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Vigneswaran J, Keskey RC, Morgan RB, Alverdy JC, Alpert L, Chang E, Weichselbaum R, Zaborina O, Shogan BD. Western Diet-induced Transcriptional Changes in Anastomotic Tissue Is Associated With Early Local Recurrence in a Mouse Model of Colorectal Surgery. Ann Surg 2023; 278:954-960. [PMID: 37522222 PMCID: PMC10775465 DOI: 10.1097/sla.0000000000006052] [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] [Indexed: 08/01/2023]
Abstract
OBJECTIVE To determine the timeframe and associated changes in the microenvironment that promote the development of a diet-induced local-regional recurrence in a mouse model of colorectal surgery. BACKGROUND Postoperative recurrence and metastasis occur in up to 30% of patients undergoing attempted resection for colorectal cancer (CRC). The underlying mechanisms that drive the development of postoperative recurrences are poorly understood. Preclinical studies have demonstrated a diet and microbial-driven pathogenesis of local-regional recurrence, yet the precise mechanisms remain undefined. METHODS BALB/C mice were fed a western diet (WD) or standard diet (SD), underwent a colon resection and anastomosis, given an Enterococcus faecalis enema on postoperative day (POD) 1, and subjected to a CT26 cancer cell enema (mimicking shed cancer cells) on POD2. Mice were sacrificed between POD3 and POD7 and cancer cell migration was tracked. Dynamic changes in gene expression of anastomotic tissue that were associated with cancer cell migration was assessed. RESULTS Tumor cells were identified in mice fed either a SD or WD in both anastomotic and lymphatic tissue as early as on POD3. Histology demonstrated that these tumor cells were viable and replicating. In WD-fed mice, the number of tumor cells increased over the early perioperative period and was significantly higher than in mice fed a SD. Microarray analysis of anastomotic tissue found that WD-fed mice had 11 dysregulated genes associated with tumorigenesis. CONCLUSIONS A WD promotes cancer cells to permeate a healing anastomosis and migrate into anastomotic and lymphatic tissue forming viable tumor nodules. These data offer a novel recurrence pathogenesis by which the intestinal microenvironment promotes a CRC local-regional recurrence.
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Affiliation(s)
- Janani Vigneswaran
- The University of Chicago Medicine, Department of Surgery, Chicago, Illinois, United States
| | - Robert C. Keskey
- The University of Chicago Medicine, Department of Surgery, Chicago, Illinois, United States
| | - Ryan B. Morgan
- The University of Chicago Medicine, Department of Surgery, Chicago, Illinois, United States
| | - John C. Alverdy
- The University of Chicago Medicine, Department of Surgery, Chicago, Illinois, United States
| | - Lindsay Alpert
- The University of Chicago Medicine, Department of Pathology, Chicago, Illinois, United States
| | - Eugene Chang
- The University of Chicago Medicine, Department of Medicine, Chicago, Illinois, United States
| | - Ralph Weichselbaum
- The University of Chicago Medicine, Department of Radiation and Cellular Oncology, Chicago, Illinois, United States
| | - Olga Zaborina
- The University of Chicago Medicine, Department of Surgery, Chicago, Illinois, United States
| | - Benjamin D. Shogan
- The University of Chicago Medicine, Department of Surgery, Chicago, Illinois, United States
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2
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Erliana UD, Fly AD. The Function and Alteration of Immunological Properties in Human Milk of Obese Mothers. Nutrients 2019; 11:nu11061284. [PMID: 31174304 PMCID: PMC6627488 DOI: 10.3390/nu11061284] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 05/28/2019] [Accepted: 06/01/2019] [Indexed: 01/08/2023] Open
Abstract
Maternal obesity is associated with metabolic changes in mothers and higher risk of obesity in the offspring. Obesity in breastfeeding mothers appears to influence human milk production as well as the quality of human milk. Maternal obesity is associated with alteration of immunological factors concentrations in the human milk, such as C-reactive protein (CRP), leptin, IL-6, insulin, TNF-Alpha, ghrelin, adiponectin, and obestatin. Human milk is considered a first choice for infant nutrition due to the complete profile of macro nutrients, micro nutrients, and immunological properties. It is essential to understand how maternal obesity influences immunological properties of human milk because alterations could impact the nutrition status and health of the infant. This review summarizes the literature regarding the impact of maternal obesity on the concentration of particular immunological properties in the human milk.
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Affiliation(s)
- Ummu D Erliana
- Indiana University Bloomington School of Public Health, Bloomington, IN 47405, USA.
| | - Alyce D Fly
- Indiana University Bloomington School of Public Health, Bloomington, IN 47405, USA.
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3
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Ming YC, Chao HC, Chu SM, Luo CC. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) protected intestinal ischemia-reperfusion injury through JNK and p38/MAPK-dependent pathway for anti-apoptosis. Pediatr Neonatol 2019; 60:332-336. [PMID: 30455099 DOI: 10.1016/j.pedneo.2018.08.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Accepted: 08/10/2018] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Heparin-Binding Epidermal Growth Factor-Like Growth Factor (HB-EGF) is a potent cytoprotective factor in various body systems, including gastrointestinal tract. In this study, we intended to examine whether HB-EGF exerts its protective effects through MAPK dependent anti-apoptosis after intestinal I/R injury. METHODS We randomly divided 30 laboratory 30 rats into 5 groups: (A) normal control group, (B) ischemia group with normal saline, (C) I/R group with normal saline, (D) ischemia group with HB-EGF (400 ug/kg), and (E) I/R group with HB-EGF (400 ug/kg). With Western blotting study, we determined JNK and p38/MAPK pathway and caspase-3 activity protein levels using Western analyses. RESULTS The JNK phosphorylation protein levels increased after intestinal ischemia or intestinal reperfusion phase, and HB-EGF pre-treatment was significantly decreased in JNK phosphorylation protein levels (p < 0.01). We found that p38 protein levels was increased after intestinal reperfusion phase, and that HB-EGF pre-treatment significantly decreased p38 protein levels (p < 0.01). The expression protein level of caspase 3 was increased after intestinal ischemia or intestinal reperfusion phase. HB-EGF pre-treatment significantly decreased Caspase 3 proteins. (p < 0.01). CONCLUSION Our study revealed that pre-treatment of HB-EGF decreased the amount of activity of JNK and p38/MAPK pathway and caspase-3 protein after intestinal I/R injury. These results may further support that the cytoprotective of HB-EGF after I/R injury could be through anti-apoptotic effect of activity of JNK and p38/MAPK pathway.
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Affiliation(s)
- Yung-Ching Ming
- Division of Pediatric Surgery, Department of Pediatrics, Chang Gung Children's Medical Center, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Hsun-Chin Chao
- Division of Pediatric Gastroenterology, Department of Pediatrics, Chang Gung Children's Medical Center, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Shih-Ming Chu
- Division of Neonatology, Department of Pediatrics, Chang Gung Children's Medical Center, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chih-Cheng Luo
- Division of Pediatric Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
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Wei Y, Gong L, Fu W, Xu S, Wang Z, Zhang J, Ning E, Chang H, Wang H, Gao Y. Unexpected regulation pattern of the IKKβ/NF‐κB/MuRF1 pathway with remarkable muscle plasticity in the Daurian ground squirrel (
Spermophilus dauricus
). J Cell Physiol 2018; 233:8711-8722. [DOI: 10.1002/jcp.26751] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 04/16/2018] [Indexed: 12/19/2022]
Affiliation(s)
- Yanhong Wei
- Key Laboratory of Resource Biology and Biotechnology in Western ChinaCollege of Life SciencesNorthwest University, Ministry of EducationXi'anChina
- School of Basic Medical SciencesNingxia Medical UniversityYinchuanChina
| | - Lingchen Gong
- Key Laboratory of Resource Biology and Biotechnology in Western ChinaCollege of Life SciencesNorthwest University, Ministry of EducationXi'anChina
| | - Weiwei Fu
- Key Laboratory of Resource Biology and Biotechnology in Western ChinaCollege of Life SciencesNorthwest University, Ministry of EducationXi'anChina
| | - Shenhui Xu
- Key Laboratory of Resource Biology and Biotechnology in Western ChinaCollege of Life SciencesNorthwest University, Ministry of EducationXi'anChina
| | - Zhe Wang
- Key Laboratory of Resource Biology and Biotechnology in Western ChinaCollege of Life SciencesNorthwest University, Ministry of EducationXi'anChina
| | - Jie Zhang
- Key Laboratory of Resource Biology and Biotechnology in Western ChinaCollege of Life SciencesNorthwest University, Ministry of EducationXi'anChina
| | - Er Ning
- Key Laboratory of Resource Biology and Biotechnology in Western ChinaCollege of Life SciencesNorthwest University, Ministry of EducationXi'anChina
| | - Hui Chang
- Key Laboratory of Resource Biology and Biotechnology in Western ChinaCollege of Life SciencesNorthwest University, Ministry of EducationXi'anChina
| | - Huiping Wang
- Key Laboratory of Resource Biology and Biotechnology in Western ChinaCollege of Life SciencesNorthwest University, Ministry of EducationXi'anChina
| | - Yunfang Gao
- Key Laboratory of Resource Biology and Biotechnology in Western ChinaCollege of Life SciencesNorthwest University, Ministry of EducationXi'anChina
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Imaizumi M, Li-Jessen NY, Sato Y, Yang DT, Thibeault SL. Retention of Human-Induced Pluripotent Stem Cells (hiPS) With Injectable HA Hydrogels for Vocal Fold Engineering. Ann Otol Rhinol Laryngol 2017; 126:304-314. [DOI: 10.1177/0003489417691296] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Objective: One prospective treatment option for vocal fold scarring is regeneration with an engineered scaffold containing induced pluripotent stem cells (iPS). In the present study, we investigated the feasibility of utilizing an injectable hyaluronic acid (HA) scaffold encapsulated with human-iPS cell (hiPS) for regeneration of vocal folds. Methods: Thirty athymic nude rats underwent unilateral vocal fold injury. Contralateral vocal folds served as uninjured controls. Hyaluronic acid hydrogel scaffold, HA hydrogel scaffold containing hiPS, and HA hydrogel scaffold containing hiPS with epidermal growth factor (EGF) were injected in both vocal folds immediately after surgery. One and 2 weeks after injection, larynges were excised for histology, immunohistochemistry, and fluorescence in situ hybridization (FISH). Results: Presence of HA hydrogel was confirmed in vocal folds 1 and 2 weeks post injection. The FISH analysis confirmed the presence and viability of hiPS in the injected vocal folds. Histological results demonstrated that vocal folds injected with HA hydrogel scaffold containing EGF demonstrated less fibrosis than those with HA hydrogel only. Conclusions: Human-iPS survived in injured rat vocal folds. The HA hydrogel with hiPS and EGF ameliorated the fibrotic response. Additional work is necessary to optimize hiPS differentiation and further confirm the safety of hiPS for clinical applications.
