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Nijssen DJ, van der Aa DC, Ali M, Kazemier G, Jamaludin FS, Eshuis WJ, van Berge Henegouwen MI, Gisbertz SS. Resection vs. Ligation vs. Preservation of the Thoracic Duct During Esophagectomy for Cancer: A Systematic Review and Meta-Analysis. Cancers (Basel) 2025; 17:967. [PMID: 40149302 PMCID: PMC11940447 DOI: 10.3390/cancers17060967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/05/2025] [Accepted: 03/11/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND/OBJECTIVES The effect of thoracic duct (TD) management-resection, ligation, or preservation-during esophagectomy for cancer remains controversial. This systematic review and meta-analysis aimed to assess the impact of TD management strategies on oncological outcomes and surgical morbidity. METHODS A systematic review and meta-analysis were performed following PRISMA reporting guidelines. Searches of OVID, Embase, and Web of Science identified studies comparing thoracic duct resection or TD ligation with TD preservation in esophagectomy for cancer. Outcomes included 5-year overall survival (OS), postoperative morbidity, postoperative chyle leakage, lymph node yield, and length of stay. Random-effects meta-analyses using the Hartung-Knapp-Sidik-Jonkman variance correction were conducted. RESULTS A total of 17 studies involving 4200 patients were included. TD resection was associated with a significantly higher lymph node yield (mean difference [MD]: 4, 95% CI: 0 to 8, p = 0.043), but also increased risk of chyle leakage (odds ratio [OR]: 2.41, 95% CI: 1.04-5.61, p = 0.044). There was no significant improvement in 5-year OS with TD resection compared to TD preservation (hazard ratio [HR]: 0.94, 95% CI: 0.76-1.17, p = 0.48). TD ligation showed no significant differences in 5-year OS (HR: 1.15, 95% CI: 0.81-1.63, p = 0.33) or morbidity compared to TD preservation. Certainty of evidence was low across outcomes. CONCLUSIONS TD resection increases lymph node yield but is associated with higher rates of chyle leakage, without a significantly improved overall survival. TD ligation does not significantly affect oncological or surgical outcomes compared to TD preservation. A higher grade of evidence is needed to determine the definitive oncological and surgical impact of TD management strategies.
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Affiliation(s)
- David J. Nijssen
- Department of Surgery, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Treatment and Quality of Life, 1066 CX Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Dillen C. van der Aa
- Department of Surgery, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Treatment and Quality of Life, 1066 CX Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Mahsoem Ali
- Cancer Center Amsterdam, Cancer Treatment and Quality of Life, 1066 CX Amsterdam, The Netherlands
- Department of Surgery, Amsterdam UMC location Vrije Universiteit, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands
| | - Geert Kazemier
- Cancer Center Amsterdam, Cancer Treatment and Quality of Life, 1066 CX Amsterdam, The Netherlands
- Department of Surgery, Amsterdam UMC location Vrije Universiteit, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands
| | - Faridi S. Jamaludin
- Medical Library AMC, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Wietse J. Eshuis
- Department of Surgery, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Treatment and Quality of Life, 1066 CX Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Mark I. van Berge Henegouwen
- Department of Surgery, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Treatment and Quality of Life, 1066 CX Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Suzanne S. Gisbertz
- Department of Surgery, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Treatment and Quality of Life, 1066 CX Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
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Aiolfi A, Bona D, Cali M, Manara M, Bonitta G, Alfieri R, Castoro C, Elshafei M, Markar SR, Bonavina L. Impact of Thoracic Duct Resection on Long-Term Survival After Esophagectomy: Individual Patient Data Meta-analysis. Ann Surg Oncol 2024; 31:6699-6709. [PMID: 39031260 DOI: 10.1245/s10434-024-15770-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 06/24/2024] [Indexed: 07/22/2024]
Abstract
BACKGROUND Radical esophagectomy, including thoracic duct resection (TDR), has been proposed to improve regional lymphadenectomy and possibly reduce the risk of locoregional recurrence. However, because of its impact on immunoregulation, some authors have expressed concerns about its possible detrimental effect on long-term survival. The purpose of this review was to assess the influence of TDR on long-term survival. PATIENTS AND METHODS PubMed, MEDLINE, Scopus, and Web of Science databases were searched through 15 March 2024. Overall survival (OS), cancer specific survival (CSS), and disease-free survival (DFS) were primary outcomes. Restricted mean survival time difference (RMSTD), risk ratio (RR), standardized mean difference (SMD), and 95% confidence intervals (CI) were used as pooled effect size measures. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology was employed to evaluate the certainty of evidence. RESULTS The analysis included six studies with 5756 patients undergoing transthoracic esophagectomy. TDR was reported in 49.1%. Patients' ages ranged from 27 to 79 years and 86% were males. At 4-year follow-up, the multivariate meta-analysis showed similar results for the comparison noTDR versus TDR in term of OS [- 0.8 months, 95% confidence interval (CI) - 3.1, 1.3], CSS (0.1 months, 95% CI - 0.9, 1.2), and DFS (1.5 months, 95% CI - 2.6, 5.5). TDR was associated with a significantly higher number of harvested mediastinal lymph nodes (SMD 0.57, 95% CI 0.01-1.13) and higher risk of postoperative chylothorax (RR = 1.32; 95% CI 1.04-2.23). Anastomotic leak and pulmonary complications were comparable. CONCLUSIONS TDR seems not to improve long-term OS, CSS, and DFS regardless of tumor stage. Routine TDR should not be routinely recommended during esophagectomy.
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Affiliation(s)
- Alberto Aiolfi
- I.R.C.C.S Ospedale Galeazzi - Sant'Ambrogio, Division of General Surgery, Department of Biomedical Science for Health, University of Milan, Milan, Italy.
