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Ren X, Deng L, Dong X, Bai Y, Li G, Wang Y. Adverse reactions of immune checkpoint inhibitors combined with angiogenesis inhibitors: A pharmacovigilance analysis of drug-drug interactions. Int J Immunopathol Pharmacol 2024; 38:3946320241305390. [PMID: 39660594 PMCID: PMC11632882 DOI: 10.1177/03946320241305390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 11/20/2024] [Indexed: 12/12/2024] Open
Abstract
The combination of immune checkpoint inhibitors (ICIs) and angiogenesis inhibitors (AGIs) is widely used in cancer treatment; however, drug-drug reactions (DDIs) remain unknown. We aimed to identify interaction signals for the concomitant use of ICIs and AGIs. Data were obtained from the US FDA Adverse Event Reporting System (FAERS) from January 1, 2015, to December 31, 2023. Disproportionality analysis was used for data mining by calculating the reporting odds ratio (ROR) and 95% confidence interval (95% CI). Adjusted RORs were analysed using logistic regression analysis, considering age, sex and reporting year. Further confirmation was assessed via additive and multiplicative models. We identified 75,936 reports on ICIs combined with AGIs. Significant interaction signals were observed for hepatobiliary disorders (RORcrude: 5.25, 95% CI: 5.07-5.44, RORadj: 5.01, 95% CI: 4.82-5.22, additive models: 0.2323), investigations (RORcrude: 1.66, 95% CI: 1.62-1.70, RORadj: 1.63, 95% CI: 1.58-1.67, additive models: 0.2187, multiplicative models: 1.1265), renal and urinary disorders (RORcrude: 1.87, 95% CI: 1.80-1.95, RORadj: 1.72, 95% CI: 1.64-1.79, additive models: 0.3239, multiplicative models: 1.1799) and vascular disorders (RORcrude: 1.94, 95% CI: 1.87-2.02, RORadj: 1.87, 95% CI: 1.80-1.95, additive models: 0.5823, multiplicative models: 1.5676). Subset data analysis showed positive interaction signals for PDL-1/CTLA-4 inhibitors + AGI in hepatobiliary disorders, PD-1 inhibitors + AGI in investigations, or PD-1/PDL-1 inhibitors + AGI in renal and urinary/ vascular disorders. Based on FAERS data, four systemic disorders were identified as having DDIs related to the combined use of ICIs and AGIs. Pre-clinical trials are required to explore the mechanisms underlying these interactions.
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Affiliation(s)
- Xiayang Ren
- Department of Pharmacy, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lei Deng
- Department of Radiation Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xin Dong
- Department of Clinical Laboratory, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ying Bai
- Clinical Trials Center, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guohui Li
- Department of Pharmacy, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yanfeng Wang
- Department of Comprehensive Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Wu YL, Li TY, Gong XY, Che L, Sheng MW, Yu WL, Weng YQ. Risk factors for myocardial injury during living donor liver transplantation in pediatric patients with biliary atresia. World J Gastrointest Surg 2023; 15:2021-2031. [PMID: 37901739 PMCID: PMC10600755 DOI: 10.4240/wjgs.v15.i9.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 07/10/2023] [Accepted: 07/27/2023] [Indexed: 09/21/2023] Open
Abstract
BACKGROUND Cold ischemia-reperfusion of the liver is an inevitable occurrence in liver transplantation that may also cause damage to the heart. Perioperative myocardial injury during liver transplantation can increase the incidence of postoperative mortality, but there is little research on the incidence of myocardial injury in children who undergo living donor liver transplantation (LDLT). Therefore, this study mainly explores the independent risk factors for myocardial injury in children who undergo LDLT. AIM To analyze the data of children who underwent LDLT to determine the risk factors for intraoperative myocardial injury. METHODS We retrospectively analyzed the inpatient records of pediatric patients who underwent LDLT in Tianjin First Central Hospital from January 1, 2020, to January 31, 2022. Recipient-related data and donor-related data were collected. The patients were divided into a myocardial injury group and a nonmyocardial injury group according to the value of the serum cardiac troponin I at the end of surgery for analysis. Univariate analysis and multivariate logistic regression were used to evaluate the risk factors for myocardial injury during LDLT in pediatric patients. RESULTS A total of 302 patients met the inclusion criteria. The myocardial injury group had 142 individuals (47%), and the nonmyocardial injury group included 160 patients (53%). Age, height, and weight were significantly lower in the myocardial injury group (P < 0.001). The pediatric end-stage liver disease (PELD) score, total bilirubin, and international standardized ratio were significantly higher in the myocardial injury group (P < 0.001). The mean arterial pressure, lactate, hemoglobin before reperfusion, duration of the anhepatic phase, cold ischemic time, incidence of postreperfusion syndrome (PRS), and fresh frozen plasma transfusion were significantly different between the two groups (P < 0.05). The postoperative intensive care unit stay and peak total bilirubin values in the first 5 d after LDLT were significantly higher in the myocardial injury group (P < 0.05). The pediatric patients with biliary atresia in the nonmyocardial injury group who underwent LDLT had a considerably higher one-year survival rate than those in the myocardial injury group (P = 0.015). Multivariate logistic regression revealed the following independent risk factors for myocardial injury: a high PELD score [odds ratio (OR) = 1.065, 95% confidence interval (CI): 1.013-1.121; P = 0.014], a long duration of the anhepatic phase (OR = 1.021, 95%CI: 1.003-1.040; P = 0.025), and the occurrence of intraoperative PRS (OR = 1.966, 95%CI: 1.111-3.480; P = 0.020). CONCLUSION A high PELD score, a long anhepatic phase duration, and the occurrence of intraoperative PRS were independent risk factors for myocardial injury during LDLT in pediatric patients with biliary atresia.
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Affiliation(s)
- Yu-Li Wu
- The First Central Clinical School, Tianjin Medical University, Tianjin 300192, China
| | - Tian-Ying Li
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Xin-Yuan Gong
- Department of Science and Education, Tianjin First Central Hospital, Tianjin 300192, China
| | - Lu Che
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China
| | - Ming-Wei Sheng
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China
| | - Wen-Li Yu
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China
| | - Yi-Qi Weng
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin 300192, China
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Bolandi SM, Abdolmaleki Z, Assarehzadegan MA. Anti-angiogenic Properties of Bevacizumab Improve Respiratory System Inflammation in Ovalbumin-Induced Rat Model of Asthma. Inflammation 2021; 44:2463-2475. [PMID: 34420156 PMCID: PMC8380193 DOI: 10.1007/s10753-021-01516-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 06/16/2021] [Accepted: 07/07/2021] [Indexed: 02/07/2023]
Abstract
Studies on the bronchial vascular bed have revealed that the number of blood vessels in the lamina propria and under the mucosa of the lung tissue increases in patients suffering from mild to severe asthma. Thus, in this study, a new strategy was employed in respiratory system disorders by angiogenesis inhibition in an ovalbumin (OVA)-induced rat model of asthma. Twenty-one male Wistar albino rats, 8 weeks old, were randomly divided into three groups (n = 7 in each group), including (1) control group, (2) OVA-treated group, and (3) OVA + Bmab (bevacizumab drug). On days 1 and 8, 1 mg of OVA and aluminum hydroxide in sterile phosphate-buffered saline (PBS) were intraperitoneally injected to rats in groups 2 and 3. The control group was only subject to intraperitoneal injection of saline on days 1 and 8. One week after the last injection, the rats (groups 2 and 3) were exposed to OVA inhalation for 30 min at 2-day intervals from days 15 to 25. After sensitization and challenge with OVA, the OVA + Bmab group (group 3) were treated with a 5 mg/kg bevacizumab drug. Genes and protein expression of IL-1β and TNF-α and the expression of vascular endothelial growth factor (VEGF) protein were assessed by real-time PCR and immunohistochemistry respectively, in lung tissue. OVA exposure increased mucosal secretion and inflammatory cell populations in lung tissue and OVA-specific IgE level in serum. Also, VEGF and cytokine factor expression were significantly elevated in the OVA-induced asthma model (p ≤ 0.05). However, rats in OVA + Bmab group showed significantly a decrease in VEGF and IL-1β and TNF-α genes as well as proteins (p ≤ 0.05). The results showed that bevacizumab efficiently diminished bronchial inflammation via downregulation of VEGF expression, followed by inflammatory cells population and cytokines reduction. Angiogenesis inhibition in rats with induced asthma not only suppresses the inflammatory process through blocking VEGF expression but also inhibits the development of new blood vessels and progressing asthmatic attacks.
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Affiliation(s)
| | - Zohreh Abdolmaleki
- Department of Pharmacology, Karaj Branch, Islamic Azad University, Karaj, Iran.
- Department of Pharmacology, Karaj Branch, Islamic Azad University, Karaj, Iran.
| | - Mohammad-Ali Assarehzadegan
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
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Bujaldon E, Cornide-Petronio ME, Gulfo J, Rotondo F, Ávalos de León C, Negrete-Sánchez E, Gracia-Sancho J, Novials A, Jiménez-Castro MB, Peralta Uroz C. Relevance of VEGFA in rat livers subjected to partial hepatectomy under ischemia-reperfusion. J Mol Med (Berl) 2019; 97:1299-1314. [PMID: 31254006 PMCID: PMC6713699 DOI: 10.1007/s00109-019-01811-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 05/13/2019] [Accepted: 06/06/2019] [Indexed: 12/20/2022]
Abstract
We examined the effects of VEGFA on damage and regeneration in steatotic and non-steatotic livers of rats submitted to PH under I/R, and characterized the underlying mechanisms involved. Our results indicated that VEGFA levels were decreased in both steatotic and non-steatotic livers after surgery. The administration of VEGFA increased VEGFA levels in non-steatotic livers, reducing the incidence of post-operative complications following surgery through the VEGFR2-Wnt2 pathway, independently of Id1. Unexpectedly, administration of VEGFA notably reduced VEGFA levels in steatotic livers, exacerbating damage and regenerative failure. After exogenous administration of VEGFA in steatotic animals, circulating VEGFA is sequestered by the high circulating levels of sFlt1 released from adipose tissue. Under such conditions, VEGFA cannot reach the steatotic liver to exert its effects. Consequently, the concomitant administration of VEGFA and an antibody against sFlt1 was required to avoid binding of sFlt1 to VEGFA. This was associated with high VEGFA levels in steatotic livers and protection against damage and regenerative failure, plus improvement in the survival rate via up-regulation of PI3K/Akt independently of the Id1-Wnt2 pathway. The current study highlights the different effects and signaling pathways of VEGFA in liver surgery requiring PH and I/R based in the presence of steatosis. KEY MESSAGES: VEGFA administration improves PH+I/R injury only in non-steatotic livers of Ln animals. VEGFA benefits are exerted through the VEGFR2-Wnt2 pathway in non-steatotic livers. In Ob rats, exogenous VEGFA is sequestered by circulating sFlt1, exacerbating liver damage. Therapeutic combination of VEGFA and anti-sFlt1 is required to protect steatotic livers. VEGFA+anti-sFlt1 treatment protects steatotic livers through a VEGFR2-PI3K/Akt pathway.
