Peng Yang1, Anatol Manaenko2, Feng Xu3, Liyan Miao4, Gaiqing Wang5, Xuezhen Hu6, Zhen-Ni Guo7, Qin Hu8, Richard E Hartman9, William J Pearce10, Andre Obenaus11, John H Zhang12, Gang Chen13, Jiping Tang14. 1. Department of Emergency Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; Departments of Physiology, Loma Linda University, Loma Linda, CA, USA. Electronic address: yangpeng@suda.edu.cn. 2. Departments of Physiology, Loma Linda University, Loma Linda, CA, USA; Departments of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany. Electronic address: anatolmanaenko@gmail.com. 3. Department of Emergency Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China. Electronic address: sz_xf@suda.edu.cn. 4. Departments of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China. Electronic address: miaolysuzhou@163.com. 5. Departments of Physiology, Loma Linda University, Loma Linda, CA, USA; Department of Neurology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China. Electronic address: wanggq08@163.com. 6. Department of Emergency Medicine, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: 649321276@qq.com. 7. Departments of Physiology, Loma Linda University, Loma Linda, CA, USA; Neuroscience Center, Department of Neurology, The First Norman Bethune Hospital of Jilin University, Chang Chun, Jilin, China. Electronic address: zhen1ni2@163.com. 8. Departments of Physiology, Loma Linda University, Loma Linda, CA, USA. Electronic address: huqinle@gmail.com. 9. Departments of Psychology, Loma Linda University, Loma Linda, CA, USA. Electronic address: behavioralneuroscience@gmail.com. 10. Departments of Physiology, Loma Linda University, Loma Linda, CA, USA. Electronic address: wpearce@llu.edu. 11. Departments of Pediatrics, Loma Linda University, Loma Linda, CA, USA. Electronic address: aobenaus@llu.edu. 12. Departments of Physiology, Loma Linda University, Loma Linda, CA, USA; Departments of Anesthesiology, Loma Linda University, Loma Linda, CA, USA; Departments of Neurosurgery, Loma Linda University, Loma Linda, CA, USA. Electronic address: johnzhang3910@yahoo.com. 13. Departments of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China. Electronic address: nju_neurosurgery@163.com. 14. Departments of Physiology, Loma Linda University, Loma Linda, CA, USA. Electronic address: jtang@llu.edu.
Abstract
OBJECTIVE: Inflammation plays a key role in the pathophysiological processes after intracerebral hemorrhage (ICH). Post-ICH macrophages infiltrate the brain and release pro-inflammatory factors (tumor necrosis factor-α), amplifying microglial activation and neutrophil infiltration. Platelet-derived growth factor receptor-β (PDGFR-β) is expressed on macrophages and it's activation induces the recruitment of macrophages. Platelet-derived growth factor-D (PDGF-D) is an agonist with a significantly higher affinity to the PDGFR-β compared to another isoform of the receptor. In this study, we investigated the role of PDGF-D in the pro-inflammatory response after ICH in mice. METHODS: A blood injection model of ICH was used in eight-week old male CD1 mice (weight 30g). Some mice received an injection of plasmin or PDGF-D. Gleevec, a PDGFR inhibitor, was administered at 1, 3 or 6h post-ICH. Plasmin was administered with or without PDGF-D siRNAs mixture or scramble siRNA. A plasmin-antagonist, ε-Aminocaproic acid (EACA), was co-administrated with the blood. The effects of ICH and treatment on the brain injury and post-ICH inflammation were investigated. RESULTS: ICH resulted in the overexpression of PDGF-D, associated with the infiltration of macrophages. PDGFR-inhibition decreased ICH-induced brain injury, attenuating macrophage and neutrophil infiltration, reducing microglial activation and TNF-α production. Administration of recombinant PDGF-D induced TNF-α production, and PDGFR-inhibition attenuated it. A plasmin-antagonist suppressed PDGFR-β activation and microglial activation. Plasmin increased PDGF-D expression, and PDGF-D inhibition reduced neutrophil infiltration. CONCLUSION: ICH-induced PDGF-D accumulation contributed to post-ICH inflammation via PDGFR activation and enhanced macrophage infiltration. The inhibition of PDGFR had an anti-inflammatory effect. Plasmin is a possible upstream effector of PDGF-D. The targeting of PDGF-D may provide a novel way to decrease brain injury after ICH.
OBJECTIVE:Inflammation plays a key role in the pathophysiological processes after intracerebral hemorrhage (ICH). Post-ICH macrophages infiltrate the brain and release pro-inflammatory factors (tumor necrosis factor-α), amplifying microglial activation and neutrophil infiltration. Platelet-derived growth factor receptor-β (PDGFR-β) is expressed on macrophages and it's activation induces the recruitment of macrophages. Platelet-derived growth factor-D (PDGF-D) is an agonist with a significantly higher affinity to the PDGFR-β compared to another isoform of the receptor. In this study, we investigated the role of PDGF-D in the pro-inflammatory response after ICH in mice. METHODS: A blood injection model of ICH was used in eight-week old male CD1mice (weight 30g). Some mice received an injection of plasmin or PDGF-D. Gleevec, a PDGFR inhibitor, was administered at 1, 3 or 6h post-ICH. Plasmin was administered with or without PDGF-D siRNAs mixture or scramble siRNA. A plasmin-antagonist, ε-Aminocaproic acid (EACA), was co-administrated with the blood. The effects of ICH and treatment on the brain injury and post-ICH inflammation were investigated. RESULTS:ICH resulted in the overexpression of PDGF-D, associated with the infiltration of macrophages. PDGFR-inhibition decreased ICH-induced brain injury, attenuating macrophage and neutrophil infiltration, reducing microglial activation and TNF-α production. Administration of recombinant PDGF-D induced TNF-α production, and PDGFR-inhibition attenuated it. A plasmin-antagonist suppressed PDGFR-β activation and microglial activation. Plasmin increased PDGF-D expression, and PDGF-D inhibition reduced neutrophil infiltration. CONCLUSION:ICH-induced PDGF-D accumulation contributed to post-ICH inflammation via PDGFR activation and enhanced macrophage infiltration. The inhibition of PDGFR had an anti-inflammatory effect. Plasmin is a possible upstream effector of PDGF-D. The targeting of PDGF-D may provide a novel way to decrease brain injury after ICH.
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