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粘液:人体的无名英雄

Mucus: The Body's Unsung Hero
粘液:人体的无名英雄
1315字
2019-08-14 11:57
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粘液:人体的无名英雄

We know it best as a stringy slime dripping from noses and as viscous, discolored goop hacked up by sickened airways. But it’s so much more than that. Coating the surfaces of guts, eyes, mouth, nasal cavity and ears, mucus plays a range of important physiological roles — hydrating, cleaning, supporting good microbes and warding off foreign invaders.

我们对其最多的认识是从鼻子里淌出的拉丝的黏液、非常黏、生病后呼吸道中脏兮兮的粘稠物。但是它远不止这些,它还覆盖在内脏、眼睛、口腔、鼻腔和耳朵的表面。粘液担任多种重要的生物角色——保持湿润、清洁、为有益微生物提供支持并抵御外来入侵。

“I like to call it the unsung hero of the body — it’s something that has such powerful effects over our health,” says Katharina Ribbeck, a biophysicist at MIT who with colleagues outlined the many roles of mucus in the 2018 Annual Review of Cell and Developmental Biology. Most of those functions come from the 5 percent of the substance that’s not water: various salts, lipids and proteins, most notably mucins, which give mucus its gel-like qualities — long, thread-like polypeptides coated in covalently bound chains of sugars called glycans.

“我想称呼它为人体的无名英雄——它对我们的健康发挥重要作用,”麻省理工学院的生物物理学家 Katharina Ribbeck说道,在2018年的细胞和发育生物学年度总结中,他和同事们中讲述了粘液的许多作用。绝大多数功能来源于5%的非水物质:各种盐类、脂肪和蛋白质。最值得注意的是黏蛋白,它使粘液具有凝胶状的特性——长的、线状的多肽,包覆在称为聚糖的糖的共价结合链中。

Scientists have uncovered many ways that mucin proteins work to keep body surfaces clean and protected, and are continuing to parse the complex interactions the molecules have with microbes. Here’s some of what they’ve learned so far, and where the research is heading.

科学家们已经发现了粘液蛋白保持人体表面清洁并提供保护的许多方法,并且正在继续分析分子与微生物之间复杂的相互作用。以下是他们目前所了解到的东西,以及研究的方向。

A multitude of mucins

黏蛋白有很多种。

Mucosal coatings vary considerably across the body, in line with needed functions. The eye, for example, is covered with a thin film of not especially viscous mucus, sufficient to keep it hydrated. The inside of the colon, in contrast, bears a thick, gummy coating that stops bacteria from sneaking through.

体内的粘液覆盖层差别很大,但与其所需功能一致。举个例子,眼睛上覆盖的一层不太粘的粘液,目的是高效的是保持水分。相反,结肠内部的一层厚厚的胶状涂层是阻止细菌入侵的。

Key to these physical properties are the mucins themselves. Produced by specialized cells in tissues that line bodily cavities and surfaces, they are some of the biggest molecules we make and come in two main flavors: secreted mucins, which are exuded to form large, mesh-like networks, and tethered mucins, which remain latched onto cells.

这些物理特性的关键是粘液本身。由组织中特殊的细胞所产生,分布在人体的腔体和表面,是我们制造的最大的分子之一。其主要有两种形式:分泌黏蛋白,会形成巨大的网状结构;束缚黏蛋白,固定在细胞上。

Mucin manufacture changes with place and circumstance. “There’s a lot of cell specificity,” says biophysicist Brian Button of the University of North Carolina School of Medicine. For example, the gel-like mucus that keeps the respiratory tract clean is made up of the secreted mucins MUC5B and MUC5AC. Usually, MUC5B is dominant — a 2017 analysis in the New England Journal of Medicine found it to be about 10 times more abundant than MUC5AC, for example. But during infections and certain other medical conditions, levels of MUC5AC rise steeply, creating a much more tenacious, sticky mucus that’s harder to clear from airways.

黏蛋白的分泌是随着环境不断变化的。“有很多细胞特异性,”北卡罗来纳大学医学院生物物理学家Brian Button说道。比如,可以保持呼吸道的清洁的胶状粘液,由分泌的黏液蛋白MUC5B和MUC5AC组成。通常MUC58占主体——2017年在《英国新医学》杂志上发布的数据表明,它(MUC58)是其他物质的十倍。但处于人体感染或其他特定医疗环境时,MUC5AC的含量急转直上,分泌出更多顽固的、粘性的黏蛋白,粘附在呼吸道很难被清除。

More MUC5AC can be good, because the goopier mucus prevents bacteria from adhering to body cells and causing harm, Button says. But in conditions such as asthma, cystic fibrosis and chronic obstructive pulmonary disease, MUC5AC overproduction can cause a harmful buildup of mucus in the airways.