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Affiliation(s)
- Esther Bujaldon
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | | | - José Gulfo
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
| | - Floriana Rotondo
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Cindy Ávalos de León
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Elsa Negrete-Sánchez
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | | | - Anna Novials
- Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain
| | | | - Carmen Peralta Uroz
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain.
- Facultad de Medicina, Universidad International de Cataluña, Barcelona, Spain.
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Xu B, Iida Y, Glover KJ, Ge Y, Wang Y, Xuan H, Hu X, Tanaka H, Wang W, Fujimura N, Miyata M, Shoji T, Guo J, Zheng X, Gerritsen M, Kuo C, Michie SA, Dalman RL. Inhibition of VEGF (Vascular Endothelial Growth Factor)-A or its Receptor Activity Suppresses Experimental Aneurysm Progression in the Aortic Elastase Infusion Model. Arterioscler Thromb Vasc Biol 2019; 39:1652-1666. [PMID: 31294623 PMCID: PMC6699755 DOI: 10.1161/atvbaha.119.312497] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 06/07/2019] [Indexed: 12/20/2022]
Abstract
OBJECTIVE We examined the pathogenic significance of VEGF (vascular endothelial growth factor)-A in experimental abdominal aortic aneurysms (AAAs) and the translational value of pharmacological VEGF-A or its receptor inhibition in aneurysm suppression. Approaches and Results: AAAs were created in male C57BL/6J mice via intra-aortic elastase infusion. Soluble VEGFR (VEGF receptor)-2 extracellular ligand-binding domain (delivered in Ad [adenovirus]-VEGFR-2), anti-VEGF-A mAb (monoclonal antibody), and sunitinib were used to sequester VEGF-A, neutralize VEGF-A, and inhibit receptor tyrosine kinase activity, respectively. Influences on AAAs were assessed using ultrasonography and histopathology. In vitro transwell migration and quantitative reverse transcription polymerase chain reaction assays were used to assess myeloid cell chemotaxis and mRNA expression, respectively. Abundant VEGF-A mRNA and VEGF-A-positive cells were present in aneurysmal aortae. Sequestration of VEGF-A by Ad-VEGFR-2 prevented AAA formation, with attenuation of medial elastolysis and smooth muscle depletion, mural angiogenesis and monocyte/macrophage infiltration. Treatment with anti-VEGF-A mAb prevented AAA formation without affecting further progression of established AAAs. Sunitinib therapy substantially mitigated both AAA formation and further progression of established AAAs, attenuated aneurysmal aortic MMP2 (matrix metalloproteinase) and MMP9 protein expression, inhibited inflammatory monocyte and neutrophil chemotaxis to VEGF-A, and reduced MMP2, MMP9, and VEGF-A mRNA expression in macrophages and smooth muscle cells in vitro. Additionally, sunitinib treatment reduced circulating monocytes in aneurysmal mice. CONCLUSIONS VEGF-A and its receptors contribute to experimental AAA formation by suppressing mural angiogenesis, MMP and VEGF-A production, myeloid cell chemotaxis, and circulating monocytes. Pharmacological inhibition of receptor tyrosine kinases by sunitinib or related compounds may provide novel opportunities for clinical aneurysm suppression.
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Affiliation(s)
- Baohui Xu
- Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
- Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Yasunori Iida
- Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
- Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Keith J Glover
- Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
- Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Yingbin Ge
- Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yan Wang
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Haojun Xuan
- Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
- Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Xiaolei Hu
- Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
- Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Hiroki Tanaka
- Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
- Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Wei Wang
- Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
- Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Naoki Fujimura
- Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
- Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Masaaki Miyata
- Department of Cardiology and Hypertension, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
| | - Takahiro Shoji
- Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
- Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Jia Guo
- Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
- Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Xiaoya Zheng
- Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
- Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Mary Gerritsen
- Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
- Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Calvin Kuo
- Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Sara A Michie
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Ronald L Dalman
- Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA
- Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
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Kohen MC, Tatlipinar S, Cumbul A, Uslu Ü. The effects of bevacizumab treatment in a rat model of retinal ischemia and perfusion injury. Mol Vis 2018; 24:239-250. [PMID: 29681725 PMCID: PMC5893009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2014] [Accepted: 03/21/2018] [Indexed: 11/16/2022] Open
Abstract
Purpose To create a model of an ischemic retina with temporary ischemia and reperfusion (IR) and to examine the possible antiapoptotic and neurodegenerative effects of a vascular endothelial growth factor (VEGF) antagonist. Methods Three groups were formed. Rats were subjected to continued ischemia for 45 min, and then reperfusion was allowed for 2 days. For the first group, ischemia was induced, but an anti-VEGF agent was not administered. For the second group, 2 days before ischemia, 0.005 ml (0.125 mg) of bevacizumab was administered intravitreally, and then the ischemic model was created. The last group's intraocular pressure was not increased as in the control group, and only a cannula was introduced into the anterior chamber through the cornea. Six animals from each group were subjected to histomorphometry, and four were subjected to immunohistochemical and histopathologic examinations. For a histomorphometric examination, the number of cells in the retinal ganglion cell (RGC) layer was counted using the optical dissector method. For immunohistochemistry, the vascular endothelial growth factor receptor-2 (VEGFR-2) levels and apoptosis were examined in the retinal and choroidal tissue. Results It was observed that in an IR injury, bevacizumab reduces the death and apoptosis of cells in the RGC layer. It was also identified that although bevacizumab is a large molecule, the agent affects the choroid and reduces the amount of VEGFR-2 in this tissue. Conclusions IR may be used as a model of ischemic retinopathy that includes VEGF-dependent vascular permeability and neurodegeneration. Although VEGF is a neurotrophic molecule, in IR injury, treatment with bevacizumab, which is an anti-VEGF agent, decreases apoptosis, showing that excess function of this molecule can be hazardous.
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Affiliation(s)
- Maryo Cenk Kohen
- Yeditepe University School of Medicine, Department of Ophthalmology, Istanbul, Turkey,Case Western Reserve University School of Medicine, Department of Ophthalmology and Visual Sciences, Cleveland, OH
| | - Sinan Tatlipinar
- Yeditepe University School of Medicine, Department of Ophthalmology, Istanbul, Turkey
| | - Alev Cumbul
- Yeditepe University School of Medicine, Department of Histology and Embryology, Istanbul, Turkey
| | - Ünal Uslu
- Yeditepe University School of Medicine, Department of Histology and Embryology, Istanbul, Turkey,Medeniyet University School of Medicine, Department of Histology and Embryology, Istanbul, Turkey
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Francis A, Kleban SR, Stephenson LL, Murphy PS, Letourneau PR, Fang XH, Wang WZ, Baynosa RC. Hyperbaric Oxygen Inhibits Reperfusion-Induced Neutrophil Polarization and Adhesion Via Plasmin-Mediated VEGF Release. PLASTIC AND RECONSTRUCTIVE SURGERY-GLOBAL OPEN 2017; 5:e1497. [PMID: 29062662 PMCID: PMC5640368 DOI: 10.1097/gox.0000000000001497] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 07/26/2017] [Indexed: 01/07/2023]
Abstract
Background: Ischemia-reperfusion (IR) injury is seen in many settings such as free flap salvage and limb replantation/revascularization. The consequences—partial/total flap loss, functional muscle loss, or amputation—can be devastating. Of the treatment options available for IR injury, hyperbaric oxygen (HBO) is the most beneficial. HBO inhibits neutrophil-endothelial adhesion through interference of CD18 neutrophil polarization in IR, a process mediated by nitric oxide. The purposes of this study were to examine the involvement of vascular endothelial growth factor (VEGF) in the beneficial HBO effect on CD18 polarization and neutrophil adhesion and investigate the effect of plasmin on VEGF expression in skeletal muscle following IR injury. Methods: A rat gracilis muscle model of IR injury was used to evaluate the effect of VEGF in IR, with and without HBO, on neutrophil CD18 polarization and adhesion in vivo and ex vivo. Furthermore, we investigated the effects that plasmin has on VEGF expression in gracilis muscle and pulmonary tissue by blocking its activation with alpha-2-antiplasmin. Results: HBO treatment following IR injury significantly decreased neutrophil polarization and adhesion ex vivo compared with the IR group. Anti-VEGF reversed the beneficial HBO effect after IR with polarization and adhesion. In vivo adhesion was also increased by anti-VEGF. HBO treatment of IR significantly increased the VEGF protein in both gracilis and pulmonary vasculature. Alpha-2-antiplasmin significantly reversed the HBO-induced increase of VEGF in gracilis muscle. Conclusions: These results suggest that HBO inhibits CD18 polarization and neutrophil adhesion in IR injury through a VEGF-mediated pathway involving the extracellular matrix plasminogen system.