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Affiliation(s)
- Mitsuyoshi Imaizumi
- Department of Otolaryngology, School of Medicine, Fukushima Medical University, Fukushima City, Japan
| | - Nicole Y.K. Li-Jessen
- School of Communication Sciences and Disorders, McGill University, Montreal, QC, Canada
| | - Yuka Sato
- Department of Otolaryngology, School of Medicine, Fukushima Medical University, Fukushima City, Japan
| | - David T. Yang
- Department of Pathology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Susan L. Thibeault
- Division of Otolaryngology-Head and Neck Surgery, University of Wisconsin-Madison, Madison, Wisconsin, USA
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Arshid S, Tahir M, Fontes B, Montero EFS, Castro MS, Sidoli S, Schwämmle V, Roepstorff P, Fontes W. Neutrophil proteomic analysis reveals the participation of antioxidant enzymes, motility and ribosomal proteins in the prevention of ischemic effects by preconditioning. J Proteomics 2016; 151:162-173. [PMID: 27208787 DOI: 10.1016/j.jprot.2016.05.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 04/05/2016] [Accepted: 05/14/2016] [Indexed: 12/13/2022]
Abstract
Intestinal ischemia and reperfusion injury are widely used models, which result into tissue injury and multiple organ failure also observed after trauma and surgery. Ischemic preconditioning (IPC) preceding ischemia and reperfusion (IR) was shown to attenuate this injury and has a potential therapeutic application; however the exact underlying mechanism is not clear. Neutrophils play an important role in the mechanism of injuries caused by ischemia and reperfusion while IPC led to a decrease in neutrophil stimulation and activation. The effect of preconditioning on the neutrophil proteome is unclear. Proteomic analysis has been ratified as an appropriate tool for studying complex systems. In order to evaluate the effect of IPC preceding 45min of ischemia on the proteome of neutrophils we used Wistar rats divided in four experimental groups: Control, sham laparotomy, intestinal ischemia reperfusion and ischemic preconditioning. After neutrophil separation, proteins were extracted, trypsin digested and the resulting peptides were iTRAQ labeled followed by HILIC fractionation and nLC-MS/MS analysis. After database searches, normalization and statistical analysis our proteomic analysis resulted in the identification of 2437 protein groups that were assigned to five different clusters based on the relative abundance profiles among the experimental groups. The clustering followed by statistical analysis led to the identification of significantly up and downregulated proteins in IR and IPC. Cluster based KEGG pathways analysis revealed up- regulation of actin cytoskeleton, metabolism, Fc gamma R mediated phagocytosis, chemokine signaling, focal adhesion and leukocyte transendothelial migration whereas downregulation in ribosome, spliceosome, RNA transport, protein processing in endoplasmic reticulum and proteasome, after intestinal ischemic preconditioning. Furthermore, enzyme prediction analysis revealed the regulation of some important antioxidant enzymes and having their role in reactive oxygen species production. To our knowledge, this work describes the most comprehensive and detailed quantitative proteomic study of the neutrophil showing the beneficial role of ischemic preconditioning and its effects on the neutrophil proteome. This data will be helpful to understand the effect of underlying protective mechanisms modulating the role of PMNs after IPC and provide a trustworthy basis for future studies. BIOLOGICAL SIGNIFICANCE Preconditioning is a relevant strategy to overcome clinical implications from ischemia and reperfusion. Such implications have the neutrophil as a major player. Although many publications describe specific biochemical and physiological roles of the neutrophil in such conditions, there is no report of a proteomic study providing a broader view of this scenario. Here we describe a group of proteins significantly regulated by ischemia and reperfusion being such regulation prevented by preconditioning. Such finding may provide relevant information for a deeper understanding of the mechanisms involved, as well as serve as basis for future biomarker or drug target assays.
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Affiliation(s)
- S Arshid
- Laboratory of Biochemistry and Protein Chemistry, Department of Cell Biology, Institute of Biology, University of Brasilia, Brasília, DF, Brazil; Laboratory of Surgical Physiopathology (LIM-62), Faculty of Medicine, University of São Paulo, Brazil
| | - M Tahir
- Laboratory of Biochemistry and Protein Chemistry, Department of Cell Biology, Institute of Biology, University of Brasilia, Brasília, DF, Brazil; Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - B Fontes
- Laboratory of Surgical Physiopathology (LIM-62), Faculty of Medicine, University of São Paulo, Brazil
| | - E F S Montero
- Laboratory of Surgical Physiopathology (LIM-62), Faculty of Medicine, University of São Paulo, Brazil
| | - M S Castro
- Laboratory of Biochemistry and Protein Chemistry, Department of Cell Biology, Institute of Biology, University of Brasilia, Brasília, DF, Brazil
| | - S Sidoli
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark; Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - V Schwämmle
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - P Roepstorff
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
| | - W Fontes
- Laboratory of Biochemistry and Protein Chemistry, Department of Cell Biology, Institute of Biology, University of Brasilia, Brasília, DF, Brazil.
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Wei J, Besner GE. M1 to M2 macrophage polarization in heparin-binding epidermal growth factor-like growth factor therapy for necrotizing enterocolitis. J Surg Res 2015; 197:126-38. [PMID: 25913486 DOI: 10.1016/j.jss.2015.03.023] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Revised: 03/01/2015] [Accepted: 03/12/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Macrophages can be polarized into proinflammatory (M1) and anti-inflammatory (M2) subtypes. However, whether macrophage polarization plays a role in necrotizing enterocolitis (NEC) remains unknown. MATERIALS AND METHODS Macrophages were derived from the THP-1 human monocyte cell line. Apoptosis of human fetal small intestinal epithelial FHs-74 cells was determined by Annexin V/propidium iodide flow cytometry and by Western blotting to detect cleaved caspase-3. The effect of heparin-binding epidermal growth factor-like growth factor (HB-EGF) on macrophage polarization was determined by flow cytometry with M1/M2 markers and real time polymerase chain reaction. In vivo, experimental NEC was induced in mouse pups by repeated exposure to hypoxia, hypothermia, and hypertonic feedings. Intestinal histologic sections were subjected to immunohistochemical staining for the detection of M1 and M2 macrophages. RESULTS In vitro, FHs-74 cell apoptosis was increased after coculture with macrophages and lipopolysaccharide (LPS). This apoptosis was increased by exposure to M1-conditioned medium and suppressed by exposure to M2-conditioned medium. HB-EGF significantly decreased LPS-induced M1 polarization and promoted M2 polarization via signal transducers and activators of transcription 3 activation. Addition of HB-EGF to LPS-stimulated macrophages suppressed the proapoptotic effects of the macrophages on FHs-74 cells. In vivo, we found enhanced intestinal macrophage infiltration in pups subjected to NEC, most of which were M1 macrophages. HB-EGF treatment of pups subjected to experimental NEC significantly reduced M1 and increased M2 polarization and protected the intestines from NEC. CONCLUSIONS M1 macrophages promote NEC by increasing intestinal epithelial apoptosis. HB-EGF protects the intestines from NEC by preventing M1 and promoting M2 polarization.
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Affiliation(s)
- Jia Wei
- The Research Institute at Nationwide Children's Hospital, Center for Perinatal Research, Department of Pediatric Surgery, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, Ohio
| | - Gail E Besner
- The Research Institute at Nationwide Children's Hospital, Center for Perinatal Research, Department of Pediatric Surgery, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, Ohio.
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8
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Caglar M, Karaguzel G, Gokhan-Ocak G, Yasar D, Berker-Karauzum S, Gelen T, Celik FN, Demir N, Melikoglu M. Multidirectional and simultaneous evaluation of gastroschisis-related intestinal damage in chick embryos. J Pediatr Surg 2014; 49:1577-84. [PMID: 25475797 DOI: 10.1016/j.jpedsurg.2014.06.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Revised: 06/05/2014] [Accepted: 06/09/2014] [Indexed: 10/24/2022]
Abstract
PURPOSE In a chick model of gastroschisis, we aimed to investigate the morphological/cellular, molecular, and ultrastructural changes taking place in gastroschisis-related intestinal damage (GRID). METHODS 13-Day fertilized eggs were divided into two groups. CONTROL GROUP chorio-amnio-allontoic membranes opened and abdominal wall exposed. Gastroschisis group: an anterior abdominal wall defect created after opening membranes. Embryos from both groups were surgically removed on post-fertilization day 19. Intestinal samples were obtained for histopathology, immunohistochemistry, molecular biology, and electron microscopy. RESULTS The histopathological grade of intestinal damage which primarily involved mucosal structures was significantly higher in the gastroschisis group when compared to the control group (p<0.001). Immunohistochemically, E-cadherin and synaptophysin immunoreactivity in the gastroschisis group was significantly lower than control group (p<0.05 and p<0.01, respectively), whereas there was no significant difference in laminin and type-4 collagen immunoreactivity between the groups (p>0.05). Molecular analyses indicated a significant decrease in NFκB and IκB expression in the gastroschisis group (p<0.05 and p=0.001, respectively). Electron microscopy showed that the gastroschisis group had considerable ultrastructural damage, manifested by apoptosis in all layers. CONCLUSIONS GRID affected all layers but was more prominent in mucosa. The damage may depend on E-cadherin and synaptophysin downregulation. Increased apoptotic activity, associated with decreased NFκB and IκB expression, may be an important component of this multifactorial damaging process.
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Affiliation(s)
- Muge Caglar
- Akdeniz University School of Medicine, Department of Pediatric Surgery, Antalya, Turkey
| | - Gungor Karaguzel
- Akdeniz University School of Medicine, Department of Pediatric Surgery, Antalya, Turkey.
| | - Guzide Gokhan-Ocak
- Akdeniz University School of Medicine, Department of Pathology, Antalya, Turkey
| | - Duygu Yasar
- Akdeniz University School of Medicine, Department of Medical Biology and Genetics, Antalya, Turkey
| | - Sibel Berker-Karauzum
- Akdeniz University School of Medicine, Department of Medical Biology and Genetics, Antalya, Turkey
| | - Tekinalp Gelen
- Akdeniz University School of Medicine, Department of Pathology, Antalya, Turkey
| | - Fatma Nur Celik
- Akdeniz University School of Medicine, Department of Histology and Embryology, Antalya, Turkey
| | - Necdet Demir
- Akdeniz University School of Medicine, Department of Histology and Embryology, Antalya, Turkey
| | - Mustafa Melikoglu
- Akdeniz University School of Medicine, Department of Pediatric Surgery, Antalya, Turkey
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Saurim R, Koike MK, Bonservizi WGS, Felix GAA, Silva SM, Taha MO, Montero EFS. Cardiac effect of ischemic preconditioning and heparin following intestinal ischemia and reperfusion in rats. Transplant Proc 2014; 46:1852-6. [PMID: 25131053 DOI: 10.1016/j.transproceed.2014.05.055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
To study the role of heparin and ischemic preconditioning (IPC) in cardiac injury after intestinal ischemia (I) and reperfusion (R), 54 rats underwent 60 minutes of I, which was produced by occlusion of the superior mesenteric artery, and/or 120 minutes of R. The IPC group had the I procedure stimulation for 5 minutes and R for 10 minutes. The control group was subjected to sham surgery only, and the other groups were injected with saline solution (SS; 0.1 mL) or heparin (100 IU/kg) via the inferior cava vein 5 minutes before I and 5 minutes before R and 55 minutes after the R begins in I-R groups. In all animals, cardiac samples were stained with hematoxylin and eosin for optical microscopy analysis, and other sample was processed for lipid peroxidation determination. In I-R groups, both heparin and IPC showed significant protection compared to the SS group; conversely, in animals subjected only to I, no protection was observed. Moreover, when heparin was associated with IPC, I-R protection was compromised and the ischemic injury increased. Data showed that IPC and heparin attenuated cardiac dysfunction caused by intestinal I and I-R, but when used in association did not show beneficial effects.