| | - Davide Bona
- I.R.C.C.S Ospedale Galeazzi - Sant'Ambrogio, Division of General Surgery, Department of Biomedical Science for Health, University of Milan, Milan, Italy
| | - Matteo Cali
- I.R.C.C.S Ospedale Galeazzi - Sant'Ambrogio, Division of General Surgery, Department of Biomedical Science for Health, University of Milan, Milan, Italy
| | - Michele Manara
- I.R.C.C.S Ospedale Galeazzi - Sant'Ambrogio, Division of General Surgery, Department of Biomedical Science for Health, University of Milan, Milan, Italy
| | - Gianluca Bonitta
- I.R.C.C.S Ospedale Galeazzi - Sant'Ambrogio, Division of General Surgery, Department of Biomedical Science for Health, University of Milan, Milan, Italy
| | - Rita Alfieri
- Upper Gastrointestinal Surgery Unit, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Carlo Castoro
- Upper Gastrointestinal Surgery Unit, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Moustafa Elshafei
- Department of Bariatric and Metabolic Medicine, Clinic Northwest, Frankfurt, Germany
| | - Sheraz R Markar
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Luigi Bonavina
- Department of Biomedical Sciences for Health, Division of General and Foregut Surgery, IRCCS Policlinico San Donato, University of Milan, Milan, Italy
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3
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Aiolfi A, Bona D, Calì M, Manara M, Rausa E, Bonitta G, Elshafei M, Markar SR, Bonavina L. Does Thoracic Duct Ligation at the Time of Esophagectomy Impact Long-Term Survival? An Individual Patient Data Meta-Analysis. J Clin Med 2024; 13:2849. [PMID: 38792391 PMCID: PMC11122204 DOI: 10.3390/jcm13102849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/01/2024] [Accepted: 05/08/2024] [Indexed: 05/26/2024] Open
Abstract
Background: Thoracic duct ligation (TDL) during esophagectomy has been proposed to reduce the risk of postoperative chylothorax. Because of its role in immunoregulation, some authors argued that it had an unfavorable TDL effect on survival. The aim of this study was to analyze the effect of TDL on overall survival (OS). Methods: PubMed, MEDLINE, Scopus, and Web of Science were searched through December 2023. The primary outcome was 5-year OS. The restricted mean survival time difference (RMSTD), hazard ratios (HRs), and 95% confidence intervals (CI) were used as pooled effect size measures. The GRADE methodology was used to summarize the certainty of the evidence. Results: Five studies (3291 patients) were included. TDL was reported in 54% patients. The patients' age ranged from 49 to 69, 76% were males, and BMI ranged from 18 to 26. At the 5-year follow-up, the combined effect from the multivariate meta-analysis is -3.5 months (95% CI -6.1, -0.8) indicating that patients undergoing TDL lived 3.5 months less compared to those without TDL. TDL was associated with a significantly higher hazard for mortality at 12 months (HR 1.54, 95% CI 1.38-1.73), 24 months (HR 1.21, 95% CI 1.12-1.35), and 28 months (HR 1.14, 95% CI 1.02-1.28). TDL and noTDL seem comparable in terms of the postoperative risk for chylothorax (RR = 0.66; p = 0.35). Conclusions: In this study, concurrent TDL was associated with reduced 5-year OS after esophagectomy. This may suggest the need of a rigorous follow-up within the first two years of follow-up.
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Affiliation(s)
- Alberto Aiolfi
- IRCCS Ospedale Galeazzi—Sant’Ambrogio, Division of General Surgery, Department of Biomedical Science for Health, University of Milan, 20157 Milan, Italy; (D.B.)
| | - Davide Bona
- IRCCS Ospedale Galeazzi—Sant’Ambrogio, Division of General Surgery, Department of Biomedical Science for Health, University of Milan, 20157 Milan, Italy; (D.B.)
| | - Matteo Calì
- IRCCS Ospedale Galeazzi—Sant’Ambrogio, Division of General Surgery, Department of Biomedical Science for Health, University of Milan, 20157 Milan, Italy; (D.B.)
| | - Michele Manara
- IRCCS Ospedale Galeazzi—Sant’Ambrogio, Division of General Surgery, Department of Biomedical Science for Health, University of Milan, 20157 Milan, Italy; (D.B.)
| | - Emanuele Rausa
- IRCCS Ospedale Galeazzi—Sant’Ambrogio, Division of General Surgery, Department of Biomedical Science for Health, University of Milan, 20157 Milan, Italy; (D.B.)
| | - Gianluca Bonitta
- IRCCS Ospedale Galeazzi—Sant’Ambrogio, Division of General Surgery, Department of Biomedical Science for Health, University of Milan, 20157 Milan, Italy; (D.B.)
| | - Moustafa Elshafei
- Department of Bariatric and Metabolic Medicine, Clinic Northwest, 60488 Frankfurt, Germany;
| | - Sheraz R. Markar
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX1 2JD, UK;
| | - Luigi Bonavina
- IRCCS Policlinico San Donato, Division of General and Foregut Surgery, Department of Biomedical Sciences for Health, University of Milan, 20097 Milan, Italy;
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dos Santos CL, dos Santos LL, Tavares G, Tristão LS, Orlandini MF, Serafim MCA, Datrino LN, Bernardo WM, Tustumi F. Prophylactic thoracic duct obliteration and resection during esophagectomy: What is the impact on perioperative risks and long‐term survival? A systematic review and meta‐analysis. J Surg Oncol 2022; 126:90-98. [DOI: 10.1002/jso.26827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 02/06/2022] [Accepted: 02/08/2022] [Indexed: 01/27/2023]
Affiliation(s)
- Clara L. dos Santos
- Department of Evidence‐based Medicine Centro Universitário Lusíada Santos SP Brazil
| | - Laura L. dos Santos
- Department of Gastroenterology Universidade de São Paulo Sao Paulo SP Brazil
| | - Guilherme Tavares
- Department of Evidence‐based Medicine Centro Universitário Lusíada Santos SP Brazil
| | - Luca S. Tristão
- Department of Evidence‐based Medicine Centro Universitário Lusíada Santos SP Brazil
| | - Marina F. Orlandini
- Department of Evidence‐based Medicine Centro Universitário Lusíada Santos SP Brazil
| | - Maria C. A. Serafim
- Department of Evidence‐based Medicine Centro Universitário Lusíada Santos SP Brazil
| | - Letícia N. Datrino
- Department of Evidence‐based Medicine Centro Universitário Lusíada Santos SP Brazil
| | - Wanderley M. Bernardo
- Department of Evidence‐based Medicine Centro Universitário Lusíada Santos SP Brazil
- Department of Gastroenterology Universidade de São Paulo Sao Paulo SP Brazil
| | - Francisco Tustumi
- Department of Evidence‐based Medicine Centro Universitário Lusíada Santos SP Brazil
- Department of Gastroenterology Universidade de São Paulo Sao Paulo SP Brazil
- Department of Surgery Hospital Israelita Albert Einstein Sao Paulo SP Brazil
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Arifa RDN, de Paula TP, Lima RL, Brito CB, Andrade MER, Cardoso VN, Pinheiro MVB, Ladeira LO, Krambrock K, Teixeira MM, Fagundes CT, Souza DG. Anti-inflammatory and antioxidant effects of the nanocomposite Fullerol decrease the severity of intestinal inflammation induced by gut ischemia and reperfusion. Eur J Pharmacol 2021; 898:173984. [PMID: 33647256 DOI: 10.1016/j.ejphar.2021.173984] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 02/15/2021] [Accepted: 02/23/2021] [Indexed: 12/12/2022]
Abstract
Intestinal ischemia is a vascular emergency that arises when blood flow to the intestine is compromised. Reperfusion is necessary to restore intestinal function but might lead to local and systemic inflammatory responses and bacterial translocation, with consequent multiple organ dysfunction syndrome (MODS). During reperfusion occurs production of reactive oxygen species. These species contribute to intestinal injury through direct toxicity or activation of inflammatory pathways. Fullerol is a nanacomposite which has been shown to act as reactive oxygen species and reactive nitrogen species (RNS) scavengers. Thus, our aim was to evaluate whether Fullerol confer anti-inflammatory activity during intestinal ischemia and reperfusion (IIR). Intestinal ischemia was induced by total occlusion of the superior mesenteric artery. Groups were treated with vehicle or Fullerol 10 min before reperfusion. Mice were euthanized after 6 h of reperfusion, and small intestines were collected for evaluation of plasma extravasation, leukocyte influx, cytokine production and histological damage. Bacterial translocation to the peritoneal cavity and reactive oxygen and nitrogen species production by lamina propria cells were also evaluated. Our results showed that treatment with Fullerol inhibited bacterial translocation to the peritoneal cavity, delayed and decreased the lethality rates and diminished neutrophil influx and intestinal injury induced by IIR. Reduced severity of reperfusion injury in Fullerol-treated mice was associated with blunted reactive oxygen and nitrogen species production in leukocytes isolated from gut lamina propria and decreased production of pro-inflammatory mediators. Thus, the present study shows that Fullerol is a potential therapy to treat inflammatory bowel disorders associated with bacterial translocation, such as IIR.