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Affiliation(s)
- Ashish Francis
- Microsurgery and Hyperbaric Laboratory, Department of Surgery, University of Nevada, Las Vegas School of Medicine, Las Vegas, Nev
| | - Shawna R Kleban
- Microsurgery and Hyperbaric Laboratory, Department of Surgery, University of Nevada, Las Vegas School of Medicine, Las Vegas, Nev
| | - Linda L Stephenson
- Microsurgery and Hyperbaric Laboratory, Department of Surgery, University of Nevada, Las Vegas School of Medicine, Las Vegas, Nev
| | - Patrick S Murphy
- Microsurgery and Hyperbaric Laboratory, Department of Surgery, University of Nevada, Las Vegas School of Medicine, Las Vegas, Nev
| | - Peter R Letourneau
- Microsurgery and Hyperbaric Laboratory, Department of Surgery, University of Nevada, Las Vegas School of Medicine, Las Vegas, Nev
| | - Xin-Hua Fang
- Microsurgery and Hyperbaric Laboratory, Department of Surgery, University of Nevada, Las Vegas School of Medicine, Las Vegas, Nev
| | - Wei Z Wang
- Microsurgery and Hyperbaric Laboratory, Department of Surgery, University of Nevada, Las Vegas School of Medicine, Las Vegas, Nev
| | - Richard C Baynosa
- Microsurgery and Hyperbaric Laboratory, Department of Surgery, University of Nevada, Las Vegas School of Medicine, Las Vegas, Nev
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8
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You ZP, Zhang YL, Shi K, Shi L, Zhang YZ, Zhou Y, Wang CY. Suppression of diabetic retinopathy with GLUT1 siRNA. Sci Rep 2017; 7:7437. [PMID: 28785055 PMCID: PMC5547104 DOI: 10.1038/s41598-017-07942-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 07/05/2017] [Indexed: 01/12/2023] Open
Abstract
To investigate the effect of glucose transporter-1 (GLUT1) inhibition on diabetic retinopathy, we divided forty-eight mice into scrambled siRNA, diabetic scrambled siRNA, and GLUT1 siRNA (intravitreally injected) groups. Twenty-one weeks after diabetes induction, we calculated retinal glucose concentrations, used electroretinography (ERG) and histochemical methods to assess photoreceptor degeneration, and conducted immunoblotting, leukostasis and vascular leakage assays to estimate microangiopathy. The diabetic scrambled siRNA and GLUT1 siRNA exhibited higher glucose concentrations than scrambled siRNA, but GLUT1 siRNA group concentrations were only 50.05% of diabetic scrambled siRNA due to downregulated GLUT1 expression. The diabetic scrambled siRNA and GLUT1 siRNA had lower ERG amplitudes and ONL thicknesses than scrambled siRNA. However, compared with diabetic scrambled siRNA, GLUT1 siRNA group amplitudes and thicknesses were higher. Diabetic scrambled siRNA cones were more loosely arranged and had shorter outer segments than GLUT1 siRNA cones. ICAM-1 and TNF-α expression levels, adherent leukocyte numbers, fluorescence leakage areas and extravasated Evans blue in diabetic scrambled siRNA were higher than those in scrambled siRNA. However, these parameters in the GLUT1 siRNA were lower than diabetic scrambled siRNA. Together, these results demonstrate that GLUT1 siRNA restricted glucose transport by inhibiting GLUT1 expression, which decreased retinal glucose concentrations and ameliorated diabetic retinopathy.
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Affiliation(s)
- Zhi-Peng You
- Department of Ophthalmology, The Second Affiliated Hospital, Nanchang University, Nanchang, 330006, China
| | - Yu-Lan Zhang
- Department of Ophthalmology, The Second Affiliated Hospital, Nanchang University, Nanchang, 330006, China
| | - Ke Shi
- Department of Ophthalmology, The Second Affiliated Hospital, Nanchang University, Nanchang, 330006, China.
| | - Lu Shi
- Department of Ophthalmology, The Second Affiliated Hospital, Nanchang University, Nanchang, 330006, China
| | - Yue-Zhi Zhang
- Department of Ophthalmology, The Second Affiliated Hospital, Nanchang University, Nanchang, 330006, China
| | - Yue Zhou
- Department of Ophthalmology, The Second Affiliated Hospital, Nanchang University, Nanchang, 330006, China
| | - Chang-Yun Wang
- Department of Ophthalmology, The Second Affiliated Hospital, Nanchang University, Nanchang, 330006, China
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Sosa RA, Zarrinpar A, Rossetti M, Lassman CR, Naini BV, Datta N, Rao P, Harre N, Zheng Y, Spreafico R, Hoffmann A, Busuttil RW, Gjertson DW, Zhai Y, Kupiec-Weglinski JW, Reed EF. Early cytokine signatures of ischemia/reperfusion injury in human orthotopic liver transplantation. JCI Insight 2016; 1:e89679. [PMID: 27942590 DOI: 10.1172/jci.insight.89679] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND. Orthotopic liver transplant (OLT) is the primary therapy for end-stage liver disease and acute liver failure. However, ischemia/reperfusion injury (IRI) can severely compromise allograft survival. To understand the evolution of immune responses underlying OLT-IRI, we evaluated longitudinal cytokine expression profiles from adult OLT recipients before transplant through 1 month after transplant. METHODS. We measured the expression of 38 cytokines, chemokines, and growth factors in preoperative and postoperative recipient circulating systemic blood (before transplant and 1 day, 1 week, and 1 month after transplant) and intraoperative portal blood (before and after reperfusion) of 53 OLT patients and analyzed this expression in relation to biopsy-proven IRI (n = 26 IRI+; 27 IRI-), clinical liver function tests early (days 1-7) after transplant, and expression of genes encoding cytokine receptors in biopsies of donor allograft taken before and after reperfusion. RESULTS. Bilirubin and arginine transaminase levels early after transplant correlated with IRI. Fourteen cytokines were significantly increased in the systemic and/or portal blood of IRI+ recipients that shifted from innate to adaptive-immune responses over time. Additionally, expression of cognate receptors for 10 of these cytokines was detected in donor organ biopsies by RNAseq. CONCLUSION. These results provide a mechanistic roadmap of the early immunological events both before and after IRI and suggest several candidates for patient stratification, monitoring, and treatment. FUNDING. Ruth L. Kirschstein National Research Service Award T32CA009120, Keck Foundation award 986722, and a Quantitative & Computational Biosciences Collaboratory Postdoctoral Fellowship.
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Affiliation(s)
| | | | | | | | | | | | - Ping Rao
- Department of Pathology and Laboratory Medicine
| | | | - Ying Zheng
- Department of Pathology and Laboratory Medicine
| | - Roberto Spreafico
- Department of Microbiology, Immunology, and Molecular Genetics, and.,Institute for Quantitative and Computational Biosciences, UCLA, California, USA
| | - Alexander Hoffmann
- Department of Microbiology, Immunology, and Molecular Genetics, and.,Institute for Quantitative and Computational Biosciences, UCLA, California, USA
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Kocak FE, Kucuk A, Ozyigit F, Tosun M, Kocak C, Kocak A, Ekici MF, Yaylak F, Genc O. Protective effects of simvastatin administered in the experimental hepatic ischemia-reperfusion injury rat model. J Surg Res 2015; 199:393-401. [DOI: 10.1016/j.jss.2015.06.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Revised: 06/01/2015] [Accepted: 06/05/2015] [Indexed: 11/26/2022]
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Marquez BV, Ikotun OF, Parry JJ, Rogers BE, Meares CF, Lapi SE. Development of a Radiolabeled Irreversible Peptide Ligand for PET Imaging of Vascular Endothelial Growth Factor. J Nucl Med 2014; 55:1029-34. [PMID: 24732153 DOI: 10.2967/jnumed.113.130898] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Accepted: 01/24/2014] [Indexed: 01/30/2023] Open
Abstract
UNLABELLED Imaging agents based on peptide probes have desirable pharmacokinetic properties provided that they have high affinities for their target in vivo. An approach to improve a peptide ligand's affinity for its target is to make this interaction covalent and irreversible. For this purpose, we evaluated a (64)Cu-labeled affinity peptide tag, (64)Cu-L19K-(5-fluoro-2,4-dinitrobenzene) ((64)Cu-L19K-FDNB), which binds covalently and irreversibly to vascular endothelial growth factor (VEGF) as a PET imaging agent. We compared the in vivo properties of (64)Cu-L19K-FDNB in VEGF-expressing tumor xenografts with its noncovalent binding analogs, (64)Cu-L19K-(2,4-dinitrophenyl) ((64)Cu-L19K-DNP) and (64)Cu-L19K. METHODS The L19K peptide (GGNECDIARMWEWECFERK-CONH2) was constructed with 1,4,7-triazacyclononane-1,4,7-triacetic acid at the N terminus for radiolabeling with (64)Cu with a polyethylene glycol spacer between peptide and chelate. 1,5-difluoro-2,4-dinitrobenzene was conjugated at the C-terminal lysine for cross-linking to VEGF, resulting in L19K-FDNB. (64)Cu-L19K-FDNB was assayed for covalent binding to VEGF in vitro. As a control, L19K was conjugated to 1-fluoro-2,4-dinitrobenzene, resulting in L19K-DNP. PET imaging and biodistribution studies of (64)Cu-L19K-FDNB, (64)Cu-L19K-DNP, and the native (64)Cu-L19K were compared in HCT-116 xenografts. Blocking studies of (64)Cu-L19K-FDNB was performed with a coinjection of excess unlabeled L19K-FDNB. RESULTS In vitro binding studies confirmed the covalent and irreversible binding of (64)Cu-L19K-FDNB to VEGF, whereas (64)Cu-L19K-DNP and (64)Cu-L19K did not bind covalently. PET imaging showed higher tumor uptake with (64)Cu-L19K-FDNB than with (64)Cu-L19K-DNP and (64)Cu-L19K, with mean standardized uptake values of 0.62 ± 0.05, 0.18 ± 0.06, and 0.34 ± 0.14, respectively, at 24 h after injection (P < 0.05), and 0.53 ± 0.05, 0.32 ± 0.14, and 0.30 ± 0.09, respectively, at 48 h after injection (P < 0.05). Blocking studies with (64)Cu-L19K-FDNB in the presence of excess unlabeled peptide showed a 53% reduction in tumor uptake at 48 h after injection. CONCLUSION In this proof-of-concept study, the use of a covalent binding peptide ligand against VEGF improves tracer accumulation at the tumor site in vivo, compared with its noncovalent binding peptide analogs. This technique is a promising tool to enhance the potency of peptide probes as imaging agents.
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Affiliation(s)
- Bernadette V Marquez
- Department of Radiology, Washington University School of Medicine, Saint Louis, Missouri
| | - Oluwatayo F Ikotun
- Department of Radiology, Washington University School of Medicine, Saint Louis, Missouri
| | - Jesse J Parry
- Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, Missouri; and
| | - Buck E Rogers
- Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, Missouri; and
| | - Claude F Meares
- Department of Chemistry, University of California, Davis, California
| | - Suzanne E Lapi
- Department of Radiology, Washington University School of Medicine, Saint Louis, Missouri
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Sozmen M, Devrim AK, Tunca R, Bayezit M, Dag S, Essiz D. Protective effects of silymarin on fumonisin B₁-induced hepatotoxicity in mice. J Vet Sci 2013; 15:51-60. [PMID: 24136215 PMCID: PMC3973766 DOI: 10.4142/jvs.2014.15.1.51] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2013] [Accepted: 10/06/2013] [Indexed: 11/20/2022] Open
Abstract
The present study was conducted to investigate the effect of silymarin on experimental liver toxication induced by Fumonisin B1 (FB1) in BALB/c mice. The mice were divided into six groups (n = 15). Group 1 served as the control. Group 2 was the silymarin control (100 mg/kg by gavage). Groups 3 and 4 were treated with FB1 (Group 3, 1.5 mg/kg FB1, intraperitoneally; and Group 4, 4.5 mg/kg FB1). Group 5 received FB1 (1.5 mg/kg) and silymarin (100 mg/kg), and Group 6 was given a higher dose of FB1 (4.5 mg/kg FB1) with silymarin (100 mg/kg). Silymarin treatment significantly decreased (p < 0.0001) the apoptotic rate. FB1 administration significantly increased (p < 0.0001) proliferating cell nuclear antigen and Ki-67 expression. Furthermore, FB1 elevated the levels of caspase-8 and tumor necrosis factor-alpha mediators while silymarin significantly reduced (p < 0.0001) the expression of these factors. Vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) expressions were significantly elevated in Group 4 (p < 0.0001). Silymarin administration alleviated increased VEGF and FGF-2 expression levels (p < 0.0001). In conclusion, silymarin ameliorated toxic liver damage caused by FB1 in BALB/c mice.