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Affiliation(s)
- R Saurim
- Escola Paulista de Medicina, Federal University of São Paulo, Brazil
| | - M K Koike
- Laboratory of Clinical Emergencies (LIM 51), Brazil
| | - W G S Bonservizi
- Escola Paulista de Medicina, Federal University of São Paulo, Brazil
| | - G A A Felix
- Escola Paulista de Medicina, Federal University of São Paulo, Brazil
| | - S M Silva
- Escola Paulista de Medicina, Federal University of São Paulo, Brazil
| | - M O Taha
- Operative Technique and Experimental Surgery Division, Escola Paulista de Medicina, Federal University of São Paulo, Brazil
| | - E F S Montero
- Operative Technique and Experimental Surgery Division, Escola Paulista de Medicina, Federal University of São Paulo, Brazil; Laboratory of Surgical Physiopathology (LIM 62), Department of Surgery, University of São Paulo, Federal University of São Paulo, Brazil.
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Yang J, Su Y, Zhou Y, Besner GE. Heparin-binding EGF-like growth factor (HB-EGF) therapy for intestinal injury: Application and future prospects. ACTA ACUST UNITED AC 2013; 21:95-104. [PMID: 24345808 DOI: 10.1016/j.pathophys.2013.11.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Throughout the past 20 years, we have been investigating the potential therapeutic roles of heparin-binding EGF-like growth factor (HB-EGF), a member of the epidermal growth factor family, in various models of intestinal injury including necrotizing enterocolitis (NEC), intestinal ischemia/reperfusion (I/R) injury, and hemorrhagic shock and resuscitation (HS/R). Our studies have demonstrated that HB-EGF acts as an effective mitogen, a restitution-inducing reagent, a cellular trophic factor, an anti-apoptotic protein and a vasodilator, via its effects on various cell types in the intestine. In the current paper, we have reviewed the application and therapeutic effects of HB-EGF in three classic animal models of intestinal injury, with particular emphasis on its protection of the intestines from NEC. Additionally, we have summarized the protective functions of HB-EGF on various target cells in the intestine. Lastly, we have provided a brief discussion focusing on the future development of HB-EGF clinical applications for the treatment of various forms of intestinal injury including NEC.
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Affiliation(s)
- Jixin Yang
- The Research Institute at Nationwide Children's Hospital, Center for Perinatal Research, Department of Pediatric Surgery, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH 43205, USA.
| | - Yanwei Su
- The Research Institute at Nationwide Children's Hospital, Center for Perinatal Research, Department of Pediatric Surgery, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH 43205, USA.
| | - Yu Zhou
- The Research Institute at Nationwide Children's Hospital, Center for Perinatal Research, Department of Pediatric Surgery, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH 43205, USA.
| | - Gail E Besner
- The Research Institute at Nationwide Children's Hospital, Center for Perinatal Research, Department of Pediatric Surgery, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH 43205, USA.
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Su Y, Yang J, Besner GE. HB-EGF promotes intestinal restitution by affecting integrin-extracellular matrix interactions and intercellular adhesions. Growth Factors 2013; 31:39-55. [PMID: 23305395 DOI: 10.3109/08977194.2012.755966] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Restitution is a critical form of intestinal epithelial cell (IEC) healing. We have previously shown that heparin-binding epidermal-like growth factor (HB-EGF) is necessary for IEC restitution; however, the mechanisms by which HB-EGF promotes restitution remain poorly understood. This study was designed to investigate whether HB-EGF promotes intestinal restitution by affecting integrin-extracellular matrix (ECM) interactions and intercellular adhesions. The effect of HB-EGF administration was examined in a murine necrotizing enterocolitis (NEC) model in vivo and an IEC line scrape-wound healing model in vitro. We evaluated the effect of HB-EGF on the expression of integrins, E-cadherin/β-catenin, and integrin α5β1-dependent cell-ECM interactions. We found that HB-EGF promoted intestinal restitution and the expression of integrin α5β1. HB-EGF promoted integrin α5β1-dependent cell adhesion and spreading. In addition, HB-EGF decreased the expression E-cadherin/β-catenin, via the activation of v-erb-b2 erythroblastic leukemia viral oncogene homolog (ErbB-1). We conclude that HB-EGF promotes intestinal restitution by affecting integrin-ECM interactions and intercellular adhesions.
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Affiliation(s)
- Yanwei Su
- Department of Pediatric Surgery, Nationwide Children's Hospital, The Research Institute at Nationwide Children's Hospital, Center for Perinatal Research, Ohio State University College of Medicine, Columbus, Ohio 43205, USA
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Zhang HY, Wang F, Feng JX. Intestinal microcirculatory dysfunction and neonatal necrotizing enterocolitis. Chin Med J (Engl) 2013; 126:1771-1778. [PMID: 23652066 DOI: 10.3760/cma.j.issn.0366-6999.20121741] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/14/2023] Open
Abstract
OBJECTIVE Based on the observation that coagulation necrosis occurs in the majority of neonatal necrotizing enterocolitis (NEC) patients, it is clear that intestinal ischemia is a contributing factor to the pathogenesis of NEC. However, the published studies regarding the role of intestinal ischemia in NEC are controversial. The aim of this paper is to review the current studies regarding intestinal microcirculatory dysfunction and NEC, and try to elucidate the exact role of intestinal microcirculatory dysfunction in NEC. DATA SOURCES The studies cited in this review were mainly obtained from articles listed in Medline and PubMed. The search terms used were "intestinal microcirculatory dysfunction" and "neonatal necrotizing enterocolitis". STUDY SELECTION Mainly original milestone articles and critical reviews written by major pioneer investigators in the field were selected. RESULTS Immature regulatory control of mesentery circulation makes the neonatal intestinal microvasculature vulnerable. When neonates are subjected to stress, endothelial cell dysfunction occurs and results in vasoconstriction of arterioles, inflammatory cell infiltration and activation in venules, and endothelial barrier disruption in capillaries. The compromised vasculature increases circulation resistance and therefore decreases intestinal perfusion, and may eventually progress to intestinal necrosis. CONCLUSION Intestinal ischemia plays an important role through the whole course of NEC. New therapeutic agents targeting intestinal ischemia, like HB-EGF, are promising therapeutic agents for the treatment of NEC.
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Affiliation(s)
- Hong-yi Zhang
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College and Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
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Carvajal JA, Delpiano AM, Cuello MA, Poblete JA. Mechanical stretch increases brain natriuretic peptide production and secretion in the human fetal membranes. Reprod Sci 2012; 20:597-604. [PMID: 23012317 DOI: 10.1177/1933719112459219] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Brain natriuretic peptide (BNP) is synthesized by human fetal membranes, both the amnion and chorion. This locally produced BNP inhibits the contraction of the human myometrium, contributing to the maintenance of myometrial quiescence during pregnancy. We tested the hypothesis that BNP production is increased by fetal membrane stretching, which is predicted to occur in the expanding uterus, and inhibited by epidermal growth factor (EGF), whose production in the fetal membranes increases in late pregnancy. Term fetal membranes were obtained during elective cesarean delivery before labor. Sections of membranes were placed in an isolated chamber containing DMEM: F12 medium (37°C) and stretched with a 35 g weight. Medium and tissue samples were collected at 0, 3, 6, 18, and 24 hours for measurement of messenger RNA (mRNA) and BNP levels in the presence/absence of EGF (2 × 10(-9 )mol/L). Inducible nitric oxide synthase (iNOS) and β-actin were also evaluated to discard a nonspecific effect of mechanical stretch on protein expression. We found that amnion and chorion stretching increased the BNP mRNA (reverse transcription-polymerase chain reaction [RT-PCR]) and protein (radioimmunosorbent assay [RIA]) levels from 18 hours onward. The effect of stretching was inhibited by EGF (2 × 10(-9) mol/L). Stretch did not increase iNOS or β-actin protein levels. We concluded that chorion and amnion stretching may increase BNP expression in the fetal membranes during pregnancy, while increasing biological activity of EGF may decrease BNP production in the chorion and amnion late in pregnancy. We postulate BNP is an important regulator of myometrial contractility during pregnancy, and its production is modulated by both stretch and progressive increase in EGF levels during pregnancy.
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Affiliation(s)
- Jorge A Carvajal
- Unidad de Medicina Materno Fetal, División de Obstetricia y Ginecología, Pontificia Universidad Católica de Chile, Santiago, Chile.
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Yang J, Watkins D, Chen CL, Bhushan B, Zhou Y, Besner GE. Heparin-binding epidermal growth factor-like growth factor and mesenchymal stem cells act synergistically to prevent experimental necrotizing enterocolitis. J Am Coll Surg 2012; 215:534-45. [PMID: 22819639 DOI: 10.1016/j.jamcollsurg.2012.05.037] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Revised: 05/30/2012] [Accepted: 05/30/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND We have shown that administration of heparin-binding EGF (epidermal growth factor)-like growth factor (HB-EGF) protects the intestines from experimental necrotizing enterocolitis (NEC). We have also demonstrated that systemically administered mesenchymal stem cells (MSC) can engraft into injured intestines. This study investigated the effects of HB-EGF on MSC in vitro, and whether MSC and HB-EGF can act synergistically to prevent NEC in vivo. STUDY DESIGN In vitro, the effect of HB-EGF on MSC proliferation, migration, and apoptosis was determined. In vivo, rat pups received MSC either intraperitoneally (IP) or intravenously (IV). Pups were assigned to 1 of 7 groups: Group 1, breast-fed; Group 2, experimental NEC; Group 3, NEC+HB-EGF; Group 4, NEC+MSC IP; Group 5, NEC+HB-EGF+MSC IP; Group 6, NEC+MSC IV; or Group 7, NEC+HB-EGF+MSC IV. Mesechymal stem cell engraftment, histologic injury, intestinal permeability, and mortality were determined. RESULTS Heparin-binding EGF-like growth factor promoted MSC proliferation and migration, and decreased MSC apoptosis in vitro. In vivo, MSC administered IV had increased engraftment into NEC-injured intestine compared with MSC administered IP (p < 0.05). Heparin binding EGF-like growth factor increased engraftment of IP-administered MSC (p < 0.01) and IV-administered MSC (p < 0.05). Pups in Groups 3 to 7 had a decreased incidence of NEC compared with nontreated pups (Group 2), with the lowest incidence in pups treated with HB-EGF+MSC IV (p < 0.01). Pups in Group 7 had a significantly decreased incidence of intestinal dilation and perforation, and had the lowest intestinal permeability, compared with other treatment groups (p < 0.01). Pups in all experimental groups had significantly improved survival compared with pups exposed to NEC, with the best survival in Group 7 (p < 0.05). CONCLUSIONS Heparin-binding EGF-like growth factor and MSC act synergistically to reduce injury and improve survival in experimental NEC.