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Affiliation(s)
| | - Talles Prosperi de Paula
- Laboratório de Interação Microrganismo Hospedeiro, Departamento de Microbiologia, Belo Horizonte, MG, Brazil
| | - Renata Lacerda Lima
- Laboratório de Interação Microrganismo Hospedeiro, Departamento de Microbiologia, Belo Horizonte, MG, Brazil
| | - Camila Bernardo Brito
- Laboratório de Interação Microrganismo Hospedeiro, Departamento de Microbiologia, Belo Horizonte, MG, Brazil
| | | | | | | | - Luiz Orlando Ladeira
- Departamento de Física, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Klaus Krambrock
- Departamento de Física, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Mauro Martins Teixeira
- Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Belo Horizonte, MG, Brazil; Centro de Pesquisa e Desenvolvimento de Fármacos, Instituto de Ciências Biológicas, Belo Horizonte, MG, Brazil
| | - Caio Tavares Fagundes
- Laboratório de Interação Microrganismo Hospedeiro, Departamento de Microbiologia, Belo Horizonte, MG, Brazil; Centro de Pesquisa e Desenvolvimento de Fármacos, Instituto de Ciências Biológicas, Belo Horizonte, MG, Brazil
| | - Daniele Gloria Souza
- Laboratório de Interação Microrganismo Hospedeiro, Departamento de Microbiologia, Belo Horizonte, MG, Brazil.
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Kamel M, Ahmed SM, Abdelzaher W. The potential protective effect of modafinil in intestinal ischemic reperfusion-induced in rats. Int Immunopharmacol 2020; 88:106983. [PMID: 33182022 DOI: 10.1016/j.intimp.2020.106983] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 08/22/2020] [Accepted: 09/04/2020] [Indexed: 01/19/2023]
Abstract
OBJECTIVE Intestinal ischemia reperfusion (IR) is a pathophysiologic process that leads to oxidative stress and acute inflammatory responses. Understanding the mechanisms explaining this inflammation is essential to developing therapeutic strategies. Therefore, the purpose of this study was to evaluate the protective outcome of modafinil (Mod) against intestinal damages caused by intestinal IR injury. METHODS/MATERIALS Fourty adult Male Wistar rats were randomly divided into four groups: sham control group; intestinal IR group; Mod pre-treated IR group and Mod post-treated IR group. Mod in a dose of 10 mg/kg was injected intraperitoneally once daily for 7 days pre or post IR treatment. RESULTS Mod significantly attenuated the IR induced elevations in intestinal malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor alpha (TNF-α), interleukin 1-β (IL-1β) and P-glycoprotein (P-gp) levels, caspase-3 activity. However, a significant increase in TAC was reported as compared with the IR group but its post-treated IR group was highly protective. Mod post-treatment down-regulated the IR induced cyclo-oxygenase-2 (COX-2) over-expression. Distorted mucosa with loss of surface epithelial cells, epithelial separation oedematous lamina propria and inflammatory cellular infiltration detected by histopathological examination of intestinal tissue, were markedly ameliorated by Mod post-treatment. On the other hand, Mod pre-treatment showed less protection against intestinal IR in rats. CONCLUSION Current study suggests that Mod post-treatment ameliorated intestinal damages, so it can be considered a potential therapeutic agent to protect against the major clinical challenge of intestinal injury resulting from IR.
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Affiliation(s)
- MahaYehia Kamel
- Department of Pharmacology, Faculty of Medicine, Minia University, Egypt
| | - Sabreen Mahmoud Ahmed
- Depatment of Human Anatomy and Embryology, Faculty of Medicine, Minia University, Delegated to Deraya University-New Minia City, Egypt
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Chen JY, Liu QW, Zhang SS, Li JB, Yang H, Wen J, Fu JH. Prophylactic thoracic duct ligation is associated with poor prognosis and regional lymph node relapse in esophageal squamous cell carcinoma. J Surg Oncol 2020; 122:336-343. [PMID: 32410255 DOI: 10.1002/jso.25948] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 03/28/2020] [Accepted: 04/13/2020] [Indexed: 01/30/2023]
Abstract
OBJECTIVES The ligation of thoracic duct interrupts the normal lymphatic circulation. Whether the ligation of thoracic duct would affect tumor recurrence and patient survival is unclear. METHODS The correlations between prophylactic thoracic duct ligation (PLG) and prognosis were examined in patients with esophageal squamous cell carcinoma. Patients who received Ivor Lewis or McKeown esophagectomy with systemic lymph node dissection and R0 resection between 2003 and 2013 in Sun Yat-sen University Cancer Center were included in the study. RESULTS A total number of 473 and 462 were included in the PLG group and non-prophylactic thoracic duct ligation (NPLG) group, respectively. The PLG group had a lower 5-year survival rate (48.2% vs 61.6%, P < .001). After a 1:1 propensity score matching, 874 cases (437 pairs) were included and the survival analysis showed that PLG was associated with worse 5-year cumulative survival of 48.6% vs 61.6% in those patients without ligation (P < .001). The multivariate analysis revealed that PLG was an independent factor for poor prognosis after esophagectomy (hazard ratio, HR = 1.56; 95% confidence interval, 95% CI, 1.26-1.93, P < .001). Additionally, PLG was associated with regional lymph node relapse (P = .015). CONCLUSIONS PLG should not be performed routinely if no sign of thoracic duct rupture or tumor invasion were identified.