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Affiliation(s)
- Mahmut Sozmen
- Department of Pathology, Samsun, Faculty of Veterinary Medicine, University of Ondokuz Mayis, Samsun 55139,
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Abstract
Diabetic retinopathy is the leading cause of blindness in working age individuals in developed countries. Most cases of diabetes related vision loss result from breakdown of the blood-retinal barrier with resultant diabetic macular edema (DME). For over 30 years, laser photocoagulation has been the standard therapy for DME, but most eyes do not experience significant improvements in visual acuity. Intravitreal injections of drugs that inhibit the action of vascular endothelial growth factor (VEGF) lead to gains in vision, but can be expensive and need to be repeated frequently. In addition to VEGF-mediated breakdown of the blood-retinal barrier, recent evidence suggests that inflammation plays an important role in the development of DME. Recognizing this, physicians have injected steroids into the vitreous and developers have created sustained release implants. Intravitreal injections of triamcinolone acetonide lead to rapid resolution of macular edema and significant short-term improvements in visual acuity, but unfortunately, visual acuities diminish when treatment is continued through 2 years. However, intravitreal triamcinolone remains an attractive treatment option for eyes that are pseudophakic, scheduled to undergo cataract surgery, resistant to laser photocoagulation, or require urgent panretinal photocoagulation for proliferative retinopathy. In controlled trials, intraocular implants that slowly release dexamethasone and fluocinolone show promise in reducing macular edema and improving visual acuity. The high incidences of drug related cataracts and glaucoma, however, require that corticosteroids be used cautiously and that patients be selected carefully. The increasing number of patients with DME, the burgeoning cost of medical care and the continuing development of intravitreal steroids suggest that the use of these agents will likely increase in coming years.
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Ohashi N, Hori T, Chen F, Jermanus S, Eckman CB, Nakao A, Uemoto S, Nguyen JH. Matrix metalloproteinase-9 contributes to parenchymal hemorrhage and necrosis in the remnant liver after extended hepatectomy in mice. World J Gastroenterol 2012; 18:2320-2333. [PMID: 22654423 PMCID: PMC3353366 DOI: 10.3748/wjg.v18.i19.2320] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2011] [Revised: 10/27/2011] [Accepted: 02/27/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effect of matrix metalloproteinase-9 (MMP-9) on the remnant liver after massive hepatectomy in the mouse. METHODS Age-matched, C57BL/6 wild-type (WT), MMP-9(-/-), and tissue inhibitors of metalloproteinases (TIMP)-1(-/-) mice were used. The mice received 80%-partial hepatectomy (PH). Samples were obtained at 6 h after 80%-PH, and we used histology, immunohistochemical staining, western blotting analysis and zymography to investigate the effect of PH on MMP-9. The role of MMP-9 after PH was investigated using a monoclonal antibody and MMP inhibitor. RESULTS We examined the remnant liver 6 h after 80%-PH and found that MMP-9 deficiency attenuated the formation of hemorrhage and necrosis. There were significantly fewer and smaller hemorrhagic and necrotic lesions in MMP-9(-/-) remnant livers compared with WT and TIMP-1(-/-) livers (P < 0.01), with no difference between WT and TIMP-1(-/-) mice. Serum alanine aminotransaminase levels were significantly lower in MMP-9(-/-) mice compared with those in TIMP-1(-/-) mice (WT: 476 ± 83 IU/L, MMP-9(-/-): 392 ± 30 IU/L, TIMP-1(-/-): 673 ± 73 IU/L, P < 0.01). Western blotting and gelatin zymography demonstrated a lack of MMP-9 expression and activity in MMP-9(-/-) mice, which was in contrast to WT and TIMP-1(-/-) mice. No change in MMP-2 expression was observed in any of the study groups. Similar to MMP-9(-/-) mice, when WT mice were treated with MMP-9 monoclonal antibody or the synthetic inhibitor GM6001, hemorrhagic and necrotic lesions were significantly smaller and fewer than in control mice (P < 0.05). These results suggest that MMP-9 plays an important role in the development of parenchymal hemorrhage and necrosis in the small remnant liver. CONCLUSION Successful MMP-9 inhibition attenuates the formation of hemorrhage and necrosis and might be a potential therapy to ameliorate liver injury after massive hepatectomy.
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Masri AAA, Eter EE. Agmatine induces gastric protection against ischemic injury by reducing vascular permeability in rats. World J Gastroenterol 2012; 18:2188-96. [PMID: 22611311 PMCID: PMC3351768 DOI: 10.3748/wjg.v18.i18.2188] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2011] [Revised: 01/04/2012] [Accepted: 03/09/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of administration of agmatine (AGM) on gastric protection against ischemia reperfusion (I/R) injury.
METHODS: Three groups of rats (6/group); sham, gastric I/R injury, and gastric I/R + AGM (100 mg/kg, i.p. given 15 min prior to gastric ischemia) were recruited. Gastric injury was conducted by ligating celiac artery for 30 min and reperfusion for another 30 min. Gastric tissues were histologically studied and immunostained with angiopoietin 1 (Ang-1) and Ang-2. Vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) were measured in gastric tissue homogenate. To assess whether AKt/phosphatidyl inositol-3-kinase (PI3K) mediated the effect of AGM, an additional group was pretreated with Wortmannin (WM) (inhibitor of Akt/PI3K, 15 μg/kg, i.p.), prior to ischemic injury and AGM treatment, and examined histologically and immunostained. Another set of experiments was run to study vascular permeability of the stomach using Evan’s blue dye.
RESULTS: AGM markedly reduced Evan’s blue dye extravasation (3.58 ± 0.975 μg/stomach vs 1.175 ± 0.374 μg/stomach, P < 0.05), VEGF (36.87 ± 2.71 pg/100 mg protein vs 48.4 ± 6.53 pg/100 mg protein, P < 0.05) and MCP-1 tissue level (29.5 ± 7 pg/100 mg protein vs 41.17 ± 10.4 pg/100 mg protein, P < 0.01). It preserved gastric histology and reduced congestion. Ang-1 and Ang-2 immunostaining were reduced in stomach sections of AGM-treated animals. The administration of WM abolished the protective effects of AGM and extensive hemorrhage and ulcerations were seen.
CONCLUSION: AGM protects the stomach against I/R injury by reducing vascular permeability and inflammation. This protection is possibly mediated by Akt/PI3K.
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Bertini R, Barcelos LS, Beccari AR, Cavalieri B, Moriconi A, Bizzarri C, Di Benedetto P, Di Giacinto C, Gloaguen I, Galliera E, Corsi MM, Russo RC, Andrade SP, Cesta MC, Nano G, Aramini A, Cutrin JC, Locati M, Allegretti M, Teixeira MM. Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor. Br J Pharmacol 2012; 165:436-54. [PMID: 21718305 DOI: 10.1111/j.1476-5381.2011.01566.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND AND PURPOSE DF 2156A is a new dual inhibitor of IL-8 receptors CXCR1 and CXCR2 with an optimal pharmacokinetic profile. We characterized its binding mode, molecular mechanism of action and selectivity, and evaluated its therapeutic potential. EXPERIMENTAL APPROACH The binding mode, molecular mechanism of action and selectivity were investigated using chemotaxis of L1.2 transfectants and human leucocytes, in addition to radioligand and [(35) S]-GTPγS binding approaches. The therapeutic potential of DF 2156A was evaluated in acute (liver ischaemia and reperfusion) and chronic (sponge-induced angiogenesis) experimental models of inflammation. KEY RESULTS A network of polar interactions stabilized by a direct ionic bond between DF 2156A and Lys(99) on CXCR1 and the non-conserved residue Asp(293) on CXCR2 are the key determinants of DF 2156A binding. DF 2156A acted as a non-competitive allosteric inhibitor blocking the signal transduction leading to chemotaxis without altering the binding affinity of natural ligands. DF 2156A effectively and selectively inhibited CXCR1/CXCR2-mediated chemotaxis of L1.2 transfectants and leucocytes. In a murine model of sponge-induced angiogenesis, DF 2156A reduced leucocyte influx, TNF-α production and neovessel formation. In vitro, DF 2156A prevented proliferation, migration and capillary-like organization of HUVECs in response to human IL-8. In a rat model of liver ischaemia and reperfusion (I/R) injury, DF 2156A decreased PMN and monocyte-macrophage infiltration and associated hepatocellular injury. CONCLUSION AND IMPLICATIONS DF 2156A is a non-competitive allosteric inhibitor of both IL-8 receptors CXCR1 and CXCR2. It prevented experimental angiogenesis and hepatic I/R injury in vivo and, therefore, has therapeutic potential for acute and chronic inflammatory diseases.