Button说,黏液越多越好,因为粘稠的黏液可以防止细菌附着在身体细胞上造成伤害。但在哮喘、囊性纤维化和慢性阻塞性肺疾病等情况下,MUC5AC的过量分泌会导致呼吸道粘液的有害积聚。

In other parts of the body, such as the stomach, high levels of MUC5AC are standard and help to protect the lining from acidic digestive juices. And in the intestine, yet another mucin — MUC2 — is the main player. In the colon, MUC2 forms two layers of mucus — a loose outer lining that houses bacteria and a densely packed inner barrier that keeps those microorganisms from penetrating the cells of the tissue underneath. Unlike the airways, “in the intestine, you really don’t have a problem with too much,” says Gunnar Hansson, a mucin biologist at the University of Gothenburg in Sweden. “You’d rather have too much than too little.”

在人体的其他部位,比如胃,MUC5AC的含量一直很高,它可以防止酸性消化液对胃部的腐蚀。在肠道中,然而另一种黏蛋白——MUC2——是主要成分。MUC2在结肠中组成两层黏蛋白——较疏松的外层用来培养细菌,紧密的内层屏障防止微生物侵入底层组织细胞。不同于呼吸道,“你不必太过担心肠道,”Gunnar Hansson说,他瑞典哥德堡大学的粘蛋白生物学家。“想多只会徒增烦恼。”

Dining on mucus

粘液的“就餐地”

Today there’s increasing appreciation that the trillions of microbes that live in our intestines — the gut microbiome — play vital roles in health and disease. And where do they live? In layers of nurturing mucus. In fact, it’s become clear that many of these commensal bacteria use the glycans studding mucin molecules as a primary source of energy. To that end, their genomes carry codes for enzymes that can cleave these carbohydrates and digest them.

如今,人们越来越了解到在肠道里生活着数万亿微生物——肠道微生物——对人类的健康和患病至关重要。他们生活哪里?在营养层粘液。事实很明显,许多共生细菌利用粘蛋白分子上的聚糖作为主要能量来源。为了达到这个目的,它们的基因组携带着酶代码,酶可以分解并消化这些碳水化合物。

The bacteria also release metabolites such as the short-chain fatty acid butyrate that gut cells use to fuel yet more mucin production. “They are using the energy to feed themselves, but they are also producing energy that they're sending back to us . . . and making it possible to make these large amounts of mucins,” Hansson says. “They benefit from this, and we benefit from it as well.”

这些细菌不断释放代谢产物,如短链脂肪酸丁酸酯,肠道细胞可以利用其产生更多的黏蛋白。“他们用能自给自足,然而他们产生的能量一部分会传递回来...从而分泌更多数量的粘液,”Hansson说,“我们跟他实现了双赢。”

Unlike our guts’ natural denizens, bacterial pathogens tend to lack the machinery needed to take advantage of the glycans on mucins, and have developed other ways to expand their populations.

与肠道原生物不同,细菌病原体往往缺乏利用黏液蛋白上的聚糖的必要机制,已发展出扩大其种群的其他方法。

Managing microbe behavior

微生物的行为管理

Mucins do more than serve as physical barriers and microbe food. Scientists have discovered that the glycans decorating the surface of these molecules can influence the behavior and physiology of pathogenic microbes and reduce their ability to spread and cause harm.

粘液不仅担任物理屏障和饲喂微生物的角色。科学家发现嵌在分子表面的多糖可以影响病原微生物的行为和物理性质,并减轻它们的繁殖能力、降低对机体的损害。

In a 2012 study in Current Biology, for example, Ribbeck and her colleagues discovered in test tube experiments that mucins could stop the bacterium Pseudomonas aeruginosa, the cause of many dangerous hospital-acquired infections, from forming biofilms — tight-knit microbial communities that are hard to eradicate. Ribbeck’s lab later showed that mucins could prevent biofilms of other pathogens from forming, including those of Streptococcus mutans, the bacterium responsible for tooth decay.

《现代生物学》2012年的研究上,Ribbeck和她的同事在试管实验中发现粘蛋白可以抑制铜绿假单胞菌,这种细菌可以通过形成生物膜造成了许多严重的院内感染——这是一种紧密连接并难以根除的微生物群落。之后Ribbeck研究表明粘液还可以阻止其他病原体形成生物膜,包括变异链球菌,一种造成蛀牙的细菌。

In addition to reining in foreign invaders, mucins can also help keep our body’s resident microbes in check. Ribbeck’s team found that the molecules quash the transition of Candida albicans, a fungus that normally resides peacefully within the healthy microbiome, to a pathogenic form. They do so by suppressing Candida’s ability to form filaments, attach to surfaces and develop other traits that enable it to cause harm.

