Faiz A, Donovan C, Nieuwenhuis M Ae, van den Berge M, Postma D S, Yao S, Park C Y, Hirsch R, Fredberg J J, Tjin G, Halayko A J, Rempel K L, Ward J P T, Lee T, Bossé Y, Nickle D C, Obeidat M, Vonk Judith M, Black J L, Oliver B G, Krishnan R, McParland B, Bourke J E, Burgess J K
Woolcock Institute of Medical Research, The University of Sydney, Glebe, New South Wales, Australia.
University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, Groningen, The Netherlands.
Thorax. 2017 Jan;72(1):74-82. doi: 10.1136/thoraxjnl-2015-207236. Epub 2016 Jun 20.
Asthma affects 300 million people worldwide. In asthma, the major cause of morbidity and mortality is acute airway narrowing, due to airway smooth muscle (ASM) hypercontraction, associated with airway remodelling. However, little is known about the transcriptional differences between healthy and asthmatic ASM cells.
To investigate the transcriptional differences between asthmatic and healthy airway smooth muscle cells (ASMC) in culture and investigate the identified targets using in vitro and ex vivo techniques.
Human asthmatic and healthy ASMC grown in culture were run on Affymetrix_Hugene_1.0_ST microarrays. Identified candidates were confirmed by PCR, and immunohistochemistry. Functional analysis was conducted using in vitro ASMC proliferation, attachment and contraction assays and ex vivo contraction of mouse airways.
We suggest a novel role for latrophilin (LPHN) receptors, finding increased expression on ASMC from asthmatics, compared with non-asthmatics in vivo and in vitro, suggesting a role in mediating airway function. A single nucleotide polymorphism in LPHN1 was associated with asthma and with increased LPHN1 expression in lung tissue. When activated, LPHNs regulated ASMC adhesion and proliferation in vitro, and promoted contraction of mouse airways and ASMC.
Given the need for novel inhibitors of airway remodelling and bronchodilators in asthma, the LPHN family may represent promising novel targets for future dual therapeutic intervention.
哮喘影响着全球3亿人。在哮喘中，发病和死亡的主要原因是由于气道平滑肌（ASM）过度收缩导致的急性气道狭窄，这与气道重塑有关。然而，关于健康和哮喘ASM细胞之间的转录差异知之甚少。
研究培养的哮喘和健康气道平滑肌细胞（ASMC）之间的转录差异，并使用体外和离体技术研究已确定的靶点。
将培养的人哮喘和健康ASMC在Affymetrix_Hugene_1.0_ST微阵列上进行检测。通过PCR和免疫组织化学对鉴定出的候选基因进行确认。使用体外ASMC增殖、黏附和收缩试验以及小鼠气道的离体收缩试验进行功能分析。
我们提出了latrophilin（LPHN）受体的新作用，发现在体内和体外，与非哮喘患者相比，哮喘患者的ASMC上LPHN受体表达增加，提示其在介导气道功能中发挥作用。LPHN1中的一个单核苷酸多态性与哮喘以及肺组织中LPHN1表达增加有关。激活后，LPHN在体外调节ASMC黏附和增殖，并促进小鼠气道和ASMC收缩。
鉴于哮喘中需要新型气道重塑抑制剂和支气管扩张剂，LPHN家族可能是未来双重治疗干预的有希望的新靶点。