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Affiliation(s)
- Jixin Yang
- The Research Institute at Nationwide Children's Hospital, Center for Perinatal Research, Department of Pediatric Surgery, Nationwide Children's Hospital, and the Ohio State University College of Medicine, Columbus, OH, USA
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Yang J, Radulescu A, Chen CL, Zhang HY, James IO, Besner GE. Heparin-binding epidermal growth factor-like growth factor improves intestinal barrier function and reduces mortality in a murine model of peritonitis. Surgery 2012; 153:52-62. [PMID: 22703966 DOI: 10.1016/j.surg.2012.04.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2011] [Accepted: 04/12/2012] [Indexed: 11/29/2022]
Abstract
BACKGROUND The morbidity and mortality associated with bacterial peritonitis remain high. Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is a potent intestinal cytoprotective agent. The aim of this study was to evaluate the effect of HB-EGF in a model of murine peritonitis. METHODS HB-EGF(-/-) knockout (KO) mice and their HB-EGF(+/+) wild-type (WT) counterparts were subjected to sham operation, cecal ligation and puncture (CLP), or CLP with HB-EGF treatment (800 μg/kg IP daily). Villous length, intestinal permeability, intestinal epithelial cell (IEC) apoptosis, bacterial load in peritoneal fluid (PF) and mesenteric lymph nodes (MLN), inflammatory cytokine levels, and survival were determined. RESULTS After exposure to CLP, HB-EGF KO mice had significantly shorter villi (1.37 ± 0.13 vs 1.96 ± 0.4 relative units; P < .03), increased intestinal permeability (17.01 ± 5.18 vs 11.50 ± 4.67 nL/min/cm2; P < .03), increased IEC apoptotic indices (0.0093 ± 0.0033 vs 0.0016 ± 0.0014; P < .01), and increased bacterial counts in PF (25,313 ± 17,558 vs 11,955 ± 6,653 colony forming units [CFU]/mL; P < .05) and MLN (19,009 ± 11,200 vs 5,948 ± 2,988 CFU/mL/g; P < .01) compared with WT mice. Administration of HB-EGF to WT and HB-EGF KO mice exposed to CLP led to significantly increased villous length and decreased intestinal permeability, IEC apoptosis and bacterial counts in MLN (P < .05). Survival of HB-EGF KO mice subjected to CLP was significantly improved with administration of HB-EGF (P < .05). CONCLUSION HB-EGF gene KO increases susceptibility to peritonitis-induced intestinal injury, which can be reversed by administration of HB-EGF. These results support a protective role of HB-EGF in peritonitis-induced sepsis.
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Affiliation(s)
- Jixin Yang
- Department of Pediatric Surgery, Nationwide Children's Hospital, Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, and The Ohio State University College of Medicine, Columbus, OH, USA
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Chen CL, Yu X, James IOA, Zhang HY, Yang J, Radulescu A, Zhou Y, Besner GE. Heparin-binding EGF-like growth factor protects intestinal stem cells from injury in a rat model of necrotizing enterocolitis. J Transl Med 2012; 92:331-44. [PMID: 22157721 PMCID: PMC3289750 DOI: 10.1038/labinvest.2011.167] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Necrotizing enterocolitis (NEC) is an often catastrophic disease that typically affects premature newborns. Although the exact etiology of NEC is uncertain, the disease is associated with formula feeding, bacterial colonization of the gut, hypoxia and hypoperfusion. In light of the pathogenesis of NEC, the integrity and function of the intestinal mucosa has a major defensive role against the initiation of NEC. Various forms of intestinal injury, including NEC, injure the intestinal epithelial cell (IEC) lineages, including the intestinal stem cells (ISCs), thereby disrupting the normal homeostasis needed to maintain gut barrier function. In the current study, we examined the effects of heparin-binding EGF-like growth factor (HB-EGF) administration on enterocytes, goblet cells, neuroendocrine cells and ISCs in a newborn rat model of experimental NEC. We also examined the cytoprotective effects of HB-EGF on ISCs in in vitro cell cultures and in ex vivo crypt-villous organoid cultures. We found that HB-EGF protects all IEC lineages, including ISCs, from injury. We further found that HB-EGF protects isolated ISCs from hypoxic injury in vitro, and promotes ISC activation and survival, and the expansion of crypt transit-amplifying cells, in ex vivo crypt-villous organoid cultures. The protective effects of HB-EGF were dependent on EGF receptor activation, and were mediated via the MEK1/2 and PI3K signaling pathways. These results show that the intestinal cytoprotective effects of HB-EGF are mediated, at least in part, through its ability to protect ISCs from injury.
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Zhang HY, James I, Chen CL, Besner GE. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) preserves gut barrier function by blocking neutrophil-endothelial cell adhesion after hemorrhagic shock and resuscitation in mice. Surgery 2011; 151:594-605. [PMID: 22153812 DOI: 10.1016/j.surg.2011.10.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2011] [Accepted: 10/07/2011] [Indexed: 11/17/2022]
Abstract
BACKGROUND We have shown that heparin-binding epidermal growth factor-like growth factor (HB-EGF) protects the intestines from injury in several different animal models, including hemorrhagic shock and resuscitation (HS/R). The current study was designed to explore the mechanisms underlying the anti-inflammatory role of HB-EGF in preservation of gut barrier function after injury. METHODS In vivo, HS/R was induced in wild-type and neutropenic mice, with or without administration of HB-EGF, and intestinal permeability determined by use of the everted gut sac method. In vitro, cultured human umbilical vein endothelial cells (HUVECs) and freshly isolated human peripheral blood mononuclear cells (PMNs) were used to determine the effects of HB-EGF on HUVEC-PMN adhesion, reactive oxygen species production in PMN, adhesion molecule expression in HUVEC and PMN, and the signaling pathways involved. RESULTS We found that administration of HB-EGF to healthy mice led to preservation of gut barrier function after HS/R. Likewise, induction of neutropenia in mice also led to preservation of gut barrier function after HS/R. Administration of HB-EGF to neutropenic mice did not lead to further improvement in gut barrier function. In vitro studies showed that HB-EGF decreased neutrophil-endothelial cell (PMN-EC) adherence by down-regulating adhesion molecule expression in EC via the phosphoinositide 3-kinase-Akt pathway, and by inhibiting adhesion molecule surface mobilization and reactive oxygen species production in PMN. CONCLUSION These results indicate that HB-EGF preserves gut barrier function by inhibiting PMN and EC activation, thereby blocking PMN-EC adherence after HS/R in mice, and support the future use of HB-EGF in disease states manifested by hypoperfusion injury.
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Affiliation(s)
- Hong-yi Zhang
- Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA
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Zhang HY, Radulescu A, Chen Y, Besner GE. HB-EGF improves intestinal microcirculation after hemorrhagic shock. J Surg Res 2011; 171:218-25. [PMID: 20421109 PMCID: PMC2911522 DOI: 10.1016/j.jss.2010.01.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2009] [Revised: 12/24/2009] [Accepted: 01/14/2010] [Indexed: 02/08/2023]
Abstract
BACKGROUND The goal of this study was to determine the role of heparin-binding epidermal growth factor-like growth factor (HB-EGF) as a mediator of gut microcirculation after hemorrhagic shock and resuscitation (HS/R) in mice. MATERIALS AND METHODS HS/R was induced in HB-EGF knockout (KO) and wild type (WT) mice. Ink-gelatin injection and vascular corrosion casting were performed to visualize the gut microvasculature. The degree of gut microcirculatory injury was graded using five patterns of injury (1-5) according to the severity of microvascular hypoperfusion. Statistical analyses were performed using linear mixed models with P < 0.05 considered statistically significant. RESULTS HB-EGF KO mice subjected to HS/R had significantly decreased perfusion of the gut microvasculature compared with WT mice subjected to HS/R (P = 0.0001). HB-EGF KO mice subjected to HS/R and treated with exogenous HB-EGF had significantly increased gut microvascular perfusion compared with non-HB-EGF treated KO mice (P = 0.01). Lastly, WT mice subjected to HS/R and treated with HB-EGF had significantly increased gut microvascular perfusion compared with non-HB-EGF-treated WT mice (P = 0.04). CONCLUSIONS HB-EGF improves gut microcirculation after HS/R. These findings support the clinical use of HB-EGF in protection of the intestines from disease states associated with intestinal hypoperfusion injury.
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Affiliation(s)
- Hong-yi Zhang
- Department of Pediatric Surgery, Nationwide Children's Hospital, The Research Institute at Nationwide Children's Hospital, Center for Perinatal Research, The Ohio State University College of Medicine, Columbus, Ohio 43205, USA
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Guzmán-De La Garza FJ, Cámara-Lemarroy CR, Ballesteros-Elizondo RG, Alarcón-Galván G, Cordero-Pérez P, Fernández-Garza NE. Ketamine reduces intestinal injury and inflammatory cell infiltration after ischemia/reperfusion in rats. Surg Today 2010; 40:1055-62. [DOI: 10.1007/s00595-009-4177-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2009] [Accepted: 08/26/2009] [Indexed: 12/17/2022]
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Zhang HY, Radulescu A, Chen CL, Olson JK, Darbyshire AK, Besner GE. Mice overexpressing the gene for heparin-binding epidermal growth factor-like growth factor (HB-EGF) have increased resistance to hemorrhagic shock and resuscitation. Surgery 2010; 149:276-83. [PMID: 20965535 DOI: 10.1016/j.surg.2010.08.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2010] [Accepted: 08/05/2010] [Indexed: 12/28/2022]
Abstract
BACKGROUND The aim of the current study was to determine whether overexpression of heparin-binding epidermal growth factor-like growth factor (HB-EGF) could protect the intestines from injury after hemorrhagic shock and resuscitation in mice. METHODS Hemorrhagic shock and resuscitation was induced in HB-EGF transgenic and wild type mice. Cross-reacting material 197 (5 mg/kg) was administered to a subset of HB-EGF transgenic mice to block the overexpressed HB-EGF. Intestinal histologic injury scores, intestinal epithelial cell apoptosis indices, and gut barrier function were determined. The Student t test and 1-way analysis of variance were employed to compare the differences between groups. RESULTS All mice subjected to hemorrhagic shock and resuscitation had significantly increased intestinal histologic injury scores, apoptosis indices, and intestinal permeability compared with sham-operated mice. Compared with wild type mice, HB-EGF transgenic mice had significantly decreased histologic injury (mean injury grade 2.79 ± 0.84 vs 3.88 ± 1.43, P = .02), apoptosis indices (mean apoptosis index 8.77 ± 5.23 vs 17.91 ± 13.23, P = .03), and mucosal permeability (FITC-dextran 4 clearance 13.06 ± 5.67 vs 20.03 ± 7.81 nL/min/ m(2), P = .02) at 3 hours of reperfusion. HB-EGF transgenic mice subjected to hemorrhagic shock and resuscitation and treated with cross-reacting material 197 had a significantly increased histologic injury (mean injury grade 3.63 ± 1.00 vs 2.79 ± 0.84, P = .04) and mucosal permeability (FITC-dextran 4 clearance 22.87 ± 9.69 vs 13.06 ± 5.67 nL/min/cm2, P = .01) at 3 hours of reperfusion compared with non-cross-reacting material 197 treated transgenic mice, with no significant changes in apoptosis indices. Cross-reacting material 197 did not reverse the decreased apoptosis observed in HB-EGF transgenic mice subjected to hemorrhagic shock and resuscitation, which suggests that mechanisms in addition to decreased apoptosis may be responsible for the intestinal cytoprotective effects of endogenous HB-EGF overexpression. CONCLUSION Overexpression of HB-EGF increases resistance to hemorrhagic shock and resuscitation in mice.