黏蛋白不仅抵御外来入侵者,还能帮助我们管理体内的常驻微生物。Ribbeck团队发现这些分子抑制了假丝酵母菌的转化,这是一种能与益性微生物和平共处的致病性真菌。它们通过抑制假丝酵母菌细丝形成力、依附力和其他可对其造成伤害的特性来抑制其转化。

Mucins can also act as decoys to prevent infection. In 2009, Mike McGuckin, a molecular biologist at the University of Melbourne in Australia, and his colleagues reported in PLOS Pathogens that when Helicobacter pylori, a bacterium that can cause peptic ulcers and gastric cancer, tries to bind a cell on the surface of the stomach, a mucin can attach to the pathogen instead. The mucin then detaches from the membrane of the cell, carrying the would-be invader along with it into the acidic gastric juice. “A lot of bacteria and viruses recognize certain sugars on the cell surface, and that’s how they know they’re getting to the cell,” Button explains. “Mucins can replicate those glycosylation patterns and act kind of like molecular decoys.”

粘液为了防止入侵还可以充当诱饵。澳大利亚墨尔本大学的分子生物学家 Mike McGuckin和他的同事在2009年在《PLOS病原体》杂志上发表报告,幽门螺杆菌是一种能引起消化性溃疡和胃癌的细菌,当它试图骗过胃壁表面细胞时,粘液可以将其吸附。之后粘液便从细胞膜上脱落,带着入侵物浸到消化液中。“许多细菌和病毒可以识别细胞表面特定的糖,这让他们知道他们侵入的是哪一种细胞,”Button解释道。“粘液可以复制他们的糖基化模式,并假装为诱饵。”

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But some disease-causing bacteria use mucins to their advantage. In another study, McGuckin and colleagues demonstrated that Campylobacter jejuni, a microbe that lives harmlessly in chickens but can cause food poisoning in people, recognizes human mucins and uses their presence as a cue to ramp up the activity of genes involved in pathogenicity.

但是有些致病性细菌可利用粘液。在另一项实验中,McGuckin跟同事们证明了空肠弯曲杆菌,一种存活于小鸡体内的无害微生物但是可以引发人体食物中毒,这种菌可以识别人体粘液,并利用它们作为一种提示来增强与致病有关的基因的活性。

“There are lots of examples where a bacterium is non-pathogenic in one species but can be pathogenic in another species — and a lot of that will relate to mucins,” says McGuckin. “The same is true for viruses.”

“对于细菌在一类物种中无害但在其他物种中有害,这样的例子还有很多——许多都与粘液有关。”McGuckin说。“病毒也是一样的。”

Making synthetic mucins

人造粘液的制作

Scientists hope to one day create synthetic mucins for both research and treatment and have put quite a bit of work into developing tissue culture for their production. But it’ll take better understanding of the molecules’ structure and biophysical properties before synthetic substitutes become a clinical reality, says molecular biologist Christopher Evans of the University of Colorado at Denver, who is working with colleagues to tease apart some of those details.

科学家们希望未来可以制作出可供研究和治疗的人造粘液,并在组织培养方面进行了大量的工作。在人造物质成为临床事实之前,必须要对分子结构和生物学特性有更深的了解。丹佛科罗拉多大学的分子生物学家Christopher Evans说道,他正在跟同事梳理其中的细节。

Once that’s done, synthetic mucins could be used in lab studies and, eventually, for health care applications such as controlling problematic pathogens, restoring damaged or defective mucus linings, and improving drug delivery by creating coatings that can bypass mucosal barriers.

一旦完成,人造粘液就可以用于实验室研究,并最终可以医疗保健应用,如控制顽固病原体,修复受损或有缺陷的黏液内里,以及通过制作可绕过黏膜屏障的涂层来改善药物的输送。

And Ribbeck sees still more potential uses: Synthetic mucins might replace antibiotics in animal feed, say, or manage microbial communities to aid in the growth of crops. “The applications could go far beyond health care,” she says.

在Ribbeck来看它还有潜在用处:人造粘液可能会代替动物饲料中的抗生素成分,或者通过管理微生物群落来帮助农作物生长。“这些应用可能远不止医疗保健的范畴,”她说。

10.1146/knowable-062619-1

10.1146/knowable-062619-1

This article originally appeared in Knowable Magazine, an independent  from Annual Reviews. Sign up for the newsletter.

本文最初在Knowable杂志上发表,这是一篇独立的年度总结新闻报道,时事通讯。

ABOUT THE AUTHOR(S)

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Diana Kwon is a freelance science journalist who covers health and the life sciences.

Diana Kwon是一名报道健康和生命科学自由科学记者。

Credit: Nick Higgins

Nick Higgins

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