Hyperglycaemia and Pseudomonas aeruginosa acidify cystic fibrosis airway surface liquid by elevating epithelial monocarboxylate transporter 2 dependent lactate-H(+) secretion.
Hyperglycaemia and Pseudomonas aeruginosa acidify cystic fibrosis airway surface liquid by elevating epithelial monocarboxylate transporter 2 dependent lactate-H(+) secretion.
复制标题
DOI：
10.1038/srep37955
复制
发表时间：
2016-11-29
影响因子：
4.6
通讯作者：
Baines DL
中科院分区：
文献类型：
--
作者：
Garnett JP;Kalsi KK;Sobotta M;Bearham J;Carr G;Powell J;Brodlie M;Ward C;Tarran R;Baines DL
囊性纤维化(CF)的呼吸道表面液体(ASL)为细菌生长提供了丰富的营养环境，包括高血糖，再加上由于异常的HCO3−转运和酸性ASL而导致的细菌杀灭缺陷，使得CF呼吸道容易受到呼吸道病原体(如铜绿假单胞菌)的侵袭。大约一半的成人CF患者患有CF相关糖尿病(CFRD)，这与呼吸减退增加有关。Cf ASL含有较高的乳酸浓度，高血糖也会增加ASL乳酸。我们发现原代人支气管上皮(HBE)细胞将乳酸分泌到ASL中，在高血糖时乳酸水平升高。这导致CFHBE中的ASL酸化，只有在去除HCO3−后才能在非CFHBE中模拟这种酸化。高血糖引起的ASL乳酸和pH的改变因铜绿假单胞菌的存在而加剧，并通过AR-C155858抑制单羧酸乳酸-H+协同转运体(MCTs)而减弱。我们的结论是，高血糖和铜绿假单胞菌诱导代谢转变，增加乳酸的生成，并通过上皮性MCT2转运蛋白外流到ASL。正常的呼吸道通过分泌HCO3HCO3−来补偿MCT驱动的H+分泌，这一过程在慢性阻塞性肺疾病的气道上皮细胞中功能失调，导致ASL酸化，这些过程可能导致慢性阻塞性肺疾病的呼吸道疾病恶化。
The cystic fibrosis (CF) airway surface liquid (ASL) provides a nutrient rich environment for bacterial growth including elevated glucose, which together with defective bacterial killing due to aberrant HCO3− transport and acidic ASL, make the CF airways susceptible to colonisation by respiratory pathogens such as Pseudomonas aeruginosa. Approximately half of adults with CF have CF related diabetes (CFRD) and this is associated with increased respiratory decline. CF ASL contains elevated lactate concentrations and hyperglycaemia can also increase ASL lactate. We show that primary human bronchial epithelial (HBE) cells secrete lactate into ASL, which is elevated in hyperglycaemia. This leads to ASL acidification in CFHBE, which could only be mimicked in non-CF HBE following HCO3− removal. Hyperglycaemia-induced changes in ASL lactate and pH were exacerbated by the presence of P. aeruginosa and were attenuated by inhibition of monocarboxylate lactate-H+ co-transporters (MCTs) with AR-C155858. We conclude that hyperglycaemia and P. aeruginosa induce a metabolic shift which increases lactate generation and efflux into ASL via epithelial MCT2 transporters. Normal airways compensate for MCT-driven H+ secretion by secreting HCO3−, a process which is dysfunctional in CF airway epithelium leading to ASL acidification and that these processes may contribute to worsening respiratory disease in CFRD.
登录
查看更多内容
跨囊性纤维化气道上皮单层的细胞旁葡萄糖通量升高是铜绿假单胞菌生长的重要因素。
影响因子：
3.7
作者：
Garnett JP;Gray MA;Tarran R;Brodlie M;Ward C;Baker EH;Baines DL
通讯作者：
Baines DL
影响因子：
4.8
作者：
Garnett, James P.;Hickman, Emma;Gray, Michael A.
通讯作者：
Gray, Michael A.
影响因子：
15.9
作者：
Worlitzsch, D;Tarran, R;Döring, G
通讯作者：
Döring, G
影响因子：
3.2
作者：
Filkins, Laura M.;Graber, Jyoti A.;O'Toole, George A.
通讯作者：
O'Toole, George A.
影响因子：
5.5
作者：
Bergman, Bryan C.;Tsvetkova, Tatiana;Wolfel, Eugene E.
通讯作者：
Wolfel, Eugene E.