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Affiliation(s)
- Hong-yi Zhang
- Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Department of Pediatric Surgery, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA
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Radulescu A, Zhang HY, Chen CL, Chen Y, Zhou Y, Yu X, Otabor I, Olson JK, Besner GE. Heparin-binding EGF-like growth factor promotes intestinal anastomotic healing. J Surg Res 2010; 171:540-50. [PMID: 20850767 DOI: 10.1016/j.jss.2010.06.036] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2010] [Revised: 06/15/2010] [Accepted: 06/24/2010] [Indexed: 11/29/2022]
Abstract
BACKGROUND We have accumulated multiple lines of evidence supporting the ability of HB-EGF to protect the intestines from injury and to augment the healing of partial-thickness scald burns of the skin. The aim of the current study was to investigate the role of heparin-binding EGF-like growth factor (HB-EGF) in intestinal anastomotic wound healing. MATERIALS AND METHODS HB-EGF (-/-) knockout (KO) mice (n=42) and their HB-EGF (+/+) wild type (WT) counterparts (n=33), as well as HB-EGF transgenic (TG) mice (n=26) and their (WT) counterparts (n=27), underwent division and reanastomosis of the terminal ileum. In addition, WT mice (n=21) that received enteral HB-EGF (800 μg/kg) underwent the same operative procedure. Anastomotic bursting pressure was measured at 3 and 6 d postoperatively. Tissue sections were stained with hematoxylin and eosin to assess anastomotic healing, and Picrosirus red to assess collagen deposition. Immunohistochemistry using anti-von Willebrand factor antibodies was performed to assess angiogenesis. Complications and mortality were also recorded. RESULTS HB-EGF KO mice had significantly lower bursting pressures, lower healing scores, higher mortality, and higher complication rates postoperatively compared with WT mice. Collagen deposition and angiogenesis were significantly decreased in KO mice compared with WT mice. Conversely, HB-EGF TG mice had increased anastomotic bursting pressure, higher healing scores, lower mortality, lower complication rates, increased collagen deposition, and increased angiogenesis postoperatively compared with WT mice. WT mice that received HB-EGF had increased bursting pressures compared with non-HB-EGF treated mice. CONCLUSION Our results demonstrate that HB-EGF is an important factor involved in the healing of intestinal anastomoses.
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Affiliation(s)
- Andrei Radulescu
- Center for Perinatal Research, Department of Pediatric Surgery, The Research Institute at Nationwide Children's Hospital, and The Ohio State University College of Medicine, Columbus, Ohio 43205, USA
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James IAO, Chen CL, Huang G, Zhang HY, Velten M, Besner GE. HB-EGF protects the lungs after intestinal ischemia/reperfusion injury. J Surg Res 2010; 163:86-95. [PMID: 20599214 DOI: 10.1016/j.jss.2010.03.062] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2009] [Revised: 03/11/2010] [Accepted: 03/29/2010] [Indexed: 01/09/2023]
Abstract
BACKGROUND Acute respiratory distress syndrome continues to be a major source of morbidity and mortality in critically-ill patients. Heparin binding EGF-like growth factor (HB-EGF) is a biologically active protein that acts as an intestinal cytoprotective agent. We have previously demonstrated that HB-EGF protects the intestines from injury in several different animal models of intestinal injury. In the current study, we investigated the ability of HB-EGF to protect the lungs from remote organ injury after intestinal ischemia/reperfusion (I/R). METHODS Mice were randomly assigned to one of the following groups: (1) sham-operated; (2) sham+HB-EGF (1200 microg/kg in 0.6 mL administered by intra-luminal injection at the jejuno-ileal junction immediately after identification of the superior mesenteric artery); (3) superior mesenteric artery occlusion for 45 min followed by reperfusion for 6 h (I/R); or (4) I/R+HB-EGF (1200 microg/kg in 0.6 mL) administered 15 min after vascular occlusion. The severity of acute lung injury was determined by histology, morphometric analysis and invasive pulmonary function testing. Animal survival was evaluated using Kaplan-Meier analysis. RESULTS Mice subjected to intestinal I/R injury showed histologic and functional evidence of acute lung injury and decreased survival compared with sham-operated animals. Compared with mice treated with HB-EGF (I/R+HB-EGF), the I/R group had more severe acute lung injury, and decreased survival. CONCLUSION Our results demonstrate that HB-EGF reduces the severity of acute lung injury after intestinal I/R in mice. These data demonstrate that HB-EGF may be a potential novel systemic anti-inflammatory agent for the prevention of the systemic inflammatory response syndrome (SIRS) after intestinal injury.
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Affiliation(s)
- Iyore A O James
- Department of Pediatric Surgery, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, Ohio, USA
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Chen CL, Mehta VB, Zhang HY, Wu D, Otabor I, Radulescu A, El-Assal ON, Feng J, Chen Y, Besner GE. Intestinal phenotype in mice overexpressing a heparin-binding EGF-like growth factor transgene in enterocytes. Growth Factors 2010; 28:82-97. [PMID: 19939201 PMCID: PMC3821006 DOI: 10.3109/08977190903407365] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
PRIMARY OBJECTIVE Heparin-binding EGF-like growth factor (HB-EGF) protects the intestine from damage in animals. Future clinical trials of HB-EGF may involve administration of repeated doses of HB-EGF. Since HB-EGF activates EGF receptors which have been implicated in tumor development, we examined the effects of HB-EGF overexpression in the intestine. RESEARCH DESIGN We generated transgenic (TG) mice in which the human HB-EGF gene is driven by the villin promoter to overexpress HB-EGF along the crypt-villous axis from the duodenum to the colon. RESULTS HB-EGF TG mice have increased enterocyte proliferation balanced by increased enterocyte apoptosis. Despite prolonged overexpression of HB-EGF, no evidence of intestinal hyperplasia or tumor formation occurs. Although HB-EGF TG mice have no significant phenotypic alterations under basal conditions, they have increased resistance to intestinal injury. CONCLUSIONS Prolonged intestinal HB-EGF overexpression results in no significant phenotypic alterations under basal conditions, but confers protection against intestinal injury.
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Affiliation(s)
- Chun-Liang Chen
- Department of Pediatric Surgery, The Research Institute at Nationwide Children's Hospital, Center for Perinatal Research, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA
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Abstract
Maternal milk is a complex fluid, with multifunctional roles within the developing gastrointestinal tract. Epidermal growth factor (EGF) and heparin-binding EGF-like growth factor (HB-EGF) are members of the family of EGF-related peptides. Biological actions of these growth factors are mediated via interaction with the EGF-receptor (EGF-R). In the early postnatal period, breast milk is the major source of EGF for the developing intestinal mucosa. HB-EGF is also detected in breast milk, but in concentrations 2 to 3 times lower than EGF. With normal physiological conditions, the intestinal epithelium undergoes a continuing process of cell proliferation, differentiation, and maturation. EGF plays an important role in these processes. In pathophysiologic situations, EGF contributes to epithelial protection from injury and post-injury mucosal repair. Necrotizing enterocolitis (NEC) is a devastating disease affecting infants born prematurely. The pathogenesis of NEC is not known, and there is no effective treatment for this disease. In an experimental NEC model, oral administration of a physiological dose of EGF significantly reduces the incidence and severity of NEC. HB-EGF provides similar protection against NEC, but only when pharmacological doses are used. Further studies are necessary before EGF can be introduced as an efficient therapeutic approach of intestinal injury.
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Affiliation(s)
- Bohuslav Dvorak
- Department of Pediatrics, University of Arizona, Tucson, AZ, USA.
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Guzmán-de la Garza FJ, Cámara-Lemarroy CR, Alarcón-Galván G, Cordero-Pérez P, Muñoz-Espinosa LE, Fernández-Garza NE. Different patterns of intestinal response to injury after arterial, venous or arteriovenous occlusion in rats. World J Gastroenterol 2009; 15:3901-7. [PMID: 19701970 PMCID: PMC2731252 DOI: 10.3748/wjg.15.3901] [Citation(s) in RCA: 13] [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] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the differences in injury patterns caused by arterial, venous or arteriovenous mesenteric occlusion.
METHODS: Male Wistar rats were separated equally into four groups. Occlusion was performed by clamping the superior mesenteric artery (A), the mesenteric vein (V) or both (AV) for 30 min, followed by 60 min of reperfusion. A control group received sham surgery only. Intestinal sections were examined for histological damage and serum tumor necrosis factor-α (TNF-α), endothelin-1 (ET-1), P-selectin, antithrombin III (ATIII) and soluble intracellular adhesion molecule-1 (ICAM-1) concentrations were measured.
RESULTS: All groups showed significant mucosal injury compared to controls. Furthermore, mucosal injury was significantly more severe in the V and AV groups compared to the A group (3.6 ± 0.55, 3.4 ± 0.55 and 2 ± 0.71, respectively, P = 0.01). ICAM-1 was similarly elevated in all groups, with no significant differences between the groups. P-selectin levels were significantly elevated in the V and AV groups but not the A group (1.4 ± 0.5 ng/mL, 2.52 ± 0.9 ng/mL and 0.02 ± 0.01 ng/mL, respectively, P = 0.01) and ET-1 was significantly elevated in the A and V groups but not the AV group (0.32 ± 0.04 pg/mL, 0.36 ± 0.05 pg/mL and 0.29 ± 0.03 pg/mL, respectively, P = 0.01) compared to sham controls. ATIII levels were markedly depleted in the V and AV groups, but not in the A group (29.1 ± 5.2 pg/mL, 31.4 ± 21.8 pg/mL and 55.8 ± 35.6 pg/mL, respectively, P = 0.01), compared to controls. Serum TNF-α was significantly increased in all groups compared to sham controls (1.32 ± 0.87 ng/mL, 1.79 ± 0.20 ng/mL and 4.4 ± 0.69 ng/mL, for groups A, V and AV, respectively, P = 0.01), with higher values in the AV group.
CONCLUSION: Different patterns of response to ischemia/reperfusion are associated with venous, arterial or arteriovenous occlusion. Venous and arteriovenous occlusion was associated with the most severe alterations.
