anti-human tissue factor antibody ameliorated intestinal ischemia reperfusion-induced acute lung injury in human tissue factor knock-in mice反组织因子抗体改善肠道缺血reperfusion-induced敲入小鼠急性肺损伤人体组织因素.pdfVIP

Anti-Human Tissue Factor Antibody Ameliorated Intestinal Ischemia Reperfusion-Induced Acute Lung Injury in Human Tissue Factor Knock-In Mice 1. 1. 1 2 1 3 3 3¤ 1 Xiaolin He , Bing Han , Marco Mura , Li Li , Marcelo Cypel , Avery Soderman , Kristen Picha , Jing Yang , Mingyao Liu * 1 Latner Thoracic Surgery Research Laboratories, Department of Surgery, University Health Network Toronto General Research Institute, University of Toronto, Toronto, Ontario, Canada, 2 Therakos, Exton, Pennsylvania, United State of America, 3 Centocor Inc., Malvern, Pennsylvania, United States of America Background. Interaction between the coagulation and inflammation systems plays an important role in the development of acute respiratory distress syndrome (ARDS). Anti-coagulation is an attractive option for ARDS treatment, and this has promoted development of new antibodies. However, preclinical trials for these antibodies are often limited by the high cost and availability of non-human primates. In the present study, we developed a novel alternative method to test the role of a humanized anti-tissue factor mAb in acute lung injury with transgenic mice. Methodology/Principal Findings. Human tissue factor knock-in (hTF-KI) transgenic mice and a novel humanized anti-human tissue factor mAb (anti-hTF mAb, CNTO859) were developed. The hTF-KI mice showed a normal and functional expression of hTF. The anti-hTF mAb specifically blocked the pro- coagulation activity of brain extracts from the hTF-KI mice and human, but not from wild type mice. An extrapulmonary ARDS model was used by intestinal ischemia-reperfusion. Significant lung tissue damage in hTF-KI mice was observed after 2 h reperfusion. Administration of CNTO859 (5 mg/kg, i.v.) attenuated the severity of lung tissue injury,