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LIGHT在低氧性肺动脉高压形成中的作用及机制
Role of LIGHT in development of hypoxic pulmonary hypertension in mice
- 第三军医大学学报 2018年40卷第8期 页码：643-651
- 作者机构：
1.400038 重庆，陆军军医大学(第三军医大学)：高原军事医学系，高原生理学与病理学教研室
2.400038 重庆，陆军军医大学(第三军医大学)：高原军事医学系，高原特殊药品与装备研究室，全军高原医学重点实验室
3.400038 重庆，陆军军医大学(第三军医大学)：基础医学院免疫学教研室
- 作者简介：
[谭小玲，E-mail：tanxl0511@163.comTAN Xiaoling, Email: tanxl0511@163.com
[高钰琪，E-mail：gaoy66@yahoo.comGAO Yuqi, E-mail: gaoy66@yahoo.com
- 基金信息：国家自然科学基金面上项目(81270108);全军“十二五”重大课题(AWS14C007)
DOI：10.16016/j.1000-5404.201711151
中图分类号： R392.11; R363.21; R544.02收稿：2017-11-12，
修回：2018-02-07，
纸质出版：2018-04-30
- 稿件说明：
移动端阅览
杨诚忠, 李满满, 罗羽莎, 等. LIGHT在低氧性肺动脉高压形成中的作用及机制[J]. 第三军医大学学报, 2018,40(8):643-651.
Chengzhong YANG, Manman LI, Yusha LUO, et al. Role of LIGHT in development of hypoxic pulmonary hypertension in mice[J]. Journal of Third Military Medical University, 2018, 40(8): 643-651.
杨诚忠, 李满满, 罗羽莎, 等. LIGHT在低氧性肺动脉高压形成中的作用及机制[J]. 第三军医大学学报, 2018,40(8):643-651. DOI： 10.16016/j.1000-5404.201711151.
Chengzhong YANG, Manman LI, Yusha LUO, et al. Role of LIGHT in development of hypoxic pulmonary hypertension in mice[J]. Journal of Third Military Medical University, 2018, 40(8): 643-651. DOI： 10.16016/j.1000-5404.201711151.
摘要
目的
2
初步探讨LIGHT在低氧性肺动脉高压(hypoxic pulmonary hypertension
HPH)形成中的作用及其机制。
方法
2
将20只8周龄雌性C57BL/6J小鼠[体质量(17.90±0.91)g
]
和20只8周龄雌性LIGHT
-/-
C57BL/6J小鼠[体质量(17.55±0.93)g
]
分为4组(
n
=10)：①野生小鼠常氧组(WT-C组)、②野生小鼠低氧组(WT-H组)、③LIGHT KO小鼠常氧组(LIGHT KO-C组)、④LIGHT KO小鼠低氧组(LIGHT KO-H组)。WT-H组和LIGHT KO-H组小鼠置于模拟6 000 m低压舱内连续低氧饲养30 d，WT-C组和LIGHT KO-C组小鼠舱外(海拔308 m)常规饲养。检测右心室收缩压(right ventricular systolic pressure，RVSP)和右心肥厚指数(right ventricular hypertrophy index，RVHI)；HE染色观察肺小动脉结构；免疫组化检测LIGHT及其受体HVEM、LTβR表达；荧光定量PCR和Western blot检测肺组织LIGHT、HVEM和LTβR、IL-6的mRNA和蛋白水平。流式细胞术检测肺组织中各类炎症细胞的比例。
结果
2
与WT-C组相比，WT-H组肺组织中LIGHT的mRNA和蛋白水平均显著增高(
P
<
0.05)，WT-H组RVSP和RVHI明显升高(
P
<
0.05)，肺小动脉明显增厚；与LIGHT KO-C组相比，LIGHT KO-H组小鼠的RVSP、RVHI和肺小动脉厚度显著增加(
P
<
0.05)，但与WT-H组相比，LIGHT KO-H组的RVSP、RVHI和肺小动脉增厚程度明显降低(
P
<
0.05)。与WT-C组相比，WT-H组LIGHT受体HVEM表达增加，LTβR表达降低，差异具有统计学意义(
P
<
0.05)。LIGHT KO-H组与WT-H组相比，肺组织IL-6 mRNA和蛋白水平显著降低(
P
<
0.05)。流式细胞检测发现，与WT-C组相比，WT-H组小鼠肺组织中单核细胞比例降低[(3
.88±0.87)%
vs
(11.03±1.71)%，
P
<
0.05
]
，间质巨噬细胞比例升高[(15.56±2.69)%
vs
(8.57±2.17)%，
P
<
0.05
]
；与WT-H组相比，LIGHT KO-H组的肺组织单核细胞增加[(6.55±1.01)%
vs
(3.88±0.87)%，
P
<
0.05
]
，而间质巨噬细胞的比例降低[(10.87±1.68)% vs.(15.56±2.69)%，
P
<
0.05
]
。
结论
2
慢性低氧诱导肺组织中LIGHT表达增加与HPH发病机制密切相关。LIGHT可能通过HVEM信号途径促进细胞增殖、上调肺组织IL-6表达、促进肺间质巨噬细胞产生，参与HPH的形成。
Abstract
Objective
2
To investigate the role of tumor necrosis factor superfamily member 14 (LIGHT/TNFSF14) in the development of hypoxic pulmonary hypertension in mice and explore the mechanism.