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Affiliation(s)
- Jun-Ying Chen
- Guangdong Esophageal Cancer Institute, Guangzhou, China.,Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qian-Wen Liu
- Guangdong Esophageal Cancer Institute, Guangzhou, China.,Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shui-Shen Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jin-Bo Li
- Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Hong Yang
- Guangdong Esophageal Cancer Institute, Guangzhou, China.,Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jing Wen
- Guangdong Esophageal Cancer Institute, Guangzhou, China.,Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jian-Hua Fu
- Guangdong Esophageal Cancer Institute, Guangzhou, China.,Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
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8
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Oshikiri T, Takiguchi G, Miura S, Goto H, Otsubo D, Hasegawa H, Yamamoto M, Kanaji S, Yamashita K, Matsuda T, Fujino Y, Tominaga M, Nakamura T, Suzuki S, Kakeji Y. Thoracic Duct Resection During Esophagectomy Does Not Contribute to Improved Prognosis in Esophageal Squamous Cell Carcinoma: A Propensity Score Matched-Cohort Study. Ann Surg Oncol 2019; 26:4053-4061. [PMID: 31313045 DOI: 10.1245/s10434-019-07627-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Indexed: 02/06/2023]
Abstract
PURPOSE Esophagectomy with extended lymphadenectomy remains the mainstay of treatment for localized esophageal squamous cell carcinoma (ESCC). Thoracic duct (TD) resection has been recommended as part of extended lymphadenectomy, although its merits are unclear. The aim of this two-institutional, matched-cohort study is to clarify whether TD resection improves prognosis in esophagectomy for ESCC. PATIENTS AND METHODS In this two-institutional, matched-cohort study of 399 patients with ESCC who underwent McKeown esophagectomy between 2010 and 2014, the primary outcomes were overall survival (OS), disease-free survival (DFS), and cause-specific survival (CSS). Secondary outcomes were perioperative results and recurrence patterns. RESULTS Based on a propensity score, 122 TD-resected or 122 TD-preserved patients in all stages were selected (median follow-up 4.5 years). The 5-year OS, DFS, and CSS rates in the TD-resected versus TD-preserved groups were 49% versus 60%, 53% versus 57%, and 58% versus 70%, respectively, without any significant differences. Operative time for the thoracic procedure was significantly longer and the number of retrieved mediastinal nodes was significantly higher in the TD-resected group (P = 0.009 and 0.005, respectively). The rates of chylothorax and left recurrent laryngeal nerve (RLN) palsy were significantly higher in the TD-resected group (P = 0.041 and 0.018, respectively). There were no significant differences in rates of local or distant metastases between the two groups. CONCLUSIONS TD resection does not contribute to improve OS, DFS, or CSS in ESCC but increases incidence of chylothorax and left RLN palsy. Prophylactic TD resection should be avoided in esophagectomy for ESCC.
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Affiliation(s)
- Taro Oshikiri
- Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe, Hyogo, Japan.
| | - Gosuke Takiguchi
- Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe, Hyogo, Japan
| | - Susumu Miura
- Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe, Hyogo, Japan
| | - Hironobu Goto
- Department of Gastroenterological Surgery, Hyogo Cancer Center, Akashi, Hyogo, Japan
| | - Dai Otsubo
- Department of Gastroenterological Surgery, Hyogo Cancer Center, Akashi, Hyogo, Japan
| | - Hiroshi Hasegawa
- Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe, Hyogo, Japan
| | - Masashi Yamamoto
- Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe, Hyogo, Japan
| | - Shingo Kanaji
- Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe, Hyogo, Japan
| | - Kimihiro Yamashita
- Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe, Hyogo, Japan
| | - Takeru Matsuda
- Division of Minimally Invasive Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe, Hyogo, Japan
| | - Yasuhiro Fujino
- Department of Gastroenterological Surgery, Hyogo Cancer Center, Akashi, Hyogo, Japan
| | - Masahiro Tominaga
- Department of Gastroenterological Surgery, Hyogo Cancer Center, Akashi, Hyogo, Japan
| | - Tetsu Nakamura
- Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe, Hyogo, Japan
| | - Satoshi Suzuki
- Division of Community Medicine and Medical Network, Department of Social Community Medicine and Health Science, Graduate School of Medicine, Kobe University, Kobe, Hyogo, Japan
| | - Yoshihiro Kakeji
- Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe, Hyogo, Japan
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Silva PL, Gama de Abreu M. Regional distribution of transpulmonary pressure. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:385. [PMID: 30460259 DOI: 10.21037/atm.2018.10.03] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The pressure across the lung, so-called transpulmonary pressure (PL), represents the main force acting toward to provide lung movement. During mechanical ventilation, PL is provided by respiratory system pressurization, using specific ventilator setting settled by the operator, such as: tidal volume (VT), positive end-expiratory pressure (PEEP), respiratory rate (RR), and inspiratory airway flow. Once PL is developed throughout the lungs, its distribution is heterogeneous, being explained by the elastic properties of the lungs and pleural pressure gradient. There are different methods of PL calculation, each one with importance and some limitations. Among the most known, it can be quoted: (I) direct measurement of PL; (II) elastance derived method at end-inspiration of PL; (III) transpulmonary driving pressure. Recent studies using pleural sensors in large animal models as also in human cadaver have added new and important information about PL heterogeneous distribution across the lungs. Due to this heterogeneous distribution, lung damage could happen in specific areas of the lung. In addition, it is widely accepted that high PL can cause lung damage, however the way it is delivered, whether it's compressible or tensile, may also further damage despite the values of PL achieved. According to heterogeneous distribution of PL across the lungs, the interstitium and lymphatic vessels may also interplay to disseminate lung inflammation toward peripheral organs through thoracic lymph tracts. Thus, it is conceivable that juxta-diaphragmatic area associated strong efforts leading to high values of PL may be a source of dissemination of inflammatory cells, large molecules, and plasma contents able to perpetuate inflammation in distal organs.
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Affiliation(s)
- Pedro Leme Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcelo Gama de Abreu
- Pulmonary Engineering Group, Department of Anesthesiology and Intensive Care, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
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Windsor JA, Escott A, Brown L, Phillips AR. Novel strategies for the treatment of acute pancreatitis based on the determinants of severity. J Gastroenterol Hepatol 2017; 32:1796-1803. [PMID: 28294403 DOI: 10.1111/jgh.13784] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 03/04/2017] [Accepted: 03/05/2017] [Indexed: 02/06/2023]
Abstract
Acute pancreatitis (AP) is a common disease for which a specific treatment remains elusive. The key determinants of the outcome from AP are persistent organ failure and infected pancreatic necrosis. The prevention and treatment of these determinants provides a framework for the development of specific treatment strategies. The gut-lymph concept provides a common mechanism for systemic inflammation and organ dysfunction. Acute and critical illness, including AP, is associated with intestinal ischemia and drastic changes in the composition of gut lymph, which bypasses the liver to drain into the systemic circulation immediately proximal to the major organ systems which fail. The external diversion of gut lymph and the targeting of treatments to counter the toxic elements in gut lymph offers novel approaches to the prevention and treatment of persistent organ failure. Infected pancreatic necrosis is increasingly treated with less invasive techniques, the mainstay of which is drainage, both endoscopic and percutaneous. Further improvements will occur with the strategies to accelerate liquefaction and through a fundamental re-design of drains, both of which will increase drainage efficacy. The determinants of severity and outcome in patients admitted with AP provide the basis for innovative treatment strategies. The priorities are to translate the gut-lymph concept to clinical practice and to improve the design and active use of drains for infected complications of AP.
