its function. So researchers are aiming their sites, first and foremost, at myofibroblasts.
減少纖維化的最佳方式是解決疾病相關的風險因素，從而避免纖維化。但是，現在，科學家正在研究將瘢痕形成細胞的生物學特性作為潛在的治療靶點的治療方法。瘢痕由稱為肌成纖維細胞的細胞產生。這些細胞活化後，增殖，並遷移至受損區域，將膠原蛋白分泌入細胞外基質。隨著膠原纖維積聚，它們交聯成網狀結構，從而使組織變僵硬並阻礙其功能。因此，研究人員將首先研究肌成纖維細胞。
One strategy is to target the messenger molecules which coordinate their activation. These are released by damaged liver cells and immune cells and could targeted by new drugs. One example is a drug called Cenicriviroc that blocks receptors for profibrosis messengers called cytokines. Another set of drugs could inactivate myofibroblasts by targeting receptors on their surface called integrins that allow them to interact with other cells and the extracellular matrix. Multiple drugs that work this way are currently being explored and will enter human trials soon.
一種策略是靶向協調其活化的信使分子。它們由受損的肝臟細胞和免疫細胞釋放，可作為靶點研發新藥。例如cenicriproc可阻斷促纖維化信使--細胞因子的受體。另一類藥物可通過靶向肌成纖維細胞表面的受體--整合素，阻斷它們與其他細胞和細胞外基質相互作用，從而使其失活。當前，研究人員正在研發多種具有這種機制的藥物，並將很快投入人體試驗。
Blocking the myofibroblasts' ability to make collagen is another option. These drugs work by inserting small bits of RNA into the nucleus of myofibroblasts, destabilising the machinery that creates collagen fibres. Another approach is to block the enzymes that cross-link collagen fibres to stiffen the scar matrix. This makes the collagen easier for the body to degrade.
另一種選擇是阻斷肌成纖維細胞製造膠原的能力。這類藥物通過將少量RNA插入肌成纖維細胞的細胞核，破壞製造膠原纖維機器的穩定性。另一種方法是阻斷交聯膠原纖維的酶，使疤痕基質變硬。這樣，膠原蛋白更容易降解。
Finally, an exciting new avenue is the use of cell therapies. Introducing extra immune cells called macrophages into rodents' livers strongly boosts the organ's intrinsic anti-scarring mechanisms and now human trials using patient's own macrophages have begun. All these therapies will require clinical trials, and due to the slow progressive nature of liver fibrosis, this may take years.
最後，一種新型途徑是使用細胞療法：將免疫細胞巨噬細胞引入齧齒動物的肝臟，極大地增強器官內在的抗瘢痕形成機制。現在已經使用患者自身的巨噬細胞開始人體試驗。所有這些療法都需要臨床試驗，肝臟纖維化進展緩慢，可能需要數年的時間。
But new biomarkers in development may speed up trials considerably by showing whether the drugs are working, even before the overall fibrosis starts to decline. Hopefully these new approaches will help us to victory in the scar wars.
但是，整體纖維化開始減少前，我們可以通過正在研發中的新標記物，驗證藥物是否有效，來大幅加速試驗進程。希望這些新方法將幫助我們贏得這場「瘢痕」修復戰爭。