Methods
2
Twenty 8-week-old wild-type (WT) female C57BL/6J mice and 20 age-matched LIGHT-deficient (LIGHT
-/-
) transgenic female C57BL/6J mice were both randomized equally into normoxia groups and hypoxia groups. In the 2 hypoxia groups
the mice were housed in a hypobaric chamber simulating the condition of 6 000 m altitude for 30 d
and mice in normoxic groups were housed in routine conditions. The changes in right ventricular systolic pressure (RVSP) were recorded and right ventricular hypertrophy index (RVHI) was evaluated. HE staining was used to observe the changes in pulmonary vascular structures. Immunohistochemical staining was performed to observe the distribution of LIGHT
HVEM and LTβR in the lung of the mice. The expressions of LIGHT
HVEM
LTβR and IL-6 at both mRNA and protein levels in the lungs were tested using RT-PCR and Western blotting. The proportions of inflammatory cells in the lungs were determined using flow cytometry.
Results
2
Compared with the WT normoxic mice
the WT mice with chronic hypoxia showed significantly increased mRNA and protein levels of LIGHT in the lungs (
P
<
0.05) with also significantly increased RVSP and RVHI and obviou
sly thickened pulmonary arterioles (
P
<
0.05). These hypoxia-induced changes were markedly in attenuated LIGHT
-/-
mice. In WT mice
hypoxia induced significantly increased protein expression of LIGHT receptor HVEM (
P
<
0.05) and decreased expression of LTβR (
P
<
0.05). LIGHT
-/-
mice with hypoxia showed significantly lower mRNA and protein levels of IL-6 in the lungs than WT hypoxic mice (
P
<
0.05). Compared with WT normoxic mice
WT hypoxic mice showed significantly decreased proportions of monocytes [(3.88±0.87)%
vs
(11.03±1.71)%
P
<
0.05
]
and increased interstitial macrophages [(15.56±2.69)%
vs
(8.57±2.17)%
P
<
0.05
]
in the lungs. In LIGHT
-/-
mice with hypoxia
the proportion of monocytes was significantly increased to (6.55±1.01)% (
P
<
0.05) and that of interstitial macrophage was significantly decreased to (10.87±1.68)% (
P
<
0.05) compared with those in WT hypoxic mice.
Conclusion
2
Chronic hypoxia-induced development of HPH is closely associated with increased pulmonary LIGHT expression
which promotes cell growth
upregulates IL-6
and increases the production of pulmonary interstitial macrophages possibly by activating HVEM under hypoxic condition.