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Affiliation(s)
- John A Windsor
- Pancreas Research Group, Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Alistair Escott
- Pancreas Research Group, Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Lisa Brown
- Pancreas Research Group, Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Anthony Rj Phillips
- Pancreas Research Group, Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
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Davis RB, Kechele DO, Blakeney ES, Pawlak JB, Caron KM. Lymphatic deletion of calcitonin receptor-like receptor exacerbates intestinal inflammation. JCI Insight 2017; 2:e92465. [PMID: 28352669 DOI: 10.1172/jci.insight.92465] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Lymphatics play a critical role in maintaining gastrointestinal homeostasis and in the absorption of dietary lipids, yet their roles in intestinal inflammation remain elusive. Given the increasing prevalence of inflammatory bowel disease, we investigated whether lymphatic vessels contribute to, or may be causative of, disease progression. We generated a mouse model with temporal and spatial deletion of the key lymphangiogenic receptor for the adrenomedullin peptide, calcitonin receptor-like receptor (Calcrl), and found that the loss of lymphatic Calcrl was sufficient to induce intestinal lymphangiectasia, characterized by dilated lacteals and protein-losing enteropathy. Upon indomethacin challenge, Calcrlfl/fl/Prox1-CreERT2 mice demonstrated persistent inflammation and failure to recover and thrive. The epithelium and crypts of Calcrlfl/fl/Prox1-CreERT2 mice exhibited exacerbated hallmarks of disease progression, and the lacteals demonstrated an inability to absorb lipids. Furthermore, we identified Calcrl/adrenomedullin signaling as an essential upstream regulator of the Notch pathway, previously shown to be critical for intestinal lacteal maintenance and junctional integrity. In conclusion, lymphatic insufficiency and lymphangiectasia caused by loss of lymphatic Calcrl exacerbates intestinal recovery following mucosal injury and underscores the importance of lymphatic function in promoting recovery from intestinal inflammation.
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Datta P, Weis MT. Calcium glycerophosphate preserves transepithelial integrity in the Caco-2 model of intestinal transport. World J Gastroenterol 2015; 21:9055-9066. [PMID: 26290632 PMCID: PMC4533037 DOI: 10.3748/wjg.v21.i30.9055] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Revised: 05/13/2015] [Accepted: 06/26/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the direct effects of ischemia on intestinal epithelial integrity. Furthermore, clinical efforts at mitigating the effect of hypoperfusion on gut permeability have focused on restoring gut vascular function.
METHODS: We report that, in the Caco-2 cell model of transepithelial transport, calcium glycerophosphate (CGP), an inhibitor of intestinal alkaline phosphatase F3, has a significant effect to preserve transepithelial electrical resistance (TEER) and to attenuate increases in mannitol flux rates during hypoxia or cytokine stimulation.
RESULTS: The effect was observable even at concentrations as low as 1 μmol/L. As celiac disease is also marked by a loss of gut epithelial integrity, the effect of CGP to attenuate the effect of the α-gliadin peptide 31-55 was also examined. In this instance, CGP exerted little effect of preservation of TEER, but significantly attenuated peptide induced increase in mannitol flux.
CONCLUSION: It appears that CGP treatment might synergize with other therapies to preserve gut epithelial integrity.
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Prophylactic thoracic duct ligation has unfavorable impact on overall survival in patients with resectable oesophageal cancer. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2014; 40:1756-62. [DOI: 10.1016/j.ejso.2014.05.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 04/06/2014] [Accepted: 05/08/2014] [Indexed: 11/16/2022]
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Mesenteric lymph diversion abrogates 5-lipoxygenase activation in the kidney following trauma and hemorrhagic shock. J Trauma Acute Care Surg 2014; 76:1214-21. [PMID: 24747451 DOI: 10.1097/ta.0000000000000231] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Early acute kidney injury (AKI) following trauma is associated with multiorgan failure and mortality. Leukotrienes have been implicated both in AKI and in acute lung injury. Activated 5-lipoxygenase (5-LO) colocalizes with 5-LO-activating protein (FLAP) in the first step of leukotriene production following trauma and hemorrhagic shock (T/HS). Diversion of postshock mesenteric lymph, which is rich in the 5-LO substrate of arachidonate, attenuates lung injury and decreases 5-LO/FLAP associations in the lung after T/HS. We hypothesized that mesenteric lymph diversion (MLD) will also attenuate postshock 5-LO-mediated AKI. METHODS Rats underwent T/HS (laparotomy, hemorrhagic shock to a mean arterial pressure of 30 mm Hg for 45 minutes, and resuscitation), and MLD was accomplished via cannulation of the mesenteric duct. Extent of kidney injury was determined via histology score and verified by urinary neutrophil gelatinase-associated lipocalin assay. Kidney sections were immunostained for 5-LO and FLAP, and colocalization was determined by fluorescence resonance energy transfer signal intensity. The end leukotriene products of 5-LO were determined in urine. RESULTS AKI was evident in the T/HS group by derangement in kidney tubule architecture and confirmed by neutrophil gelatinase-associated lipocalin assay, whereas MLD during T/HS preserved renal tubule morphology at a sham level. MLD during T/HS decreased the associations between 5-LO and FLAP demonstrated by fluorescence resonance energy transfer microscopy and decreased leukotriene production in urine. CONCLUSION 5-LO and FLAP colocalize in the interstitium of the renal medulla following T/HS. MLD attenuates this phenomenon, which coincides with pathologic changes seen in tubules during kidney injury and biochemical evidence of AKI. These data suggest that gut-derived leukotriene substrate predisposes the kidney and the lung to subsequent injury.
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Protective Effect of Estradiol on Acute Lung Inflammation Induced by an Intestinal Ischemic Insult is Dependent on Nitric Oxide. Shock 2013; 40:203-9. [DOI: 10.1097/shk.0b013e3182a01e24] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Lloris Carsi JM, Cejalvo Lapeña D, Toledo AH, Zaragoza Fernandez C, Toledo Pereyra LH. Pentoxifylline Protects the Small Intestine After Severe Ischemia and Reperfusion. EXP CLIN TRANSPLANT 2013; 11:250-8. [DOI: 10.6002/ect.2012.0222] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Schander A, Downey HF, Hodge LM. Lymphatic pump manipulation mobilizes inflammatory mediators into lymphatic circulation. Exp Biol Med (Maywood) 2012; 237:58-63. [DOI: 10.1258/ebm.2011.011220] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Lymph stasis can result in edema and the accumulation of particulate matter, exudates, toxins and bacteria in tissue interstitial fluid, leading to inflammation, impaired immune cell trafficking, tissue hypoxia, tissue fibrosis and a variety of diseases. Previously, we demonstrated that osteopathic lymphatic pump techniques (LPTs) significantly increased thoracic and intestinal duct lymph flow. The purpose of this study was to determine if LPT would mobilize inflammatory mediators into the lymphatic circulation. Under anesthesia, thoracic or intestinal lymph of dogs was collected at resting (pre-LPT), during four minutes of LPT, and for 10 min following LPT (post-LPT), and the lymphatic concentrations of interleukin-2 (IL-2), IL-4, IL-6, IL-10, interferon- γ, tissue necrosis factor α, monocyte chemotactic protein-1 (MCP-1), keratinocyte chemoattractant, superoxide dismutase (SOD) and nitrotyrosine (NT) were measured. LPT significantly increased MCP-1 concentrations in thoracic duct lymph. Further, LPT increased both thoracic and intestinal duct lymph flux of cytokines and chemokines as compared with their respective pre-LPT flux. In addition, LPT increased lymphatic flux of SOD and NT. Ten minutes following cessation of LPT, thoracic and intestinal lymph flux of cytokines, chemokines, NT and SOD were similar to pre-LPT, demonstrating that their flux was transient and a response to LPT. This re-distribution of inflammatory mediators during LPT may provide scientific rationale for the clinical use of LPT to enhance immunity and treat infection.
