Blockade of CXC chemokine receptor 3 on endothelial cells protects against sepsis-induced acute lung injury

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• 作者：Xuejiao Zhu ; MD^a ; ^b ; ^c ; ¹ ; Yun Zou ; MD^c ; ¹ ; Bing Wang ; MD^c ; ¹ ; Jiali Zhu ; MD^c ; Yi Chen ; MD^c ; Lei Wang ; MD^c ; Jinbao Li ; MD ; PhD^c ; ^d ; ^{lijinbaoshanghai@163.com" class="auth_mail" title="E-mail the corresponding author} ; Xiaoming Deng ; MD ; PhD^c ; ^{deng_x@yahoo.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Sepsis ; Acute lung injury ; CXCR3 ; Pulmonary microvascular endothelial cells ; Apoptosis
• 刊名：Journal of Surgical Research
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：204
• 期：2
• 页码：288-296
• 全文大小：2394 K

文摘

CXCR3, a G-protein coupled chemokine receptor, has been shown to play a critical role in recruiting inflammatory cells into lungs in several studies. However, its roles in polymicrobial septic acute lung injury (ALI) is yet unknown. Therefore, the purpose of this study was to elucidate the protective effects of CXCR3 blockade on pulmonary microvascular endothelial cells (PMVECs) in septic ALI and explore potential mechanisms.

Materials and methods

ALI was induced by polymicrobial sepsis through cecal ligation and puncture surgery. The expression of CXCR3 on pulmonary microvascular endothelial cells was measured 24 h after cecal ligation and puncture surgery. In addition, the protective effects of neutralizing antibody were detected, including protein concentration, inflammation cell counts, lung ​wet-to-dry ratio, and lung damages. In human umbilical vein endothelial cells (HUVECs) culture condition, CXCR3 expression was measured after exposure to tumor necrosis factor-α. The permeability and apoptosis ratio were detected through CXCR3 gene silencing on HUVECs. The p38 mitogen-activated protein kinase (MAPK) was analyzed with Western blot.

Results

CXCR3 expression was upregulated both in vivo and in vitro. After CXCR3 neutralizing antibody administrated intraperitoneally, the protein concentration, inflammatory cell counts in BALF and lung ​wet-to-dry ratio were decreased significantly, as well as the lung tissue damages. In vitro, CXCR3 gene silencing inhibited tumor necrosis factor-α and CXCL10-induced hyperpermeability and apoptosis in HUVECs. In addition, p38 mitogen-activated protein kinase activation was essential for CXCR3-mediated apoptosis.

Conclusions

CXCR3 blockade exerts protective effects on ALI at least partly by inhibiting endothelial cells apoptosis and decreasing the leakage of protein-rich fluid and inflammatory cells. Blockade of CXCR3 may be a promising therapeutic strategy for severe sepsis-induced ALI.