关键词
Keywords
references
MCLAUGHLIN V V, ARCHER SL, BADESCH D B, et al . ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association[J ] . J Am Coll Cardiol, 2009. 53(17): 1573-619. DOI: 10.1016/j.jacc.2009.01.004
PUGLIESE SC, POTH JM, FINI MA, et al . The role of inflammation in hypoxic pulmonary hypertension: from cellular mechanisms to clinical phenotypes[J ] . Am J Physiol Lung Cell Mol Physiol, 2015. 308(3): L229-52. DOI: 10.1152/ajplung.00238.2014
HALVORSEN B, SANTILLI F, SCHOLZ H, et al . LIGHT/TNFSF14 is increased in patients with type 2 diabetes mellitus and promotes islet cell dysfunction and endothelial cell inflammation in vitro[J ] . Diabetologia, 2016. 59(10): 2134-2144. DOI: 10.1007/s00125-016-4036-y
KRAUSE P, ZAHNER S P, KIM G, et al . The tumor necrosis factor family member TNFSF14 (LIGHT) is required for resolution of intestinal inflammation in mice[J ] . Gastroenterology, 2014. 146(7): 1752-1762 e4. DOI: 10.1053/j.gastro.2014.02.010
DOHERTY T A, SOROOSH P, KHORRAM N, et al . The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling[J ] . Nat Med, 2011. 17(5): 596-603. DOI: 10.1038/nm.2356
OTTERDAL K, ANDREASSEN AK, YNDESTAD A, et al . Raised LIGHT levels in pulmonary arterial hypertension: potential role in thrombus formation[J ] . Am J Respir Crit Care Med, 2008. 177(2): 202-207. DOI: 10.1164/rccm.200703-506OC
BECHILL J, MULLER W J. Herpesvirus entry mediator (HVEM) attenuates signals mediated by the lymphotoxin beta receptor (LTbetaR) in human cells stimulated by the shared ligand LIGHT[J]. Mol Immunol, 2014. 62(1): 96-103. DOI: 10.1016/j.molimm.2014.06.013
FLORENTIN J, DUTTA P. Origin and production of inflammatory perivascular macrophages in pulmonary hypertension[J]. Cytokine, 2017. 100: 11-15. DOI: 10.1016/j.cyto.2017.08.015
WEI C Y, CHOU Y H, HO F M, et al . Signaling pathways of LIGHT induced macrophage migration and vascular smooth muscle cell proliferation[J ] . J Cell Physiol, 2006. 209(3): 735-743. DOI: 10.1002/jcp.20742
FRID M G, BRUNETTI J A, BURKE D L, et al . Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage[J ] . Am J Pathol, 2006. 168(2): 659-669. DOI: 10.2353/ajpath.2006.050599
CHEN T, YANG C, LI M, et al . Alveolar Hypoxia-Induced Pulmonary Inflammation: From Local Initiation to Secondary Promotion by Activated Systemic Inflammation[J ] . J Vasc Res, 2016. 53(5-6): 317-329. DOI: 10.1159/000452800
BURKE D L, FRID M G, KUNRATH C L, et al . Sustained hypoxia promotes the development of a pulmonary artery-specific chronic inflammatory microenvironment[J ] . Am J Physiol Lung Cell Mol Physiol, 2009. 297(2): L238-250. DOI: 10.1152/ajplung.90591.2008
BEDORET D, WALLEMACQ H, MARICHAL T, et al . Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice[J ] . J Clin Invest, 2009. 119(12): 3723-3738. DOI: 10.1172/JCI39717
GIBBINGS S L, THOMAS S M, ATIF S M, et al . Three Unique Interstitial Macrophages in the Murine Lung at Steady State[J ] . Am J Respir Cell Mol Biol, 2017. 57(1): 66-76. DOI: 10.1165/rcmb.2016-0361OC
GUILLIAMS M, DE KLEER I, HENRI S, et al . Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF[J ] . J Exp Med, 2013. 210(10): 1977-1992. DOI: 10.1084/jem.20131199
PUGLIESE S C, KUMAR S, JANSSEN W J, et al . A Time-and Compartment-Specific Activation of Lung Macrophages in Hypoxic Pulmonary Hypertension[J ] . J Immunol, 2017. 198(12): 4802-4812. DOI: 10.4049/jimmunol.1601692
HASHIMOTO-KATAOKA T, HOSEN N, SONOBE T, et al . Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension[J ] . Proc Natl Acad Sci U S A, 2015. 112(20): E2677-2686. DOI: 10.1073/pnas.1424774112
MASTON L D, JONES D T, GIERMAKOWSKA W, et al . Central role of T helper 17 cells in chronic hypoxia-induced pulmonary hypertension[J ] . Am J Physiol Lung Cell Mol Physiol, 2017. 312(5): L609-L624. DOI: 10.1152/ajplung.00531.2016
SAVALE L, TU L, RIDEAU D, et al . Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice[J ] . Respir Res, 2009. 10: 6. DOI: 10.1186/1465-9921-10-6
STEINER M K, SYRKINA O L, KOLLIPUTI N, et al . Interleukin-6 overexpression induces pulmonary hypertension[J ] . Circ Res, 2009. 104(2): 236-244, 28p following 244. DOI: 10.1161/CIRCRESAHA.108.182014
KAWANO H, KAYAMA H, NAKAMA T, et al . IL-10-producing lung interstitial macrophages prevent neutrophilic asthma[J ] . Int Immunol, 2016. 28(10): 489-501. DOI: 10.1093/intimm/dxw012
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