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Zhang HY, Radulescu A, Besner GE. Heparin-binding epidermal growth factor-like growth factor is essential for preservation of gut barrier function after hemorrhagic shock and resuscitation in mice. Surgery 2009; 146:334-9. [PMID: 19628093 DOI: 10.1016/j.surg.2009.02.020] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2009] [Accepted: 02/06/2009] [Indexed: 01/17/2023]
Abstract
BACKGROUND The aim of the current study was to determine the role of heparin-binding (HB) epidermal growth factor (EGF)-like growth factor as a mediator of gut barrier function after hemorrhagic shock and resuscitation (HS/R) in mice. METHODS HS/R was induced in HB-EGF knockout (KO) and wild-type (WT) mice. Intestinal histologic injury scores, intestinal epithelial cell apoptosis, and gut barrier function were determined. Statistical analyses were performed using linear mixed models with P<.05 considered significant. RESULTS All mice subjected to HS/R had significantly increased intestinal histologic injury scores, apoptosis indices, and intestinal permeability compared with mice subjected to sham operation. Compared with WT mice, HB-EGF KO mice subjected to HS/R had significantly increased histologic injury (mean injury grade, 4.5 +/- 1 vs 2.75 +/- 0.5 at 3 hours of resuscitation; P<.05), increased apoptosis indices (mean apoptosis index, 6.84 +/- 1.95 vs 3.24 +/- 1.00 at 3 hours of resuscitation; P < .05), and increased mucosal permeability (FD4 clearance 78 +/- 18.91 vs 47.75 +/- 8.06 nL/min/cm(2) at 3 hours of resuscitation; P<.05). CONCLUSION HB-EGF is essential for the preservation of gut barrier function after HS/R. These findings support the clinical use of HB-EGF in protection of the intestines from disease states associated with intestinal hypoperfusion injury.
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Affiliation(s)
- Hong-Yi Zhang
- Department of Pediatric Surgery, Nationwide Children's Hospital, Columbus, OH 43205, USA
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Zhou Y, Brigstock D, Besner GE. Heparin-binding EGF-like growth factor is a potent dilator of terminal mesenteric arterioles. Microvasc Res 2009; 78:78-85. [PMID: 19389413 DOI: 10.1016/j.mvr.2009.04.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2008] [Revised: 01/24/2009] [Accepted: 04/14/2009] [Indexed: 12/19/2022]
Abstract
OBJECTIVE We have previously shown that heparin-binding EGF-like growth factor (HB-EGF) protects the intestines from multiple forms of injury via direct cytoprotective effects on the intestinal mucosa. In this study, we examined the effects of HB-EGF on the hemodynamics of intestinal arterioles, the major resistance vessels that regulate blood flow to the intestines, as an additional mechanism of HB-EGF-mediated intestinal protection. METHODS The hemodynamic effects of HB-EGF in rodent terminal mesenteric arterioles and human submucosal arterioles were examined ex vivo using a video dimension analyzer. Cultured human intestinal microvascular endothelial cells (HIMEC) were used to elucidate the mechanisms of HB-EGF-induced vasodilation. RESULTS HB-EGF significantly increased vessel diameter under conditions of increasing intraluminal pressure and increased flow rate. These HB-EGF-mediated vasodilatory effects were observed in terminal mesenteric arterioles from adult rats and 3 day old rat pups. These effects were confirmed in submucosal arterioles from human intestine. Furthermore, HB-EGF significantly reduced endothelin-1-induced mesenteric arteriolar vasoconstriction. The vasodilatory effects of HB-EGF were blocked by ET(B) receptor antagonism in adult rat arterioles, and also by nitric oxide synthase inhibition in rat pup and human infant arterioles. In HIMEC, HB-EGF significantly increased endothelin B (ET(B)) receptor protein expression and provoked intracellular calcium mobilization. CONCLUSIONS HB-EGF is a potent vasodilator of the intestinal microvasculature, further supporting its use in diseases manifested by decreased intestinal blood flow, including necrotizing enterocolitis.
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Affiliation(s)
- Yu Zhou
- Department of Pediatric Surgery, The Ohio State University College of Medicine, Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA
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28
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Cuzzocrea S, Masini E. Plant histaminase as an investigational drug in splanchnic artery occlusion and reperfusion. Expert Opin Investig Drugs 2008; 17:1151-60. [PMID: 18616412 DOI: 10.1517/13543784.17.8.1151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Amine oxidases are ubiquitous enzymes involved in the metabolism of biogenic amines. Copper amine oxidases catalyze the oxidative deamination of primary amine groups of several biogenic amines, such as putrescine, cadaverine and histamine. OBJECTIVE In the present review the effects of a plant amine oxidase (histaminase, EC1.4.3.6), purified from pea seedlings, in the prevention of splanchnic postischemic reperfusion damage are reported. CONCLUSION Various studies have clearly indicated that the use of histaminase will offer a good perspective for a novel therapeutic approach in the medical treatment of intestinal ischemia.
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Affiliation(s)
- Salvatore Cuzzocrea
- University of Messina, School of Medicine, Department of Clinical, Experimental Medicine and Pharmacology, Torre Biologica-Policlinico Universitario, Via Consolare Valeria-Gazzi, 98100 Messina, Italy.
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29
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Keay S. Cell signaling in interstitial cystitis/painful bladder syndrome. Cell Signal 2008; 20:2174-9. [PMID: 18602988 DOI: 10.1016/j.cellsig.2008.06.004] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2008] [Accepted: 06/13/2008] [Indexed: 01/08/2023]
Abstract
Evidence for several types of cell signaling abnormalities has been presented for patients with interstitial cystitis/painful bladder syndrome (IC/PBS), a poorly understood chronic painful bladder disorder for which currently there is no reliable effective therapy. Increases or decreases in various urine cytokines and growth factors have been found in patient specimens, along with abnormal expression of epithelial differentiation markers, growth factors, cell membrane proteins, neurotransmitters, and other cytokines in tissue biopsies and/or explanted bladder cells from IC/PBS patients. Some of the abnormalities found in bladder epithelial cells from IC/PBS patients have been shown to be induced in normal cells by an antiproliferative factor from IC/PBS bladder epithelial cells that binds to a functional cell membrane receptor (CKAP4/p63). Greater understanding of cell signaling events associated with this debilitating disorder may lead to the development of more effective therapies.
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Affiliation(s)
- Susan Keay
- Department of Medicine, University of Maryland School of Medicine and Veterans Administration Maryland Health Care System, Baltimore, Maryland, United States.
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El-Assal ON, Paddock H, Marquez A, Besner GE. Heparin-binding epidermal growth factor-like growth factor gene disruption is associated with delayed intestinal restitution, impaired angiogenesis, and poor survival after intestinal ischemia in mice. J Pediatr Surg 2008; 43:1182-90. [PMID: 18558204 PMCID: PMC2495084 DOI: 10.1016/j.jpedsurg.2008.02.053] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2008] [Accepted: 02/09/2008] [Indexed: 10/21/2022]
Abstract
PURPOSE We have demonstrated that administration of heparin-binding epidermal growth factor-like growth factor (HB-EGF) protects the intestines from injury. The aim of the current study was to evaluate the effect of HB-EGF gene disruption on intestinal restitution, angiogenesis, and long-term survival after intestinal ischemia/reperfusion (I/R) injury. METHODS HB-EGF (-/-) and wild-type HB-EGF (+/+) littermate mice were subjected to 45 minutes of superior mesenteric artery occlusion followed by reperfusion. Functional recovery of the gut permeability barrier was evaluated with Ussing chamber studies, and microvessel density was evaluated immunohistochemically. Animal survival was evaluated using the Kaplan-Meier method. RESULTS Histologic damage after ischemia was significantly higher in HB-EGF (-/-) mice compared with HB-EGF (+/+) mice, associated with a significantly higher number of incompetent (nonhealed, nonresurfaced) villi indicative of delayed structural healing by restitution. HB-EGF (-/-) mice had increased intestinal permeability after intestinal I/R. HB-EGF (-/-) mice had significantly lower microvessel density at 3 and 7 days after I/R, indicating that HB-EGF gene deletion resulted in delayed onset of angiogenesis. Two-week mortality rates were significantly higher in HB-EGF (-/-) mice. CONCLUSIONS Endogenous HB-EGF significantly enhances healing by restitution, prolongs survival, and enhances angiogenesis in mice subjected to intestinal I/R injury. These findings support our hypothesis that HB-EGF administration may improve outcome in patients with intestinal I/R injury, including necrotizing enterocolitis.
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Sukhotnik I, Coran AG, Greenblatt R, Brod V, Mogilner J, Shiloni E, Shaoul R, Bitterman H. Effect of 100% oxygen on E-selectin expression, recruitment of neutrophils and enterocyte apoptosis following intestinal ischemia-reperfusion in a rat. Pediatr Surg Int 2008; 24:29-35. [PMID: 17962962 DOI: 10.1007/s00383-007-2039-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Recent evidence suggests that neutrophil recruitment may initiate cell apoptosis in ischemic tissues. We have recently shown that enterocyte apoptosis is increased following intestinal ischemia-reperfusion (IR) injury. The purpose of the present study was to examine the effect of hyperoxia on E-selectin expression, neutrophil recruitment and enterocyte apoptosis following intestinal IR in a rat. Male Sprague-Dawley rats were divided into three experimental groups: (1) sham rats underwent laparotomy without vascular occlusion and were ventilated with air (Sham) (2) IR rats underwent occlusion of both the superior mesenteric artery and portal vein for 30 min and were ventilated with air (IR), and (3) IR-O2 rats underwent IR and were ventilated with 100% started 10 min before reperfusion and continued for 6 h (IR-O2). Intestinal structural changes were determined 24 h following IR. Immunohistochemistry for E-selectin (using E-selectin cleaved concentrated polyclonal antibody) was performed to identify E-selectin immunoreactivity localized to the endothelium of venules. The recruitment of neutrophils was calculated per 100 venules. Immunohistochemistry for Caspase-3 was performed for identification of apoptotic cells. Non-parametric one-way ANOVA test was used for statistical analysis with p less than 0.05 considered statistically significant. A significant increase in E-selectin expression in the jejunum (6.1 +/- 2.2 vs. 2.5 +/- 1.0 E-selectin positive vessels/100 vessels, p < 0.05) and ileum (12.1 +/- 2.7 vs. 3.3 +/- 1.2 E-selectin positive vessels/100 vessels, p < 0.05) and a concomitant increase in neutrophil recruitment in the ileum (5.5 +/- 1.6 vs. 1.3 +/- 0.6 adhered PMN's per 100 venules) were observed in IR rats compared to sham animals and were accompanied by increased cell apoptosis (p < 0.05). Treatment with 100% oxygen resulted in a significant attenuation in E-selectin expression in the ileum (2.7 +/- 1.1 vs. 12.1 +/- 2.7 E-selectin positive vessels/100 vessels, p < 0.05), and neutrophil recruitment in the jejunum (2.5 +/- 1.4 vs. 7.7 +/- 1.9 adhered PMN's per 100 venules, p < 0.05) and ileum (1.5 +/- 0.7 vs. 5.5 +/- 1.6 adhered PMN's per 100 venules, p < 0.05) compared to IR animals, and was accompanied by decreased cell apoptosis (p < 0.05). Hyperoxia inhibits enterocyte apoptosis following intestinal ischemia-reperfusion. Down-regulation of E-selectin expression with subsequent decrease in neutrophil recruitment may be responsible for this effect.
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Affiliation(s)
- Igor Sukhotnik
- Department of Pediatric Surgery, Bnai Zion Medical Center, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, 47 Golomb St, POB 4940, Haifa, Israel.