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Machida T, Tanemura M, Ohmura Y, Tanida T, Wada H, Kobayashi S, Marubashi S, Eguchi H, Ito T, Nagano H, Mori M, Doki Y, Sawa Y. Significant improvement in islet yield and survival with modified ET-Kyoto solution: ET-Kyoto/Neutrophil elastase inhibitor. Cell Transplant 2012; 22:159-73. [PMID: 22472201 DOI: 10.3727/096368912x637028] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Although islet transplantation can achieve insulin independence in patients with type 1 diabetes, sufficient number of islets derived from two or more donors is usually required to achieve normoglycemia. Activated neutrophils and neutrophil elastase (NE), which is released from these neutrophils, can directly cause injury in islet grafts. We hypothesized that inhibition of NE improves islet isolation and islet allograft survival. We tested our hypothesis by examining the effects of modified ET-Kyoto solution supplemented with sivelestat, a NE inhibitor (S-Kyoto solution), on islet yield and viability in islet isolation and the effect of intraperitoneally injected sivelestat on islet graft survival in a mouse allotransplant model. NE and proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 increased markedly at the end of warm digestion during islet isolation and exhibited direct cytotoxic activity against the islets causing their apoptosis. The use of S-Kyoto solution significantly improved islet yield and viability. Furthermore, treatment with sivelestat resulted in significant prolongation of islet allograft survival in recipient mice. Furthermore, serum levels of IL-6 and TNF-α at 1 and 2 weeks posttransplantation were significantly higher in islet recipients than before transplantation. Our results indicated that NE released from activated neutrophils negatively affects islet survival and that its suppression both in vitro and in vivo improved islet yield and prolonged islet graft survival. The results suggest that inhibition of NE activity could be potentially useful in islet transplantation for patients with type 1 diabetes mellitus.
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Affiliation(s)
- Tomohiko Machida
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
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Nath B, Szabo G. Hypoxia and hypoxia inducible factors: diverse roles in liver diseases. HEPATOLOGY (BALTIMORE, MD.) 2012. [PMID: 22120903 DOI: 10.1002/hep.25497]] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hypoxia has been shown to have a role in the pathogenesis of several forms of liver disease. The hypoxia inducible factors (HIFs) are a family of evolutionarily conserved transcriptional regulators that affect a homeostatic response to low oxygen tension and have been identified as key mediators of angiogenesis, inflammation, and metabolism. In this review we summarize the evidence for a role of HIFs across a range of hepatic pathophysiology. We describe regulation of the HIFs and review investigations that demonstrate a role for HIFs in the development of liver fibrosis, activation of innate immune pathways, hepatocellular carcinoma, as well as other liver diseases in both human disease as well as murine models.
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Affiliation(s)
- Bharath Nath
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
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Abstract
Hypoxia has been shown to have a role in the pathogenesis of several forms of liver disease. The hypoxia inducible factors (HIFs) are a family of evolutionarily conserved transcriptional regulators that affect a homeostatic response to low oxygen tension and have been identified as key mediators of angiogenesis, inflammation, and metabolism. In this review we summarize the evidence for a role of HIFs across a range of hepatic pathophysiology. We describe regulation of the HIFs and review investigations that demonstrate a role for HIFs in the development of liver fibrosis, activation of innate immune pathways, hepatocellular carcinoma, as well as other liver diseases in both human disease as well as murine models.
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Affiliation(s)
- Bharath Nath
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
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Li S, Chen X, Wu T, Zhang M, Zhang X, Ji Z. Role of heparin on serum VEGF levels and local VEGF contents in reducing the severity of experimental severe acute pancreatitis in rats. Scand J Gastroenterol 2012; 47:237-44. [PMID: 22214372 DOI: 10.3109/00365521.2011.647063] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The aims of this study were to examine the effects of prophylactic heparin treatment during taurocholate-induced pancreatitis in rats and its impact on serum VEGF levels and local VEGF contents within the pancreas. METHODS Severe acute pancreatitis (SAP) was induced by injecting 4% sodium taurocholate into the pancreatic duct. Heparin at a dose of 150 IU/kg s.c. was administered 30 min before the operation. The rats were sacrificed 1 h, 3 h, 6 h and 12 h (n = 5 per time point) after the onset of pancreatitis. The severity of pancreatitis, serum VEGF levels and local VEGF contents were evaluated with and without heparin pretreatment. RESULTS The serum VEGF levels increased at an early phase of pancreatitis, and the highest level was found at 12 h after inducing pancreatitis. The gray value of the local VEGF showed a remarkable increase from the onset of the pancreatitis. However, the gray value of VEGF did not show an increase over time but maintained a high level during the entire process. Prophylactic heparin treatment significantly improved the morphologic changes, myeloperoxidase (MPO), TNF-α and malondialdehyde (MDA) activities. Meanwhile, it decreased the serum VEGF levels and the contents of VEGF within the pancreatic tissue. CONCLUSIONS The present study suggests that prophylactic heparin ameliorates the severity of taurocholate-induced pancreatitis via its anti-inflammatory properties. These protective effects may be partly due to decreasing serum VEGF levels and VEGF contents within the pancreas.
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Affiliation(s)
- Shunle Li
- First Department of General Surgery, the 2nd Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, PR, China
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Kim AR, Lim JY, Jeong DC, Park G, Lee BC, Min CK. Blockade of Vascular Endothelial Growth Factor (VEGF) Aggravates the Severity of Acute Graft-versus-host Disease (GVHD) after Experimental Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT). Immune Netw 2011; 11:368-75. [PMID: 22346777 PMCID: PMC3275706 DOI: 10.4110/in.2011.11.6.368] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Revised: 10/28/2011] [Accepted: 11/03/2011] [Indexed: 12/01/2022] Open
Abstract
BACKGROUND Recent clinical observation reported that there was a significant correlation between change in circulating vascular endothelial growth factor (VEGF) levels and the occurrence of severe acute graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the action mechanisms of VEGF in GVHD have not been demonstrated. METHODS This study investigated whether or not blockade of VEGF has an effect on acute GVHD in a lethally irradiated murine allo-HSCT model of B6 (H-2(b))→B6D2F1 (H-2(b/d)). Syngeneic or allogeneic recipient mice were injected subcutaneously with anti-VEGF peptides, dRK6 (50 µg/dose) or control diluent every other day for 2 weeks (total 7 doses). RESULTS Administration of the dRK6 peptide after allo-HSCT significantly reduced survival with greaterclinical GVHD scores and body weight loss. Allogeneic recipients injected with the dRK6 peptide exhibited significantly increased circulating levels of VEGF and expansion of donor CD3(+) T cells on day +7 compared to control treated animals. The donor CD4(+) and CD8(+) T-cell subsets have differential expansion caused by the dRK6 injection. The circulating VEGF levels were reduced on day +14 regardless of blockade of VEGF. CONCLUSION Together these findings demonstrate that the allo-reactive responses after allo-HSCT are exaggerated by the blockade of VEGF. VEGF seems to be consumed during the progression of acute GVHD in this murine allo-HSCT model.
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Affiliation(s)
- Ai-Ran Kim
- Department of Pediatrics, The Catholic University of Korea, Seoul 137-701, Korea
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Abstract
Pneumococcal meningitis continues to be associated with high rates of mortality and long-term neurological sequelae. The most common route of infection starts by nasopharyngeal colonization by Streptococcus pneumoniae, which must avoid mucosal entrapment and evade the host immune system after local activation. During invasive disease, pneumococcal epithelial adhesion is followed by bloodstream invasion and activation of the complement and coagulation systems. The release of inflammatory mediators facilitates pneumococcal crossing of the blood-brain barrier into the brain, where the bacteria multiply freely and trigger activation of circulating antigen-presenting cells and resident microglial cells. The resulting massive inflammation leads to further neutrophil recruitment and inflammation, resulting in the well-known features of bacterial meningitis, including cerebrospinal fluid pleocytosis, cochlear damage, cerebral edema, hydrocephalus, and cerebrovascular complications. Experimental animal models continue to further our understanding of the pathophysiology of pneumococcal meningitis and provide the platform for the development of new adjuvant treatments and antimicrobial therapy. This review discusses the most recent views on the pathophysiology of pneumococcal meningitis, as well as potential targets for (adjunctive) therapy.
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Xue F, Zhang JJ, Xu LM, Zhang C, Xia Q. Protective effects of HGF-MSP chimer (metron factor-1) on liver ischemia-reperfusion injury in rat model. J Dig Dis 2010; 11:299-305. [PMID: 20883426 DOI: 10.1111/j.1751-2980.2010.00453.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
OBJECTIVE It has been reported that metron factor-1 (MF-1), an engineered chimerical factor containing selected functional domains of hepatocyte growth factor and macrophage-stimulating protein (HGF-MSP), could prevent apoptosis and have an anti-inflammatory effect. In this study, we investigate the protective effect of MF-1 on liver ischemia-reperfusion (I/R) injury. METHODS Overall 30 Sprague Dawley rats were randomly divided into three groups: the I/R model group (n=12), the MF-1 treatment group (n=12), and the sham-operated group (n=6). Liver I/R injury was induced by clamping the blood supply to the left and median lobes of liver by an atraumatic clamp for 90 min, then removing the clamp and allowing reperfusion. Blood samples were obtained on days 1, 2, 3 and 7 to assess liver biochemistry and the histology of liver tissue. Levels of malondialdehyde (MDA), superoxide dismutase (SOD), nitric oxide (NO), endothelial nitric oxide synthase and inducible nitric oxide synthase were measured. In addition, the anti-oxidative effect of MF-1 on hepatocytes was assessed in vitro. RESULTS MF-1 treatment improved the rat survival rate significantly (P < 0.05). Liver biochemistry and histological changes were significantly ameliorated. MDA increased and SOD and NO decreased in the liver tissue. In vitro, MF-1 protected the human hepatic cell line HL-7702 from damage of oxidative stress. CONCLUSION MF-1 could protect the liver from I/R injury, which might involve the reduction of oxygen free radicals and the increase of NO synthesis in an injured liver.
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Affiliation(s)
- Feng Xue
- Organ Transplantation Center, Renji Hospital, Shanghai Jiaotong University School of Medicine, China.
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Nakao A, Huang CS, Stolz DB, Wang Y, Franks JM, Tochigi N, Billiar TR, Toyoda Y, Tzeng E, McCurry KR. Ex vivo carbon monoxide delivery inhibits intimal hyperplasia in arterialized vein grafts. Cardiovasc Res 2010; 89:457-63. [PMID: 20851811 DOI: 10.1093/cvr/cvq298] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
AIMS Veins are still the best conduits available for arterial bypass surgery. When these arterialized vein grafts fail, it is often due to the development of intimal hyperplasia (IH). We investigated the feasibility and efficacy of the ex vivo pre-treatment of vein grafts with soluble carbon monoxide (CO) in the inhibition of IH. METHODS AND RESULTS The inferior vena cava was excised from donor rats and placed as an interposition graft into the abdominal aorta of syngeneic rats. Prior to implantation, vein grafts were stored in cold Lactated Ringer (LR) solution with or without CO saturation (bubbling of 100% CO) for 2 h. Three and 6 weeks following grafting, vein grafts treated with cold LR for 2 h developed IH, whereas grafts implanted immediately after harvest demonstrated significantly less IH. Treatment in CO-saturated LR significantly inhibited IH and reduced vascular endothelial cell (VEC) apoptosis. Electron microscopy revealed improved VEC integrity with less platelet/white blood cell aggregation in CO-treated grafts. The effects of CO in preventing IH were associated with activation of hypoxia inducible factor-1α (HIF-1α) and an increase in vascular endothelial growth factor (VEGF) expression at 3-6 h after grafting. Treatment with a HIF-1α inhibitor completely abrogated the induction of VEGF by CO and reversed the protective effects of CO on prevention of IH. CONCLUSION Ex vivo treatment of vein grafts in CO-saturated LR preserved VEC integrity perioperatively and significantly reduced neointima formation. These effects appear to be mediated through the activation of the HIF1α/VEGF pathway.