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Affiliation(s)
| | - H Fred Downey
- Department of Integrative Physiology
- Osteopathic Research Center, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA
| | - Lisa M Hodge
- Department of Molecular Biology and Immunology
- Osteopathic Research Center, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA
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The effects of n-3 PUFA and intestinal lymph drainage on high-mobility group box 1 and Toll-like receptor 4 mRNA in rats with intestinal ischaemia-reperfusion injury. Br J Nutr 2011; 108:883-92. [PMID: 22186663 DOI: 10.1017/s0007114511006040] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The aim of the present study was to investigate the impacts of n-3 PUFA and lymph drainage (D) on intestinal ischaemia-reperfusion (I/R) injury in rats. A total of forty-eight Sprague-Dawley male rats were randomly divided into three groups (n 16): normal diet (N), enteral nutrition (EN) and EN plus n-3 PUFA. Each group was further divided into lymph drainage (I/R+D) and non-drainage (I/R) sub-groups (n 8). After 5 d with different nutrition regimens, the rats were subjected to 60 min ischaemia by clamping the superior mesenteric artery, followed by 120 min reperfusion. At the same time, the rats in the I/R+D sub-groups were treated with intestinal lymph drainage for 180 min. Organs were harvested and we detected the cytokine, endotoxin, and expression of Toll-like receptor (TLR) 4 mRNA and its endogenous ligand high-mobility group box 1 (HMGB1). We found that the serum levels of HMGB1, inflammatory cytokine and endotoxin in the three I/R+D sub-groups were significantly lower than those in the N (I/R) and EN (I/R) sub-groups (P < 0·05). The activation of NF-κB and the expression of HMGB1 and TLR4 mRNA significantly increased in the jejunum, ileum, liver and lung after intestinal I/R injury, but notably lower in the I/R+D groups than those in I/R (P < 0·05). The injury degree and HMGB1 expression were decreased in the n-3 PUFA group than in the N and EN groups. We preliminarily concluded that nutrition with n-3 PUFA and/or intestinal lymph drainage may reduce HMGB1 and inflammatory cytokine in serum and lymph and inhibit the expression and signal transmission of TLR4 mRNA, thereby alleviating intestinal I/R injury in rats.
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Wohlauer M, Moore E, Harr J, Eun J, Fragoso M, Banerjee A, Silliman CC. Cross-transfusion of postshock mesenteric lymph provokes acute lung injury. J Surg Res 2011; 170:314-8. [PMID: 21550053 PMCID: PMC3154326 DOI: 10.1016/j.jss.2011.03.045] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2011] [Revised: 02/24/2011] [Accepted: 03/17/2011] [Indexed: 01/30/2023]
Abstract
OBJECTIVE Substantial investigation has implicated mesenteric lymph as the mechanistic link between gut ischemia/reperfusion (I/R) and distant organ injury. Specifically, lymph diversion prevents acute lung injury (ALI) in vitro, and bioactive lipids and proteins isolated from postshock mesenteric lymph (PSML) maintain bioactivity in vitro. However, Koch's postulates remain to be satisfied via direct cross-transfusion into a naïve animal. We therefore hypothesized that real time cross-transfusion of postshock mesenteric lymph provokes acute lung injury. METHODS One set of Sprague-Dawley rats (lymph donors) was anesthetized, with the mesenteric lymph ducts cannulated and exteriorized to drain freely into a siliconates plastic cup; concurrently, a second group of rats ( lymph recipients) was anesthetized, with a cannula inserted into the animal's right internal jugular vein. Blood was removed from the donor rats to induce hemorrhagic shock (MAP of 35 mmHg × 45 min). The recipient rats were positioned 10 cm below the plastic cup, which emptied into the jugular vein cannula. Thus, mesenteric lymph from the shocked donor rat was delivered to the recipient rat at the rate generated during shock and the subsequent 3 h of resuscitation. RESULTS Neutrophil (PMN) accumulation in the lungs was substantially elevated in the postshock lymph cross-transfusion group compared to both sham lymph cross-transfusion and instrumented control (MPO: 9.42 ± 1.55 versus 2.81 ± 0.82 U/mg lung tissue in postshock versus sham lymph cross-transfusion, n = 6 in each group, P = 0.02). Additionally, cross-transfusion of PSML induced oxidative stress in the lung (0.21 ± 0.03 versus 0.10 ± 0.01 micromoles MDA per mg lung tissue in lymph cross-transfusion versus instrumented control, n = 6 in each group, P = 0.046). Furthermore, transfusion of PSML provoked lung injury (BAL protein 0.77 ± 0.18 versus 0.15 ± 0.02 mg/mL protein in BALF, postshock versus sham lymph cross-transfusion, n = 6 in each group, P = 0.004). CONCLUSION Cross-transfusion of PSML into a naïve animal leads to PMN accumulation and provokes ALI. These data provide evidence that postshock agents released into mesenteric lymph are capable of provoking distant organ injury.