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Meng FW, Shimoda H, Kajiwara T, Matsuda M, Kato S. Reconstruction of central lacteals in the murine jejunum following ischemia-reperfusion injury. ACTA ACUST UNITED AC 2007; 70:135-46. [PMID: 17827671 DOI: 10.1679/aohc.70.135] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The intestinal mucosa is vulnerable to an ischemia-reperfusion (I/R) attendant on some bowel diseases and surgery; thus, the restoration of the mucosal integrity is critical to achieving functional recovery of the intestine injured by I/R. In this histochemical study, we investigated the alteration of the central lacteals--which are essential for the transport of fat, tissue fluid, and immune cells in the intestinal mucosa--in the murine jejunum after I/R. The intestine inflicted with I/R demonstrated mucosal injury involving the inflammatory response, with interstitial edema, disruption of the villous tissue, and subsequent tissue regeneration of the villi. The regenerative villous tissue revealed lymphatic regrowth showing proliferative activity from the residual mucosal lymphatics behind the regenerated blood vasculature. During the regenerative phase, the blood vascular pericytes expressed an intense immunoreaction for VEGF-A, an inducer for monocyte/macrophage recruitment as well as angiogenesis. Also, the F4/80-immunopositive macrophages significantly increased in number in the regenerating villous stroma. Furthermore, the macrophages recruited around the regrowing lacteals expressed the immunoreactivity for VEGF-C, which is a highly specific lymphangiogenic factor. The present study is first to delineate alterations in the central lacteals in the small intestine following I/R, thereby suggesting that the recruitment of the macrophages induced by upregulation of VEGF-A in the pericytes of regenerative blood vessels might promote reconstruction of the central lacteals through their release of VEGF-C.
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Affiliation(s)
- Fan-Wei Meng
- Department of Anatomy, Biology and Medicine, Faculty of Medicine, Oita University, Japan
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Rocourt DV, Mehta VB, Wu D, Besner GE. Heparin-Binding EGF-like Growth Factor Decreases Neutrophil–Endothelial Cell Interactions. J Surg Res 2007; 141:262-6. [PMID: 17574583 DOI: 10.1016/j.jss.2007.01.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2006] [Revised: 12/15/2006] [Accepted: 01/12/2007] [Indexed: 12/28/2022]
Abstract
BACKGROUND Hyperadhesiveness of neutrophils (PMN) to vascular endothelial cells (EC) followed by neutrophil transendothelial migration play important roles in the initiation of ischemia/reperfusion (I/R)-mediated injury. We investigated whether the ability of heparin-binding EGF-like growth factor (HB-EGF) to decrease intestinal injury after intestinal I/R is mediated, in part, by its ability to affect PMN-EC interactions and EC junctional integrity. MATERIALS AND METHODS Human umbilical vein EC monolayers were treated with HB-EGF (100 ng/mL) or phosphate-buffered saline followed by anoxia/reoxygenation (A/R). Simultaneously, labeled human PMN were treated with HB-EGF or phosphate-buffered saline and then co-incubated with EC for determination of PMN-EC adherence and PMN transendothelial migration. EC junctional integrity was also determined. RESULTS PMN-EC adhesion increased after exposure of EC to A/R compared to EC exposed to normoxia (87% versus 64% binding, P < 0.05, Wilcoxon rank sum test). A/R-induced PMN-EC hyperadherence was significantly decreased by treatment of PMN with HB-EGF compared to nontreated cells (51% versus 87% binding, P < 0.05). HB-EGF significantly decreased PMN transendothelial migration and also augmented EC tight junctional integrity after A/R. CONCLUSIONS HB-EGF significantly reduces A/R-induced PMN-EC adhesion and PMN transendothelial migration and augments junctional integrity in vitro. Thus, HB-EGF acts not only as a potent cytoprotective agent for the intestine, but as an anti-inflammatory agent as well.
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Affiliation(s)
- Dorothy V Rocourt
- Department of Pediatric Surgery, Children's Hospital, The Ohio State University College of Medicine and Public Health, Columbus, Ohio, USA
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34
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El-Assal ON, Radulescu A, Besner GE. Heparin-binding EGF-like growth factor preserves mesenteric microcirculatory blood flow and protects against intestinal injury in rats subjected to hemorrhagic shock and resuscitation. Surgery 2007; 142:234-42. [PMID: 17689691 DOI: 10.1016/j.surg.2007.04.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2007] [Revised: 04/04/2007] [Accepted: 04/06/2007] [Indexed: 10/23/2022]
Abstract
BACKGROUND The gut is highly susceptible to injury after hemorrhagic shock and resuscitation (HS/R) because of progressive mesenteric hypoperfusion. The aim of the current study was to evaluate the effect of heparin-binding EGF-like growth factor (HB-EGF) on mesenteric microcirculatory blood flow and intestinal injury in rats subjected to HS/R. METHODS HS/R was induced in adult rats, with some rats receiving HB-EGF (600 mug/kg) IV at the onset of resuscitation (HS/R+HB-EGF) and others receiving vehicle only (HS/R). FITC-dextran was administered intra-arterially to evaluate mesenteric microcirculation, and intestinal damage and restitution were evaluated histologically. Data were expressed as mean +/- SE, with P < .05 considered statistically significant. RESULTS Microcirculatory blood flow was significantly reduced 1 hour after HS/R. HS/R+HB-EGF rats had significantly increased microcirculatory flow compared with HS/R rats at 1 hour (4.5 +/- 0.43 vs 2.64 +/- 0.46, P < .05) and 3 hours (8.04 +/- 1.58 vs 2.89 +/- 0.63, P < .05) after HS/R. HS/R+HB-EGF rats had significantly less intestinal damage compared with HS/R rats 3 hours after resuscitation (2.04 +/- 0.5 vs 3.08 +/- 0.5, P < .05), along with significantly fewer incompetent (nonresurfaced, nonhealed) villi, which is indicative of improved restitution. CONCLUSIONS HB-EGF significantly improved postresuscitation microcirculatory blood flow in rats subjected to HS/R, associated with significantly decreased intestinal damage and increased restitution. These results suggest that HB-EGF may be a useful therapeutic agent that improves intestinal blood flow in patients with intestinal injury secondary to hemorrhagic shock.
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Affiliation(s)
- Osama N El-Assal
- Department of Pediatric Surgery, Children's Hospital, Columbus, Ohio, USA
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35
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Di Paola R, Cuzzocrea S. Peroxisome proliferator-activated receptors ligands and ischemia-reperfusion injury. Naunyn Schmiedebergs Arch Pharmacol 2007; 375:157-75. [PMID: 17394034 DOI: 10.1007/s00210-007-0141-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2006] [Accepted: 01/28/2007] [Indexed: 12/19/2022]
Abstract
Peroxisome proliferator-activated receptors (PPARs) belong to a subfamily of transcription nuclear factors. Three isoforms of PPARs have been identified: alpha, beta/delta and gamma, encoded by different genes and distributed in various tissues. They play important roles in metabolic processes like regulation of glucose and lipid redistribution. They also have anti-atherogenic, anti-inflammatory as well as antihypertensive functions. There is good evidence that ligands of PPARs reduce tissue injury associated with ischemia and reperfusion. The potential utility of PPAR ligands in ischemia and reperfusion will be discussed in this review.
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Affiliation(s)
- Rosanna Di Paola
- Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Torre Biologica-Policlinico Universitario, Via C. Valeria-Gazzi, 98100 Messina, Italy
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Rocourt DV, Mehta VB, Besner GE. Heparin-binding EGF-like growth factor decreases inflammatory cytokine expression after intestinal ischemia/reperfusion injury. J Surg Res 2007; 139:269-73. [PMID: 17291530 PMCID: PMC1905844 DOI: 10.1016/j.jss.2006.10.047] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2006] [Revised: 10/11/2006] [Accepted: 10/30/2006] [Indexed: 01/23/2023]
Abstract
BACKGROUND Intestinal ischemia/reperfusion (I/R) injury is believed to be the major initiator of the systemic inflammatory response syndrome. As a result of intestinal I/R, the gut becomes a major source of inflammatory cytokine production. We have previously shown that heparin-binding EGF-like growth factor (HB-EGF) is cytoprotective after intestinal I/R and down-regulates pro-inflammatory cytokine production in vitro. We now examine the effects of HB-EGF on pro-inflammatory cytokine expression in vivo. MATERIALS AND METHODS Rats were randomized into three groups: sham-operated, superior mesenteric artery occlusion (SMAO) for 90 min followed by 8 h of reperfusion (I/R), and I/R with intraluminal administration of HB-EGF 25 min after the initiation of ischemia (I/R + HB-EGF). Serum was drawn at 2, 4, 6, and 8 h post reperfusion for determination of cytokine protein levels using a bioplex suspension array system. Additional animals underwent the same ischemic protocol followed by 30 and 60 min of reperfusion with harvesting of ileal mucosa. Ileal pro-inflammatory cytokine gene expression was determined using reverse transcriptase polymerase chain reaction (RT-PCR) with primers specific for TNF-alpha, IL-6, and IL-1beta. RESULTS HB-EGF decreased TNF-alpha, IL-6, and IL-1beta serum protein levels at 4, 6, and 8 h after intestinal I/R injury. In addition, HB-EGF decreased local intestinal mucosal mRNA expression of TNF-alpha, IL-6, and IL-1beta 30 and 60 min after intestinal injury. CONCLUSIONS We conclude that pro-inflammatory cytokine expression is increased both locally and in the systemic circulation after intestinal I/R and that the administration of HB-EGF significantly reduces intestinal I/R-induced pro-inflammatory cytokine expression in vivo.
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Affiliation(s)
- Dorothy V. Rocourt
- Department of Pediatric Surgery, Children’s Hospital and The Ohio State University College of Medicine and Public Health
| | - Veela B. Mehta
- The Center for Perinatal Research, Children’s Research Institute, Columbus, OH
| | - Gail E. Besner
- Department of Pediatric Surgery, Children’s Hospital and The Ohio State University College of Medicine and Public Health
- The Center for Perinatal Research, Children’s Research Institute, Columbus, OH
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Fayad R, Pini M, Sennello JA, Cabay RJ, Chan L, Xu A, Fantuzzi G. Adiponectin deficiency protects mice from chemically induced colonic inflammation. Gastroenterology 2007; 132:601-14. [PMID: 17258715 DOI: 10.1053/j.gastro.2006.11.026] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2006] [Accepted: 10/19/2006] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Adiponectin (APN) is an adipokine that regulates insulin sensitivity and is anti-inflammatory in atherosclerosis. The goal of this study was to investigate the role of APN in intestinal inflammation. METHODS APN knockout (KO) mice and their wild-type (WT) littermates received dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS) to induce intestinal inflammation. Clinical and histologic scores and proliferation of epithelial cells were assessed. Cytokines and APN levels were measured. Expression of APN and heparin binding epidermal growth factor (HB-EGF) was analyzed by immunohistochemistry. Expression of APN and its receptors, HB-EGF, and basic fibroblast growth factor (bFGF) messenger RNA was assessed by reverse-transcription polymerase chain reaction. Association of serum APN with HB-EGF and bFGF was studied by coimmunoprecipitation. RESULTS APN KO mice are protected from chemically induced colitis; administration of APN restores inflammation. APN is expressed in the colon, luminal APN associates with colonic epithelial cells. In vitro, APN increases production of proinflammatory cytokines from colonic tissue. Expression of colonic APN overlaps with that of bFGF and HB-EGF, which play a protective role in colitis. Circulating APN binds to bFGF and HB-EGF, likely inhibiting their protective activity. Inhibition of EGF receptor signaling, which is required for biologic activity of HB-EGF, restores inflammation in APN KO mice. CONCLUSIONS APN deficiency is associated with protection from chemically induced colitis. APN exerts proinflammatory activities in the colon by inducing production of proinflammatory cytokines and inhibiting bioactivity of protective growth factors. Thus, in colitis, APN exerts an opposite role compared with atherosclerosis.