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Affiliation(s)
- Atsunori Nakao
- Department of Surgery, University of Pittsburgh Medical Center, E1551, Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
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Wang J, Xu X, Elliott MH, Zhu M, Le YZ. Müller cell-derived VEGF is essential for diabetes-induced retinal inflammation and vascular leakage. Diabetes 2010; 59:2297-2305. [PMID: 20530741 PMCID: PMC2927953 DOI: 10.2337/db09-1420] [Citation(s) in RCA: 283] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2009] [Accepted: 05/24/2010] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Vascular endothelial growth factor (VEGF-A or VEGF) is a major pathogenic factor and therapeutic target for diabetic retinopathy (DR). Since VEGF has been proposed as a survival factor for retinal neurons, defining the cellular origin of pathogenic VEGF is necessary for the effectiveness and safety of long-term anti-VEGF therapies for DR. To determine the significance of Müller cell-derived VEGF in DR, we disrupted VEGF in Müller cells with an inducible Cre/lox system and examined diabetes-induced retinal inflammation and vascular leakage in these conditional VEGF knockout (KO) mice. RESEARCH DESIGN AND METHODS Leukostasis was determined by counting the number of fluorescently labeled leukocytes inside retinal vasculature. Expression of biomarkers for retinal inflammation was assessed by immunoblotting of TNF-alpha, ICAM-1, and NF-kappaB. Vascular leakage was measured by immunoblotting of retinal albumin and fluorescent microscopic analysis of extravascular albumin. Diabetes-induced vascular alterations were examined by immunoblotting and immunohistochemistry for tight junctions, and by trypsin digestion assays for acellular capillaries. Retinal integrity was analyzed with morphologic and morphometric analyses. RESULTS Diabetic conditional VEGF KO mice exhibited significantly reduced leukostasis, expression of inflammatory biomarkers, depletion of tight junction proteins, numbers of acellular capillaries, and vascular leakage compared to diabetic control mice. CONCLUSIONS Müller cell-derived VEGF plays an essential and causative role in retinal inflammation, vascular lesions, and vascular leakage in DR. Therefore, Müller cells are a primary cellular target for proinflammatory signals that mediates retinal inflammation and vascular leakage in DR.
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Affiliation(s)
- Juanjuan Wang
- Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China
- Department of Medicine Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- Harold Hamm Oklahoma Diabetes Center, University of Oklahoma, Oklahoma City, Oklahoma
| | - Xueliang Xu
- Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China
| | - Michael H. Elliott
- Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- Dean A. McGee Eye Institute, Oklahoma City, Oklahoma
| | - Meili Zhu
- Department of Medicine Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- Harold Hamm Oklahoma Diabetes Center, University of Oklahoma, Oklahoma City, Oklahoma
| | - Yun-Zheng Le
- Department of Medicine Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- Harold Hamm Oklahoma Diabetes Center, University of Oklahoma, Oklahoma City, Oklahoma
- Dean A. McGee Eye Institute, Oklahoma City, Oklahoma
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
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Abu-Amara M, Yang SY, Tapuria N, Fuller B, Davidson B, Seifalian A. Liver ischemia/reperfusion injury: processes in inflammatory networks--a review. Liver Transpl 2010; 16:1016-32. [PMID: 20818739 DOI: 10.1002/lt.22117] [Citation(s) in RCA: 261] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Liver ischemia/reperfusion (IR) injury is typified by an inflammatory response. Understanding the cellular and molecular events underpinning this inflammation is fundamental to developing therapeutic strategies. Great strides have been made in this respect recently. Liver IR involves a complex web of interactions between the various cellular and humoral contributors to the inflammatory response. Kupffer cells, CD4+ lymphocytes, neutrophils, and hepatocytes are central cellular players. Various cytokines, chemokines, and complement proteins form the communication system between the cellular components. The contribution of the danger-associated molecular patterns and pattern recognition receptors to the pathophysiology of liver IR injury are slowly being elucidated. Our knowledge on the role of mitochondria in generating reactive oxygen and nitrogen species, in contributing to ionic disturbances, and in initiating the mitochondrial permeability transition with subsequent cellular death in liver IR injury is continuously being expanded. Here, we discuss recent findings pertaining to the aforementioned factors of liver IR, and we highlight areas with gaps in our knowledge, necessitating further research.
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Affiliation(s)
- Mahmoud Abu-Amara
- Liver Transplantation and Hepatobiliary Unit, Royal Free Hospital, London, United Kingdom
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27
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Lin J, Zeng Z. Advances in research on the protective mechanisms of ischemic postconditioning against hepatic ischemia-reperfusion injury. Shijie Huaren Xiaohua Zazhi 2010; 18:1799-1803. [DOI: 10.11569/wcjd.v18.i17.1799] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation is the only effective treatment for end-stage liver diseases. Ischemia-reperfusion injury remains a major cause of post-transplantation liver dysfunction and even failure. Ischemic postconditioning is defined as rapid intermittent periods of reperfusion and ischemia in the early phase of repefusion after long ischemia of the tissues and organs. Many investigations have demonstrated that ischemic postconditioning has a protective effect against hepatic ichemia-reperfusion injury. Ischemic postconditioning exerts protective effects through many possible mechanisms such as oxygen free radicals, calcium overload, polymorphonuclear neutrophils, cytokines, cell apoptosis and mitochondria.
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Zhang J, Silva T, Yarovinsky T, Manes TD, Tavakoli S, Nie L, Tellides G, Pober JS, Bender JR, Sadeghi MM. VEGF blockade inhibits lymphocyte recruitment and ameliorates immune-mediated vascular remodeling. Circ Res 2010; 107:408-17. [PMID: 20538685 DOI: 10.1161/circresaha.109.210963] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
RATIONALE There are conflicting data on the effects of vascular endothelial growth factor (VEGF) in vascular remodeling. Furthermore, there are species-specific differences in leukocyte and vascular cell biology and little is known about the role of VEGF in remodeling of human arteries. OBJECTIVE We sought to address the role of VEGF blockade on remodeling of human arteries in vivo. METHODS AND RESULTS We used an anti-VEGF antibody, bevacizumab, to study the effect of VEGF blockade on remodeling of human coronary artery transplants in severe combined immunodeficient mice. Bevacizumab ameliorated peripheral blood mononuclear cell-induced but not interferon-gamma-induced neointimal formation. This inhibitory effect was associated with a reduction in graft T-cell accumulation without affecting T-cell activation. VEGF enhanced T-cell capture by activated endothelium under flow conditions. The VEGF effect could be recapitulated when a combination of recombinant intercellular adhesion molecule 1 and vascular cell adhesion molecule-1 rather than endothelial cells was used to capture T cells. A subpopulation of CD3+ T cells expressed VEGF receptor (VEGFR)-1 by immunostaining and FACS analysis. VEGFR-1 mRNA was also detectable in purified CD4+ T cells and Jurkat and HSB-2 T-cell lines. Stimulation of HSB-2 and T cells with VEGF triggered downstream ERK phosphorylation, demonstrating the functionality of VEGFR-1 in human T cells. CONCLUSIONS VEGF contributes to vascular remodeling in human arteries through a direct effect on human T cells that enhances their recruitment to the vessel. These findings raise the possibility of novel therapeutic approaches to vascular remodeling based on inhibition of VEGF signaling.
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Affiliation(s)
- Jiasheng Zhang
- Yale University School of Medicine, New Haven, Conn., USA
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29
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The protective function of neutrophil elastase inhibitor in liver ischemia/reperfusion injury. Transplantation 2010; 89:1050-6. [PMID: 20160675 DOI: 10.1097/tp.0b013e3181d45a98] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND.: A neutrophil elastase (NE) inhibitor, Sivelestat, has been approved for the treatment of acute lung injury associated with systemic inflammation in humans. Some reports have also shown its protective effects in liver inflammatory states. We have recently documented the importance of NE in the pathophysiology of liver ischemia/reperfusion injury, a local Ag-independent inflammation response. This study was designed to explore putative cytoprotective functions of clinically available Sivelestat in liver ischemia/reperfusion injury. METHODS.: Partial warm ischemia was produced in the left and middle hepatic lobes of C57BL/6 mice for 90 min, followed by 6 or 24 hr of reperfusion. The mice were given Sivelestat (100 mg/kg, subcutaneous) at 10 min before ischemia, 10 min before reperfusion, and at 1 and 3 hr of reperfusion thereafter. RESULTS.: Sivelestat treatment significantly reduced serum alanine aminotransferase levels and NE activity, when compared with controls. Histological liver examination has revealed that unlike in controls, Sivelestat ameliorated the hepatocellular damage and decreased local neutrophil activity and infiltration. The expression of proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6), chemokines (CXCL-1, CXCL-2, and CXCL-10), and toll-like receptor 4 was significantly reduced in the treatment group, along with diminished apoptosis through caspase-3 pathway. Moreover, in vitro studies confirmed downregulation of proinflammatory cytokine and chemokine programs in mouse macrophage cell cultures, along with depression of innate toll-like receptor 4 signaling. CONCLUSION.: Sivelestat-mediated NE inhibition may represent an effective therapeutic option in liver transplantation and other inflammation disease states.
