Vascular endothelial growth factor contributes to lung vascular hyperpermeability in sepsis-associated acute lung injury
Vascular endothelial growth factor contributes to lung vascular hyperpermeability in sepsis-associated acute lung injury
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血管内皮生长因子导致脓毒症相关急性肺损伤中肺血管通透性过高
DOI：
10.1007/s00210-020-01947-6
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Hattori Y
中科院分区：
文献类型：
--
作者：
Tomita K;Saito Y;Suzuki T;Imbaby S;Hattori K;Matsuda N;Hattori Y
血管内皮生长因子（VEGF）是血管通透性的主要调节因子。急性肺损伤（acute lung injury，ALI）是一种以高通透性肺水肿为特征的急性肺损伤，伴有顽固性低氧血症和弥漫性肺浸润。在这项研究中，我们研究了VEGF是否可以牵连作为肺血管通透性因子在脓毒症相关的急性肺损伤。我们发现，一个很大的增加，肺血管渗漏发生在小鼠鼻内滴注脂多糖（LPS），作为评估的IgM水平在支气管肺泡灌洗液。用VEGF中和单克隆抗体贝伐单抗治疗显著降低了这种高通透性反应，表明VEGF积极参与了与LPS诱导的ALI相关的非心源性肺水肿。然而，这并不仅仅是由于肺内VEGF水平过高。鼻内LPS给药和盲肠结扎穿孔（CLP）诱导的脓毒症小鼠肺组织中VEGF的表达水平显著降低，这可能源于肺中非内皮细胞依赖性VEGF产生的减少。为了支持这一假设，用LPS和干扰素-γ（IFN-γ）刺激显著增加人肺微血管内皮细胞（HPMEC）中VEGF的mRNA和蛋白水平。此外，在CLP诱导的脓毒症小鼠中观察到血浆VEGF水平显著升高。LPS/IFN-γ刺激后HPMECs释放VEGF的增加被丝裂原活化蛋白激酶（MAPK）亚组的特异性抑制剂完全阻断。综上所述，我们的研究结果表明，VEGF可以促进非心源性肺水肿的发展脓毒症相关的急性肺损伤由于增加VEGF分泌从肺血管内皮细胞通过多种MAPK依赖性途径。
Vascular endothelial growth factor (VEGF) is a prime regulator of vascular permeability. Acute lung injury (ALI) is characterized by high-permeability pulmonary edema in addition to refractory hypoxemia and diffuse pulmonary infiltrates. In this study, we examined whether VEGF can be implicated as a pulmonary vascular permeability factor in sepsis-associated ALI. We found that a great increase in lung vascular leak occurred in mice instilled intranasally with lipopolysaccharide (LPS), as assessed by IgM levels in bronchoalveolar lavage fluid. Treatment with the VEGF-neutralizing monoclonal antibody bevacizumab significantly reduced this hyperpermeability response, suggesting active participation of VEGF in non-cardiogenic lung edema associated with LPS-induced ALI. However, this was not solely attributable to excessive levels of intrapulmonary VEGF. Expression levels of VEGF were significantly reduced in lung tissues from mice with both intranasal LPS administration and cecal ligation and puncture (CLP)-induced sepsis, which may stem from decreases in non-endothelial cells-dependent VEGF production in the lungs. In support of this assumption, stimulation with LPS and interferon-γ (IFN-γ) significantly increased VEGF in human pulmonary microvascular endothelial cells (HPMECs) at mRNA and protein levels. Furthermore, a significant rise in plasma VEGF levels was observed in CLP-induced septic mice. The increase in VEGF released from HPMECs after LPS/IFN-γ challenge was completely blocked by either specific inhibitor of mitogen-activated protein kinase (MAPK) subgroups. Taken together, our results indicate that VEGF can contribute to the development of non-cardiogenic lung edema in sepsis-associated ALI due to increased VEGF secretion from pulmonary vascular endothelial cells through multiple MAPK-dependent pathways.
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影响因子：
3.1
作者：
Unger, RE;Krump-Konvalinkova, V;Kirkpatrick, CJ
通讯作者：
Kirkpatrick, CJ
DOI：
10.1165/ajrcmb.22.6.3779
发表时间：
2000-06-01
影响因子：
6.4
作者：
Kaner, RJ;Ladetto, JV;Crystal, RG
通讯作者：
Crystal, RG
DOI：
10.1152/ajplung.00045.2009
发表时间：
2009-10-01
影响因子：
4.9
作者：
Kantrow, Stephen P.;Shen, Zhiwei;Nelson, Steve
通讯作者：
Nelson, Steve
影响因子：
24.3
作者：
Abadie, Y;Bregeon, F;Delclaux, C
通讯作者：
Delclaux, C
DOI：
10.1165/rcmb.2009-0210st
发表时间：
2011-05-01
影响因子：
6.4
作者：
Matute-Bello, Gustavo;Downey, Gregory;Villar, Jesus
通讯作者：
Villar, Jesus