title: Blockade of CXC chemokine receptor 3 on endothelial cells protects against sepsis-induced acute lung injury.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou, Jiangsu, China; Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors: Xuejiao
authors: X
authors: Zhu
authors: Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors: Yun
authors: Y
authors: Zou
authors: Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors: Bing
authors: B
authors: Wang
authors: Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors: Jiali
authors: J
authors: Zhu
authors: Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors: Yi
authors: Y
authors: Chen
authors: Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors: Lei
authors: L
authors: Wang
authors: Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai, China; Department of Anesthesiology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: lijinbaoshanghai@163.com.
authors: Jinbao
authors: J
authors: Li
authors: Department of Anesthesiology and Intensive Care, Changhai Hospital, Second Military Medical University, Shanghai, China. Electronic address: deng_x@yahoo.com.
authors: Xiaoming
authors: X
authors: Deng
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D017209:Apoptosis; D054357:Chemokine CXCL10 / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008168:Lung / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D008810:Mice, Inbred C57BL; D011654:Pulmonary Edema / Q000209:etiology / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018805:Sepsis / Q000150:complications*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D054367:Receptors, CXCR3; D014409:Tumor Necrosis Factor-alpha
keywords: Acute lung injury; Apoptosis; CXCR3; Pulmonary microvascular endothelial cells; Sepsis