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Affiliation(s)
- M. Wohlauer
- Department of Surgery, University of Colorado Denver, Denver, CO
| | - E. Moore
- Department of Surgery, University of Colorado Denver, Denver, CO
- Department of Surgery, Denver Health Medical Center, Denver, CO
| | - J. Harr
- Department of Surgery, University of Colorado Denver, Denver, CO
| | - J. Eun
- Department of Surgery, University of Colorado Denver, Denver, CO
| | - M. Fragoso
- Department of Surgery, University of Colorado Denver, Denver, CO
| | - A. Banerjee
- Department of Surgery, Denver Health Medical Center, Denver, CO
| | - CC Silliman
- Department of Pediatrics, University of Colorado Denver, Denver, CO
- Research Department, Bonfils Blood Center, Denver, CO
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Paulino AS, Palombit K, Cavriani G, Tavares-de-Lima W, Mizuno MS, Marosti AR, da Silva MV, Girotti PA, Liberti EA, Castelucci P. Effects of ischemia and reperfusion on P2X2 receptor expressing neurons of the rat ileum enteric nervous system. Dig Dis Sci 2011; 56:2262-2275. [PMID: 21409380 DOI: 10.1007/s10620-011-1588-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2010] [Accepted: 01/17/2011] [Indexed: 12/12/2022]
Abstract
PURPOSE We investigated the effects of ischemia/reperfusion in the intestine (I/R-i) on purine receptor P2X2-immunoreactive (IR) neurons of the rat ileum. METHODS The superior mesenteric artery was occluded for 45 min with an atraumatic vascular clamp and animals were sacrificed 4 h later. Neurons of the myenteric and submucosal plexuses were evaluated for immunoreactivity against the P2X2 receptor, nitric oxide synthase (NOS), choline acetyl transferase (ChAT), calbindin, and calretinin. RESULTS Following I/R-i, we observed a decrease in P2X2 receptor immunoreactivity in the cytoplasm and surface membranes of neurons of the myenteric and submucosal plexuses. These studies also revealed an absence of calbindin-positive neurons in the I/R-i group. In addition, the colocalization of the P2X2 receptor with NOS, ChAT, and calretinin immunoreactivity in the myenteric plexus was decreased following I/R-i. Likewise, the colocalization between P2X2 and calretinin in neurons of the submucosal plexus was also reduced. In the I/R-i group, there was a 55.8% decrease in the density of neurons immunoreactive (IR) for the P2X2 receptor, a 26.4% reduction in NOS-IR neuron, a 25% reduction in ChAT-IR neuron, and a 47% reduction in calretinin-IR neuron. The density of P2X2 receptor and calretinin-IR neurons also decreased in the submucosal plexus of the I/R-i group. In the myenteric plexus, P2X2-IR, NOS-IR, ChAT-IR and calretinin-IR neurons were reduced in size by 50%, 49.7%, 42%, and 33%, respectively, in the I/R-i group; in the submucosal plexus, P2X2-IR and calretinin-IR neurons were reduced in size by 56% and 72.6%, respectively. CONCLUSIONS These data demonstrate that ischemia/reperfusion of the intestine affects the expression of the P2X2 receptor in neurons of the myenteric and submucosal plexus, as well as density and size of neurons in this population. Our findings indicate that I/R-i induces changes in P2X2-IR enteric neurons that could result in alterations in intestinal motility.
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Affiliation(s)
- Ariane Silva Paulino
- Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Dr. Lineu Prestes, 2415, CEP 05508-900, São Paulo, Brazil
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Intestinal lymph-borne factors induce lung release of inflammatory mediators and expression of adhesion molecules after an intestinal ischemic insult. J Surg Res 2011; 176:195-201. [PMID: 21872880 DOI: 10.1016/j.jss.2011.06.074] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2011] [Revised: 06/29/2011] [Accepted: 06/30/2011] [Indexed: 12/30/2022]
Abstract
BACKGROUND Intestinal ischemia and reperfusion (I/R) is a documented cause of acute lung injury (ALI) and systemic inflammation. We previously reported that obstruction of thoracic lymphatic flow during intestinal I/R blunts pulmonary neutrophil recruitment and microvascular injury and decreases the systemic levels of tumor necrosis factor. Here, we consider the existence of a gut-lung axis promoting the induction of systemic inflammation, whereby drained intestinal lymph stimulates lung expression of adhesion molecules and matrix components and generation of inflammatory mediators. MATERIAL AND METHODS Upon administration of anesthesia, male Wistar rats were subjected to occlusion of the superior mesenteric artery for 45 min, followed by 2 h of intestinal reperfusion (I/R); groups of rats were subjected to I/R with or without thoracic lymphatic duct ligation immediately before the procedure. The non-manipulated rats were used to investigate basal parameters. RESULTS Obstruction of thoracic lymphatic flow before intestinal I/R decreased the ability of cultured lung tissue explants to release IL-1β, IL-10, and VEGF. In contrast, lymphatic obstruction normalized the elevated lung expression of PECAM-1 caused by intestinal I/R. On the other hand, lung E-selectin expression was significantly reduced, whereas fibronectin expression and collagen synthesis were not affected. Lymph levels of LTB(4) and TXB(2) were found to be significantly increased. CONCLUSIONS These data suggest that lymph factors drained from the intestine during ischemic trauma stimulate the lung to generate inflammatory mediators and alter the expression of adhesion molecules. Disturbances in lung homeostasis mediated by lymph might contribute to the spread of inflammatory processes, thereby accounting for the systemic inflammation induced by intestinal I/R.
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He GZ, Dong LG, Chen XF, Zhou KG, Shu H. Lymph duct ligation during ischemia/reperfusion prevents pulmonary dysfunction in a rat model with ω-3 polyunsaturated fatty acid and glutamine. Nutrition 2011; 27:604-14. [PMID: 20817408 DOI: 10.1016/j.nut.2010.06.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2009] [Revised: 05/31/2010] [Accepted: 06/03/2010] [Indexed: 01/17/2023]
Abstract
OBJECTIVE The release of injurious factors into the mesenteric lymph from the ischemic intestine has been shown to contribute to lung injury and systemic inflammation after severe injury. We studied the effects of lung injury and systemic inflammatory reaction after intestinal ischemia/reperfusion and mesenteric lymph duct ligation with different nutritional statuses. METHODS Rats (n = 72) were fed with a normal diet or received one of three diets (enteral nutrition, glutamine, or ω-3 polyunsaturated fatty acid) that were isocaloric and isonitrogenous. After 7 d, rats were subjected to 60 min of intestinal ischemia, ischemia plus mesenteric lymph duct ligation, or sham procedures. After 3 d of ischemia, the lymph nodes, lung, intestinal, liver, and blood were harvested and analyzed. RESULTS In the different groups, lung injury, including levels of myeloperoxidase, nitric oxide, nitric oxide synthase, and the index of alveolar apoptosis, were partly prevented by mesenteric lymph duct ligation (P < 0.05). Likewise, the rats with ischemia/reperfusion, but not those with duct ligation plus ischemia/reperfusion, had a significant increase in intestinal permeability and decreased mucosal thickness. The serum cytokine and endotoxin concentrations were also lower in the lymph duct ligation groups, although there was no significant difference between lymph duct ligation and sham procedure. The lung and intestinal injuries were attenuated in the groups fed with glutamine and ω-3 polyunsaturated fatty acid. CONCLUSION These results indicate that lymph duct ligation prevents lung injury, a systemic inflammation reaction, and gut-barrier dysfunction. Enteral glutamine and ω-3 polyunsaturated fatty acid modified the gut inflammation, prevented lung injury, and attenuated the systemic inflammation reaction.
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Affiliation(s)
- Gui-zhen He
- Department of Parenteral and Enteral Nutrition, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing 100730, China.