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Affiliation(s)
- Raja Fayad
- Department of Human Nutrition, University of Illinois at Chicago, 60612, USA
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Okwueze MI, Cardwell NL, Pollins AC, Nanney LB. Modulation of porcine wound repair with a transfected ErbB3 gene and relevant EGF-like ligands. J Invest Dermatol 2006; 127:1030-41. [PMID: 17124505 DOI: 10.1038/sj.jid.5700637] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Our in vivo study used an ErbB3 receptor transfection strategy to determine if topical application of EGF-like ligands would enhance repair. Partial-thickness porcine wounds transfected with adenoviral particles containing an ErbB3 receptor gene or a vehicle beta-galactosidase gene were introduced and wounds were concomitantly supplied with a variety of EGF-like ligands--EGF, epiregulin (EPR), heparin binding EGF (HB-EGF), and heregulin/neuregulin (HRG). Comparisons of cutaneous repair (resurfacing, dermal depth, proliferation, macrophage infiltration, microvascular density, apoptosis) were assessed after a 5-day healing interval. Differential effects were noted. In wounds transfected with additional ErbB3, either EPR or HB-EGF promoted resurfacing greater than EGF, HRG, or controls. Dermal responses differed significantly after EPR or HB-EGF treatments compared to EGF, HRG, ErbB3 only, or empty vehicle. Hallmarks of enhanced wound maturity were noted in EPR- and HB-EGF-treated wounds transfected with ErbB3. Our data confirmed that an ErbB3-driven pathway mediates a net positive influence in an in vivo model closely resembling human repair. The sensitivity in this system was sufficient to reveal differential outcomes following stimulation with various EGF ligands. We conclude that selective stimulation through an ErbB3-driven pathway shows promise as a therapeutic strategy to hasten wound maturity.
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Affiliation(s)
- Martina I Okwueze
- Department of Plastic Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
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Feng J, El-Assal ON, Besner GE. Heparin-binding EGF-like growth factor (HB-EGF) and necrotizing enterocolitis. Semin Pediatr Surg 2005; 14:167-174. [PMID: 16084404 DOI: 10.1053/j.sempedsurg.2005.05.005] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Necrotizing enterocolitis (NEC) is a common and devastating gastrointestinal disease that occurs predominantly in premature infants. Despite various advances in management, the mortality of this disease remains high. During the last decade, studies from our laboratory have shown that heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the epidermal growth factor (EGF) family, can protect intestinal epithelial cells (IEC) from various forms of injury in vitro. Furthermore, we have used both an intestinal I/R injury model in adult rats, and a neonatal rat pup model of NEC, to show that HB-EGF can protect the intestines from injury. On administration of HB-EGF in the neonatal rat model, the incidence of NEC is reduced from 65% to 27.3% (P < 0.05), and the histological injury score is decreased from 2 to 1.1 (P < 0.05). In addition, the survival rate is increased from 25% to 63.6% and the survival time extended from 59 hours to 73 hours (P < 0.05). In addition, using human specimens from newborns undergoing bowel resection for NEC, we found that the expression of endogenous HB-EGF mRNA in normal areas of the intestine at the resection margins was higher than that of the intestine afflicted with acute NEC. Endogenous HB-EGF may be involved in epithelial cell repair, proliferation, and regeneration during recovery from injury. Exogenous administration of HB-EGF potentiates recovery from intestinal injury in vitro and in vivo. Taken together, these results support a potential therapeutic role for HB-EGF in the treatment of NEC in the future.
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Affiliation(s)
- Jiexiong Feng
- Department of Surgery, Children's Hospital and The Ohio State University College of Medicine and Public Health, Columbus, Ohio 43205, USA
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Abstract
During ischemia, the cell structures are progressively damaged, but restoration of the blood flow, paradoxically, intensifies the lesions caused by the ischemia. The mechanisms of ischemia injury and reperfusion (I/R) have not been completely defined and many studies have been realized in an attempt to find an ideal therapy for mesenteric I/R. The occlusion and reperfusion of the splanchnic arteries provokes local and systemic alterations principally derived from the release of cytotoxic substances and the interaction between neutrophils and endothelial cells. Substances involved in the process are discussed in the present review, like oxygen-derived free radicals, nitric oxide, transcription factors, complement system, serotonin and pancreatic proteases. The mechanisms of apoptosis, alterations in other organs, therapeutic and evaluation methods are also discussed.
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Wang SF, Liang Q, Li GW, Gao K. Gene expression profile in rat small intestinal allografts after cold preservation/reperfusion. World J Gastroenterol 2005; 11:885-9. [PMID: 15682487 PMCID: PMC4250603 DOI: 10.3748/wjg.v11.i6.885] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the changes of gene expression profile in small intestinal allografts in rats after cold preservation/reperfusion, and to identify the genes relevant to cold preservation/reperfusion injury.
METHODS: Heterotopic segmental small bowel transpla-ntation was performed in six rats with a sham operation and they were used as controls. Total RNA was extracted from the allografts (experimental group) and normal intestines (control group) 1 h after cold preservation/reperfusion, and then purified to mRNA, which was then reversely transcribed to cDNA, and labeled with fluorescent Cy5-dUTP and Cy3-dUTP to prepare hybridization probes. The mixed probes were hybridized to the cDNA microarray. After high-stringent washing, the fluorescent signals on cDNA microarray chip were scanned and analyzed.
RESULTS: Among the 4 096 target genes, 82 differentially expressed genes were identified between the two groups. There were 18 novel genes, 33 expression sequence tags, and 31 previously reported genes. The selected genes may be divided into four classes: genes modulating cellular adhesion, genes regulating cellular energy, glucose and protein metabolism, early response genes and other genes.
CONCLUSION: A total of 82 genes that may be relevant to cold preservation/reperfusion injury in small intestinal allografts are identified. Abnormal adhesion between polymorphonuclears and endothelia and failure in energy, glucose and protein metabolism of the grafts may contribute to preservation/reperfusion injury. The functions of the novel genes identified in our study need to be clarified further.
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Affiliation(s)
- Shu-Feng Wang
- Department of General Surgery, First Hospital, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.
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Kozuch PL, Brandt LJ. Review article: diagnosis and management of mesenteric ischaemia with an emphasis on pharmacotherapy. Aliment Pharmacol Ther 2005; 21:201-15. [PMID: 15691294 DOI: 10.1111/j.1365-2036.2005.02269.x] [Citation(s) in RCA: 121] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Mesenteric ischaemia results from decreased blood flow to the bowel, causing cellular injury from lack of oxygen and nutrients. Acute mesenteric ischaemia (AMI) is an uncommon disorder with high morbidity and mortality, but outcomes are improved with prompt recognition and aggressive treatment. Five subgroups of AMI have been identified, with superior mesenteric artery embolism (SMAE) the most common. Older age and cardiovascular disease are common risk factors for AMI, excepting acute mesenteric venous thrombosis (AMVT), which affects younger patients with hypercoaguable states. AMI is characterized by sudden onset of abdominal pain; a benign abdominal exam may be observed prior to bowel infarction. Conventional angiography and more recently, computed tomography angiography, are the cornerstones of diagnosis. Correction of predisposing conditions, volume resuscitation and antibiotic treatment are standard treatments for AMI, and surgery is mandated in the setting of peritoneal signs. Intra-arterial vasodilators are used routinely in the treatment of non-occlusive mesenteric ischaemia (NOMI) and also are advocated in the treatment of occlusive AMI to decrease associated vasospasm. Thrombolytics have been used on a limited basis to treat occlusive AMI. A variety of agents have been studied in animal models to treat reperfusion injury, which sometimes can be more harmful than ischaemic injury. Chronic mesenteric ischaemia (CMI) usually is caused by severe obstructive atherosclerotic disease of two or more splanchnic vessels, presents with post-prandial pain and weight loss, and is treated by either surgical revascularization or percutaneous angioplasty and stenting.
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Affiliation(s)
- P L Kozuch
- Division of Gastroenterology, Department of Medicine, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY 10467, USA
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Walters JRF. Cell and molecular biology of the small intestine: new insights into differentiation, growth and repair. Curr Opin Gastroenterol 2004; 20:70-6. [PMID: 15703624 DOI: 10.1097/00001574-200403000-00004] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
PURPOSE OF REVIEW This paper will discuss recent research that has provided new insights into the molecular and cell biology of the small intestine. RECENT FINDINGS Differentiation of the epithelial cell lineages, including the enterocytes, enteroendocrine, Goblet and Paneth cells, from the stem cells is better understood. Important interactions have been demonstrated between these cells, luminal bacteria, and underlying mesenchymal tissue. Intestine-specific gene expression is regulated by transcription factors that are becoming well characterized, including CDX1, CDX2 and HNF1. The actions of growth factors such as GLP-2 and EGF are now known to be complex, demonstrating multiple effects in this tissue at a number of levels. SUMMARY Progress in the cellular and molecular biology of the small intestine is producing many intriguing new findings.
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Affiliation(s)
- Julian R F Walters
- Gastroenterology Section, Department of Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK.
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El-Assal ON, Besner GE. Heparin-binding epidermal growth factor-like growth factor and intestinal ischemia-reperfusion injury. Semin Pediatr Surg 2004; 13:2-10. [PMID: 14765365 DOI: 10.1053/j.sempedsurg.2003.09.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Intestinal ischemia/reperfusion (I/R) injury affects patients of different ages, especially premature babies and the elderly. The outcome after intestinal I/R is often dismal, which may be attributed to loss of the barrier and immune functions of the intestines, as well as development of secondary injury in remote organs. The available treatment for advanced gut ischemia mandates extensive resection, which may cause growth retardation in infants and nutritional problems in the elderly. Throughout the past decade we have been investigating the potential therapeutic role of heparin-binding epidermal growth factor-like factor (HB-EGF) in intestinal I/R. The mitogenic and chemoattractant functions of HB-EGF formed the initial rationale for our investigations. In addition, HB-EGF is a potent antiapoptotic protein that enables cells and tissues exposed to different apoptotic stimuli to survive hypoxic, oxidative, and nutritional stresses. HB-EGF is known to have a vital role in wound healing and postischemic regeneration in different organs. In the current review, we summarize the results of our findings of the beneficial effects of HB-EGF in intestinal I/R, supported by additional evidence from the literature and an explanation of different possible mechanisms of its actions. Collectively, the data strongly suggest a potential therapeutic role for the use of HB-EGF to treat intestinal ischemic diseases such as I/R and necrotizing enterocolitis.
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Affiliation(s)
- Osama N El-Assal
- Department of Surgery, Children's Hospital and The Ohio State University College of Medicine and Public Health, Columbus, OH 43205, USA
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