Dev Cell :囊胞性纤维症中粘膜下层腺体酸性pH和高浓度蛋白含量导致异常粘液

2020-07-30 BioArt

囊胞性纤维症 是在高加索人种中常见的由调控囊性纤维化跨膜型传导调节蛋白的基因突变引起的隐形遗传病。CFTR的功能缺失引发呼吸道粘液纤毛清除功能障碍,导致了上呼吸道和肺部粘液栓塞。

囊胞性纤维症(Cystic Fibrosis, CF) 是在高加索人种中常见的由调控囊性纤维化跨膜型传导调节蛋白(CFTR)的基因突变引起的隐形遗传病。CFTR的功能缺失引发呼吸道粘液纤毛清除功能障碍,导致了上呼吸道和肺部粘液栓塞。一旦入侵的病原体、细菌、颗粒等滞留在呼吸道就会引起反复炎症,最终缩短寿命。肺部粘液栓塞作为CF中带来后期疾病恶化的关键事件,其成因与机制尚不清楚。

2020年7月29日,来自爱荷华大学(University of Iowa)的美国科学院院士,霍华德休斯医学研究院(HHMI)研究员Michael J. Welsh团队在Developmental Cell上发表了题目为Acidic Submucosal Gland pH and Elevated Protein Concentration Produce Abnormal Cystic Fibrosis Mucus的文章。其中爱荷华大学的助理教授谢瑜亮(Yuliang Xie)和鹿琳(Lin Lu)博士为并列第一作者。该研究发现在CF中,产生粘液的粘膜下层腺体(Submucosal gland)中的酸性pH和高蛋白质浓度改变了粘液的机械性能,从而导致粘液栓塞。而一旦异常的粘液形成,改变呼吸道上表面的pH无法逆转其机械性能。

首先,研究人员使用和人类CF病人症状相同的病理动物,新生CFTR基因敲除猪(CF猪)的气管来研究黏膜下层腺体的黏液分泌。首先,研究人员采集了微量的气管粘膜下层腺体的粘液进行分析。与野生型猪气管粘液相比,新生CF猪 pH更低,粘液分泌体积减少,并且蛋白浓度升高。

粘液在粘膜下层腺体形成之前包裹在低pH和高钙离子浓度的粘液小泡中,通过胞外分泌快速释放到腺体囊管中,急速膨胀,并最终形成具有一定机械性能的呼吸道粘液。为了研究粘液形成时期,pH,钙离子浓度和蛋白质浓度对粘液弹性和黏度的影响,研究人员建立了一种新型鼻涕虫(Banana slug)动物模型。鼻涕虫粘液分泌细胞和猪粘液下层腺体中的粘液分泌细胞,形成的粘液结构,糖蛋白染色都十分相似。因为鼻涕虫分泌粘液小泡到体表,通过收集粘液小泡,控制粘液小泡的破裂,研究人员就能够研究环境因素对粘液机械性能的影响。通过研究并粘液小泡破裂和粘液膨胀,研究人员发现在粘液形成时,低pH下粘液膨胀体积远小于高pH下的膨胀体积,同时粘液形成的弹性增加。且在高钙离子浓度和低pH中膨胀体积最小,弹性(Elastic modulus)最大。而且粘液弹性和黏度都随蛋白质浓度升高而增加,且增加幅度在低pH下更加明显。在粘液形成之后,再次改变粘液的pH和钙离子浓度或蛋白质浓度时,都不能够再改变粘液的弹性。

为了进一步在器官层面验证这一发现,研究人员借鉴了生物体中粘液形成的机制,使用微流体技术研发了人工粘膜下层腺体。这种人工粘膜下层腺体能够形成粘液束,并定量研究粘液束的拉伸和断裂。研究发现同样表明在粘液形成初期低pH和高钙离子浓度使形成的粘液束很难拉伸和断裂;与之相对,在粘液形成之后改变pH或钙离子浓度都不再改变粘液束的拉伸和断裂。更进一步,研究人员利用离体的新生猪气管中进行试验,发现在已经形成的粘液束中改变呼吸道表面的pH或钙离子浓度不能够更有效的清除粘液。

作为总结,本研究创造性的使用了三个不同的技术平台(鼻涕虫粘液小泡,微流体人工粘膜下层腺体,和离体活气管),研究表明呼吸道粘液的物理性质(膨胀体积,弹性,黏度,拉伸,断裂)受粘液形成时的pH,钙离子浓度,蛋白质浓度影响。而粘液形成之后,其物理性质不再受这些因素的影响。本研究提供了一种CF粘液栓塞的机制:在CF时,低pH,高钙离子浓度,和高蛋白质浓度的粘膜下层腺体内生理环境,会形成高弹性,高黏度,不易断裂的粘液。同时,本研究为缓解或治疗CF中粘液栓塞提供了潜在的策略:介入粘液形成时的生理条件会更有效清除呼吸道粘液。

原始出处:

YuliangXie,LinLu,Xiao XiaoTang,et al.Acidic Submucosal Gland pH and Elevated Protein Concentration Produce Abnormal Cystic Fibrosis Mucus.Developmental Cell.Available online 29 July 2020.https://doi.org/10.1016/j.devcel.2020.07.002

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    2021-05-09 维他命
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    2020-12-11 guoyibin
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    2021-01-30 fzwish20000
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    2020-07-30 akiark

    原来如此

    0

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