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Gandolfo MT, Jang HR, Bagnasco SM, Ko GJ, Agreda P, Soloski MJ, Crow MT, Rabb H. Mycophenolate mofetil modifies kidney tubular injury and Foxp3+ regulatory T cell trafficking during recovery from experimental ischemia-reperfusion. Transpl Immunol 2010; 23:45-52. [PMID: 20412855 DOI: 10.1016/j.trim.2010.04.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2009] [Revised: 03/02/2010] [Accepted: 04/05/2010] [Indexed: 01/25/2023]
Abstract
Lymphocytes participate in the early pathogenesis of ischemia-reperfusion injury (IRI) in kidney; however, their role during repair is largely unknown. Recent data have shown that Foxp3(+) regulatory T cells (Tregs) traffic into kidney during healing from IRI and directly participate in repair. Since lymphocyte-targeting therapy is currently administered to prevent rejection during recovery from IRI in renal transplants, we hypothesized that mycophenolate mofetil (MMF) would alter Treg trafficking and kidney repair. C57BL/6J and T cell deficient mice underwent unilateral clamping of renal pedicle for 45 min, followed by reperfusion, and were sacrificed at day 10. Mice were treated with saline (C) or MMF (100mg/kg) i.p. daily starting at day 2 until sacrifice (n=5-12/group). MMF worsened kidney tubular damage compared to C at 10 days (cortex and outer medulla: p<0.05) in wild-type mice; tubular apoptotic index was increased in cortex in MMF group as well (p=0.01). MMF reduced the total number of kidney-infiltrating mononuclear cells (p<0.001 versus C) and the percentages of TCRbeta(+)CD4(+) and TCRbeta(+)CD8(+) T cells (p<0.01), but not natural killer (NK), NKT or B lymphocytes. MMF specifically reduced kidney Foxp3(+) Tregs (0.82+/-0.11% versus 1.75+/-0.17%, p<0.05). Tubular proliferative index and tissue levels of basic FGF were increased in MMF group (p<0.05), IL-10 and IL-6 were decreased (p<0.05). To evaluate if MMF effect occurred through non-lymphocytic cells, T cell deficient mice were treated with MMF. Tubular injury in T cell deficient mice was not affected by MMF treatment, though MMF-treated animals had increased VEGF and decreased PDGF-BB protein tissue levels compared to controls (p<0.05). Thus, MMF modifies the structural, epithelial proliferative and inflammatory response during healing, likely through effects on T cells and possibly Tregs. Kidney repair after IRI can be altered by agents that target lymphocytes.
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Affiliation(s)
- Maria Teresa Gandolfo
- Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA
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31
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Zhou WP, Sun HY. Effects of hepatic ischemia/reperfusion injury on tumor proliferation and metastasis. Shijie Huaren Xiaohua Zazhi 2010; 18:861-864. [DOI: 10.11569/wcjd.v18.i9.861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatic ischemia/reperfusion injury (HIRI) is a common pathophysiological process encountered in liver surgery. It has significant effects on the migration, adhesion, colonization and growth of circulating tumor cells by affecting the expression of some cytokines such as chemokines, adhesion molecules, matrix metalloproteinases, and vascular endothelial growth factor. Therefore, HIRI is highly correlated with the postoperative recurrence and metastasis of liver cancer.
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Bar J, Herbst RS, Onn A. Multitargeted inhibitors in lung cancer: new clinical data. Clin Lung Cancer 2009; 9 Suppl 3:S92-9. [PMID: 19419930 DOI: 10.3816/clc.2008.s.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Novel therapies have been added to the treatment arsenal of physicians treating lung cancer in recent years. Most promising are agents that target the major pathways involved in cancer evolution, mostly proliferation and angiogenesis. Some of these treatments have been shown to synergize with traditional chemotherapy and radiation therapy. Multitargeted therapy seems to be the next step of advancement in the treatment of lung cancer. This can refer not only to molecules that autonomously inhibit several pathways but also to combinations of therapies that, by targeting more than one pathway, act in concert to inhibit the malignant growth. In this review, we present the background and current status of multitargeted treatments in the management of patients with lung cancer, mostly non-small-cell lung cancer (NSCLC). Novel agents in clinical use and important ongoing clinical trials are reviewed.
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Affiliation(s)
- Jair Bar
- Division of Oncology, Chaim Sheba Medical Center, Tel Hashomer, Israel
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Increased vascular permeability after cardiopulmonary bypass in patients with diabetes is associated with increased expression of vascular endothelial growth factor and hepatocyte growth factor. J Thorac Cardiovasc Surg 2009; 138:185-91. [PMID: 19577077 DOI: 10.1016/j.jtcvs.2008.12.024] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2008] [Revised: 12/08/2008] [Accepted: 12/25/2008] [Indexed: 12/28/2022]
Abstract
BACKGROUND Several inflammatory mediators such as vascular endothelial growth factor and hepatocyte growth factor are known to play a critical role in the regulation of vascular permeability and angiogenesis. We studied the serum levels of growth factors and gene expression profiles of genes involved in growth factor signaling in the peripheral blood of patients with and patients without diabetes following cardiopulmonary bypass and cardioplegic arrest. METHODS Serum and total RNA were obtained from the blood samples collected from patients with diabetes and matched patients without diabetes (n = 7 patients each) who had coronary artery bypass graft before and 6 hours and 4 days after cardiopulmonary bypass/cardioplegic arrest. The cytokine panel, consisting of growth factors such as vascular endothelial growth factor, hepatocyte growth factor, fibroblast growth factor, and epidermal growth factor, was quantified in patients with diabetes and patients without diabetes before and 6 hours and 4 days post-cardiopulmonary bypass/cardioplegic arrest using multiplex cytokine quantification system. cDNA microarray analysis was performed and fold-change was calculated. RESULTS Length of hospitalization (10 vs 6 days; P = .04) and weight gain (5 vs 2.5 kg; P = .001) were significantly greater for patients with diabetes compared with patients without diabetes. The serum levels of vascular endothelial growth factor and hepatocyte growth factor were significantly elevated in patients with diabetes when compared with patients without diabetes before versus 6 hours post-cardiopulmonary bypass/cardioplegic arrest. In addition, significantly elevated mRNA expression of hypoxia-inducible factor-1alpha, cyclic adenosine monophosphate response element binding protein, and E1A binding protein p300 (more than twofold) was observed 4 days post-cardiopulmonary bypass/cardioplegic arrest exclusively in patients with diabetes. CONCLUSIONS The differential profile of gene and protein expression of growth factors and their related genes in patients with diabetes and patients without diabetes could be associated with increased edema and weight gain in patients with diabetes after cardiopulmonary bypass/cardioplegic arrest.
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Holt AP, Haughton EL, Lalor PF, Filer A, Buckley CD, Adams DH. Liver myofibroblasts regulate infiltration and positioning of lymphocytes in human liver. Gastroenterology 2009; 136:705-14. [PMID: 19010327 DOI: 10.1053/j.gastro.2008.10.020] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2008] [Revised: 10/01/2008] [Accepted: 10/09/2008] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The recruitment of lymphocytes to tissues via endothelium has been studied extensively but less is known about the signals that direct migration and positioning within tissues. Liver myofibroblasts associate with lymphocytes in hepatitis and are positioned below the sinusoidal endothelium, through which lymphocytes are recruited to the liver. We investigated whether activated human liver myofibroblasts (aLMF) affect the migration and accumulation of lymphocytes within the inflamed liver. METHODS The ability of human aLMF and hepatic stellate cells to promote lymphocyte chemotaxis, adhesion, and migration was studied in vitro. RESULTS When cultured in vitro, aLMF from diseased human liver and hepatic stellate cells from noninflamed liver secrete a distinct profile of cytokines comprising interleukin (IL)-6, IL-12, hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and the chemokines CCL2, CCL3, CCL5, CXCL8, CXCL9, and CXCL10. aLMF-conditioned media had chemotactic activity for lymphocytes, which partially was inhibited by pertussis toxin. IL-6, HGF, and VEGF all contributed to G-protein-coupled receptor-independent chemotaxis of lymphocytes. Lymphocytes adhered to aLMF via intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 and a proportion of adherent cells migrated through the fibroblast monolayer, mediated by IL-6, HGF, and VEGF. CONCLUSIONS Human aLMF support G-protein coupled receptor-dependent and -independent lymphocyte adhesion and migration and thereby regulate the recruitment and positioning of lymphocytes in chronic hepatitis.
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Affiliation(s)
- Andrew P Holt
- Liver Research Group, Institute of Biomedical Research, Division of Medicine, University of Birmingham, Birmingham, United Kingdom
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35
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Faleo G, Neto JS, Kohmoto J, Tomiyama K, Shimizu H, Takahashi T, Wang Y, Sugimoto R, Choi AMK, Stolz DB, Carrieri G, McCurry KR, Murase N, Nakao A. Carbon Monoxide Ameliorates Renal Cold Ischemia-Reperfusion Injury With an Upregulation of Vascular Endothelial Growth Factor by Activation of Hypoxia-Inducible Factor. Transplantation 2008; 85:1833-40. [DOI: 10.1097/tp.0b013e31817c6f63] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Bar J, Onn A. Combined anti-proliferative and anti-angiogenic strategies for cancer. Expert Opin Pharmacother 2008; 9:701-15. [PMID: 18345949 DOI: 10.1517/14656566.9.5.701] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND In recent years, anti-angiogenic treatments have been shown to synergize with traditional chemotherapeutic and radiotherapeutic regimens. Combining anti-angiogenesis with targeted anti-proliferative agents might also be synergistic. Several lines of evidence point to the validity of this approach, and preliminary results of ongoing and recent studies support it. OBJECTIVE The background and current status of anti-angiogenic and anti-proliferative treatments will be summarized, as well as the evidence supporting and antagonizing their combined use in the clinic. METHODS Relevant literature was reviewed using PubMed search, and recent major conference proceedings and other relevant data were searched through internet publications. RESULTS/CONCLUSION Combining anti-angiogenic and anti-proliferative treatments seems a promising approach, although not in all clinical circumstances.
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Affiliation(s)
- Jair Bar
- Chaim Sheba Medical Center, Division of Oncology, 52621 Tel Hashomer, Israel.
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Zhou Z, Bolontrade MF, Reddy K, Duan X, Guan H, Yu L, Hicklin DJ, Kleinerman ES. Suppression of Ewing's Sarcoma Tumor Growth, Tumor Vessel Formation, and Vasculogenesis Following Anti–Vascular Endothelial Growth Factor Receptor-2 Therapy. Clin Cancer Res 2007; 13:4867-73. [PMID: 17699866 DOI: 10.1158/1078-0432.ccr-07-0133] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE We previously showed that bone marrow cells participate in new tumor vessel formation in Ewing's sarcoma, and that vascular endothelial growth factor 165 (VEGF(165)) is critical to this process. The purpose of this study was to determine whether blocking VEGF receptor 2 (VEGFR-2) with DC101 antibody suppresses tumor growth, reduces tumor vessel formation, and inhibits the migration of bone marrow cells into the tumor. EXPERIMENTAL DESIGN An H-2 MHC-mismatched bone marrow transplant Ewing's sarcoma mouse model was used. Bone marrow cells from CB6F1 (MHC H-2(b/d)) mice were injected into irradiated BALB/cAnN mice (MHC H-2(d)). TC71 Ewing's sarcoma cells were s.c. injected 4 weeks after the bone marrow transplantation. Mice were then treated i.p. with DC101 antibody or immunoglobulin G (control) twice a week for 3 weeks starting 3 days after tumor cell injection. RESULTS DC101 antibody therapy significantly reduced tumor growth and tumor mean vessel density (P < 0.05) and increased tumor cell apoptosis. Decreased bone marrow cell migration into the tumor was also shown after DC101 therapy as assessed by the colocalization of H-2K(b) and CD31 using immunohistochemistry. DC101 inhibited the migration of both human and mouse vessel endothelial cells in vitro. CONCLUSION These results indicated that blocking VEGFR-2 with DC101 antibodies may be a useful therapeutic approach for treating patients with Ewing's sarcoma.
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Affiliation(s)
- Zhichao Zhou
- Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
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Chidlow JH, Shukla D, Grisham MB, Kevil CG. Pathogenic angiogenesis in IBD and experimental colitis: new ideas and therapeutic avenues. Am J Physiol Gastrointest Liver Physiol 2007; 293:G5-G18. [PMID: 17463183 DOI: 10.1152/ajpgi.00107.2007] [Citation(s) in RCA: 117] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Angiogenesis is now understood to play a major role in the pathology of chronic inflammatory diseases and is indicated to exacerbate disease pathology. Recent evidence shows that angiogenesis is crucial during inflammatory bowel disease (IBD) and in experimental models of colitis. Examination of the relationship between angiogenesis and inflammation in experimental colitis shows that initiating factors for these responses simultaneously increase as disease progresses and correlate in magnitude. Recent studies show that inhibition of the inflammatory response attenuates angiogenesis to a similar degree and, importantly, that inhibition of angiogenesis does the same to inflammation. Recent data provide evidence that differential regulation of the angiogenic mediators involved in IBD-associated chronic inflammation is the root of this pathological angiogenesis. Many factors are involved in this phenomenon, including growth factors/cytokines, chemokines, adhesion molecules, integrins, matrix-associated molecules, and signaling targets. These factors are produced by various vascular, inflammatory, and immune cell types that are involved in IBD pathology. Moreover, recent studies provide evidence that antiangiogenic therapy is a novel and effective approach for IBD treatment. Here we review the role of pathological angiogenesis during IBD and experimental colitis and discuss the therapeutic avenues this recent knowledge has revealed.
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Affiliation(s)
- John H Chidlow
- Department of Pathology, LSU Health Sciences Center-Shreveport, 1501 Kings Highway, Shreveport, LA 71130, USA
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Cursio R, Miele C, Filippa N, Van Obberghen E, Gugenheim J. Alterations in protein tyrosine kinase pathways in rat liver following normothermic ischemia-reperfusion. Transplant Proc 2007; 38:3362-5. [PMID: 17175272 DOI: 10.1016/j.transproceed.2006.10.165] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2006] [Indexed: 10/23/2022]
Abstract
The phosphoregulation of signal transduction pathways is a complex series of reactions that modulate the cellular response to ischemia-reperfusion (I-R). The aim of this study was to evaluate the effect of normothermic liver I-R on protein tyrosine phosphorylation, production of angiogenic growth factors, and activation of signal proteins in tyrosine kinase pathways. A segmental normothermic ischemia of the liver was induced in rats by occluding the blood vessels (including the bile duct) to the median and left lateral lobes for 120 minutes. Liver extracts from either ischemic or nonischemic lobes were prepared at 0, 1, 3, and 6 hours after reperfusion. Liver tyrosine phosphorylation of proteins was examined by Western blot analysis, whereas vascular endothelial growth factor (VEGF) mRNA was analyzed by Northern blot. In ischemic liver lobes, VEGF mRNA and total protein levels increased at 1 and 3 hours after reperfusion. Tyrosine phosphorylation of the VEGF receptor Flk-1 and the platelet-derived growth factor receptor (PDGF-R) was increased only at 1 hour after reperfusion, while c-Src tyrosine phosphorylation remained increased at 3 hours and remained up to 6 hours after reperfusion. In conclusion, 1-R led to alterations in protein tyrosine phosphorylation and increased expression of VEGF in rat liver.
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Affiliation(s)
- R Cursio
- Laboratoire de Recherches Chirurgicales, IFR 50, Faculté de Médecine, Université de Nice Sophia Antipolis, Nice, France.
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Vinores SA, Xiao WH, Shen J, Campochiaro PA. TNF-alpha is critical for ischemia-induced leukostasis, but not retinal neovascularization nor VEGF-induced leakage. J Neuroimmunol 2006; 182:73-9. [PMID: 17107717 PMCID: PMC1800833 DOI: 10.1016/j.jneuroim.2006.09.015] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2006] [Revised: 09/18/2006] [Accepted: 09/29/2006] [Indexed: 01/18/2023]
Abstract
Vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-alpha) show significant overlap with regard to their effects in the eye. It has been postulated that VEGF-induced leukostasis, breakdown of the blood-retinal barrier, and ischemia-induced retinal neovascularization may be mediated, at least in part, through TNF-alpha. In this study, we used mice deficient in TNF-alpha to test our hypothesis. Compared to wild type mice, TNF-alpha-deficient mice showed an 80% reduction in leukocyte accumulation in retinal vessels after intravitreous injection of VEGF, and 100% reductions after intravitreous injections of interleukin-1beta (IL-1beta) or platelet-activating factor (PAF). The increase in retinal vascular permeability induced by injection of PAF was significantly reduced in mice lacking TNF-alpha, but VEGF- and IL-1beta-induced leakage was unaffected. Compared to wild type mice with oxygen-induced ischemic retinopathy, TNF-alpha-deficient mice with ischemic retinopathy showed significantly reduced leukostasis and mild reduction in vascular leakage, but no significant difference in retinal neovascularization. These data suggest that TNF-alpha mediates VEGF-, IL-1beta-, and PAF-induced leukostasis and vascular leakage mediated by PAF, but not leakage caused by VEGF or IL-1beta. Ischemia-induced retinal neovascularization, which has previously been shown to require VEGF, does not require TNF-alpha and is unaffected by attenuation of leukostasis.
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Affiliation(s)
- Stanley A Vinores
- The Department of Ophthalmology, The Johns Hopkins University School of Medicine, Maumenee 825, 600 N. Wolfe Street Baltimore, Maryland 21287-9289, United States.
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Eskens FALM, Verweij J. The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review. Eur J Cancer 2006; 42:3127-39. [PMID: 17098419 DOI: 10.1016/j.ejca.2006.09.015] [Citation(s) in RCA: 260] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2006] [Accepted: 09/27/2006] [Indexed: 01/09/2023]
Abstract
Clinical experience with vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors is rapidly increasing, and some compounds have already been approved for regular anticancer treatment. Apart from their activity, much attention has been focussed on the clinical toxicity profile of these compounds. This review describes the most frequently occurring side-effects of both antibodies and tyrosine kinase inhibitors and discusses some of the underlying mechanisms. Some practical guidelines for treatment of the side-effects are given.
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Affiliation(s)
- Ferry A L M Eskens
- Erasmus University Medical Center, Department of Medical Oncology PO Box 2040, 3000 CA Rotterdam, Netherlands.
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Tsuchihashi S, Kaldas F, Chida N, Sudo Y, Tamura K, Zhai Y, Qiao B, Busuttil RW, Kupiec-Weglinski JW. FK330, a novel inducible nitric oxide synthase inhibitor, prevents ischemia and reperfusion injury in rat liver transplantation. Am J Transplant 2006; 6:2013-22. [PMID: 16796718 DOI: 10.1111/j.1600-6143.2006.01435.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nitric oxide (NO), produced via inducible NO synthase (iNOS), is implicated in the pathophysiology of liver ischemia/reperfusion injury (IRI). We examined the effects of a novel iNOS inhibitor, FK330 (FR260330), in well-defined rat liver IRI models. In a model of liver cold ischemia followed by ex vivo reperfusion, treatment with FK330 improved portal venous flow, increased bile production and decreased hepatocellular damage. FK330 prevented IRI in rat model of 40-h cold ischemia followed by syngeneic orthotopic liver transplantation (OLT), as evidenced by: (1) increased OLT survival (from 20% to 80%); (2) decreased hepatocellular damage (serum glutamic oxaloacetic transaminase/glutamic pyruvic transaminase levels); (3) improved histological features of IRI; (4) reduced intrahepatic leukocyte infiltration, as evidenced by decreased expression of P-selectin/intracellular adhesion molecule 1, ED-1/CD3 cells and neutrophils; (5) depressed lymphocyte activation, as evidenced by expression of pro-inflammatory cytokine (TNF-alpha, IL-1beta, IL-6) and chemokine (IP-10, MCP-1, MIP-2) programs; (6) prevented hepatic apoptosis and down-regulated Bax/Bcl-2 ratio. Thus, by modulating leukocyte trafficking and cell activation patterns, treatment of rats with FK330, a specific iNOS inhibitor, prevented liver IRI. These results provide the rationale for novel therapeutic approaches to maximize organ donor pool through the safer use of liver grafts despite prolonged periods of cold ischemia.
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Affiliation(s)
- S Tsuchihashi
- The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
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Pak M, Lopez MA, Gabayan V, Ganz T, Rivera S. Suppression of hepcidin during anemia requires erythropoietic activity. Blood 2006; 108:3730-5. [PMID: 16882706 PMCID: PMC1895477 DOI: 10.1182/blood-2006-06-028787] [Citation(s) in RCA: 375] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepcidin, the principal iron regulatory hormone, regulates the absorption of iron from the diet and the mobilization of iron from stores. Previous studies indicated that hepcidin is suppressed during anemia, a response that would appropriately increase the absorption of iron and its release from stores. Indeed, in the mouse model, hepcidin-1 was suppressed after phlebotomy or erythropoietin administration but the suppression was reversed by inhibitors of erythropoiesis. The suppression of hepcidin necessary to match iron supply to erythropoietic demand thus requires increased erythropoiesis and is not directly mediated by anemia, tissue hypoxia, or erythropoietin.
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Affiliation(s)
- Mihwa Pak
- Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at the University of California (UCLA), Los Angeles, USA
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N/A, 李 柏. N/A. Shijie Huaren Xiaohua Zazhi 2006; 14:1621-1626. [DOI: 10.11569/wcjd.v14.i16.1621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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