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Alexander JS, Ganta VC, Jordan PA, Witte MH. Gastrointestinal lymphatics in health and disease. ACTA ACUST UNITED AC 2011; 17:315-35. [PMID: 20022228 DOI: 10.1016/j.pathophys.2009.09.003] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2009] [Revised: 09/28/2009] [Accepted: 09/28/2009] [Indexed: 12/17/2022]
Abstract
Lymphatics perform essential transport and immune regulatory functions to maintain homeostasis in the gastrointestinal (GI) system. Although blood and lymphatic vessels function as parallel and integrated systems, our understanding of lymphatic structure, regulation and functioning lags far behind that of the blood vascular system. This chapter reviews lymphatic flow, differences in lymphangiogenic and hemangiogenic factors, lymphatic fate determinants and structural features, and examines how altered molecular signaling influences lymphatic function in organs of the GI system. Innate errors in lymphatic development frequently disturb GI functioning and physiology. Expansion of lymphatics, a prominent feature of GI inflammation, may also play an important role in tissue restitution following injury. Destruction or dysregulation of lymphatics, following injury, surgery or chronic inflammation also exacerbates GI disease activity. Understanding the physiological roles played by GI lymphatics is essential to elucidating their underlying contributions to forms of congenital and acquired forms of GI pathology, and will provide novel approaches for therapy.
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Affiliation(s)
- J S Alexander
- Louisiana State University Health Sciences Center-Shreveport, Molecular and Cellular Physiology, Shreveport, LA, United States
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Tumor necrosis factor is not associated with intestinal ischemia/reperfusion-induced lung inflammation. Shock 2011; 34:306-13. [PMID: 20160673 DOI: 10.1097/shk.0b013e3181cdc585] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Intestinal ischemia-reperfusion (I/R) injury may cause acute systemic and lung inflammation. Here, we revisited the role of TNF-alpha in an intestinal I/R model in mice, showing that this cytokine is not required for the local and remote inflammatory response upon intestinal I/R injury using neutralizing TNF-alpha antibodies and TNF ligand-deficient mice. We demonstrate increased neutrophil recruitment in the lung as assessed by myeloperoxidase activity and augmented IL-6, granulocyte colony-stimulating factor, and KC levels, whereas TNF-alpha levels in serum were not increased and only minimally elevated in intestine and lung upon intestinal I/R injury. Importantly, TNF-alpha antibody neutralization neither diminished neutrophil recruitment nor any of the cytokines and chemokines evaluated. In addition, the inflammatory response was not abrogated in TNF and TNF receptors 1 and 2-deficient mice. However, in view of the damage on the intestinal barrier upon intestinal I/R with systemic bacterial translocation, we asked whether Toll-like receptor (TLR) activation is driving the inflammatory response. In fact, the inflammatory lung response is dramatically reduced in TLR2/4-deficient mice, confirming an important role of TLR receptor signaling causing the inflammatory lung response. In conclusion, endogenous TNF-alpha is not or minimally elevated and plays no role as a mediator for the inflammatory response upon ischemic tissue injury. By contrast, TLR2/4 signaling induces an orchestrated cytokine/chemokine response leading to local and remote pulmonary inflammation, and therefore disruption of TLR signaling may represent an alternative therapeutic target.
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Moore EE. Claude H. Organ, Jr. memorial lecture: splanchnic hypoperfusion provokes acute lung injury via a 5-lipoxygenase-dependent mechanism. Am J Surg 2011; 200:681-9. [PMID: 21146002 DOI: 10.1016/j.amjsurg.2010.05.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2010] [Revised: 05/31/2010] [Accepted: 05/31/2010] [Indexed: 01/01/2023]
Abstract
Postinjury multiple organ failure (MOF) is the net result of a dysfunctional immune response to injury characterized by a hyperactive innate system and a suppressed adaptive system. Acute lung injury (ALI) is the first clinical manifestation of organ failure, followed by renal and hepatic dysfunction. Circulatory shock is integral in the early pathogenesis of MOF, and the gut has been invoked as the motor of MOF. Mesenteric lymph is recognized as the mechanistic link between splanchnic ischemia/reperfusion and distant organ dysfunction, but the specific mediators remain to be defined. Current evidence suggests the lipid fraction of postshock mesenteric lymph is central in the etiology of ALI. Specifically, our recent work suggests that intestinal phospholipase A2 generated arachidonic acid and its subsequent 5-lipoxygenase products are essential in the pathogenesis of ALI. Proteins conveyed via postshock mesenteric lymph also may have an important role. Elucidating these mediators and the timing of their participation in pulmonary inflammation is critical in translating our current knowledge to new therapeutic strategies at the bedside.
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Affiliation(s)
- Ernest E Moore
- Department of Surgery, University of Colorado Denver, Denver, CO 80204, USA.
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Alexander JS, Chaitanya GV, Grisham MB, Boktor M. Emerging roles of lymphatics in inflammatory bowel disease. Ann N Y Acad Sci 2010; 1207 Suppl 1:E75-85. [PMID: 20961310 DOI: 10.1111/j.1749-6632.2010.05757.x] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The mobilization and recruitment of blood and lymphatic vasculatures are widely described in inflammatory bowel diseases (IBDs). Although angiogenesis contributes to intense gut inflammation, it remains unclear whether and when lymphangiogenesis amplifies or protects in IBD. The prolonged maintenance of lymphatic (over blood vessels) in inflammation indicates that lymphatic-blood vessel interactions may regulate IBD pathogenesis and restitution. Although lymphatic expansion helps to restore fluid balance and clear cytokines and immune cells, lymphatic failure results in accumulation of these factors and exacerbates IBD. Lymphatic obstruction and remodeling may impair lymphatic pumping, leading to repeated rounds of lymphangiogenesis. Early descriptions of Crohn's disease and ulcerative colitis describe colon lymphatic congestion, remodeling, expansion, and many other features that are recapitulated in experimental IBD and also by intestinal lymphatic obstruction, supporting lymphangitis as a cause and consequence of IBD. Growth factors, cytokines, gut flora, Toll receptors, and leukocytes all regulate inflammation and gut lymphatic remodeling in IBD. This review summarizes the importance of lymphatics and lymphangiogenesis in IBD etiology that may be useful in diagnosis and therapy of gut inflammation.
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Affiliation(s)
- J Steven Alexander
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana 71130-3932, USA.
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Lung inflammation is induced by renal ischemia and reperfusion injury as part of the systemic inflammatory syndrome. Inflamm Res 2010; 59:861-9. [PMID: 20396927 DOI: 10.1007/s00011-010-0198-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2009] [Revised: 03/27/2010] [Accepted: 03/31/2010] [Indexed: 10/19/2022] Open
Abstract
INTRODUCTION Ischemia and reperfusion injury (IRI) are mainly caused by leukocyte activation, endothelial dysfunction and production of reactive oxygen species. Moreover, IRI can lead to a systemic response affecting distant organs, such as the lungs. AIM The objective was to study the pulmonary inflammatory systemic response after renal IRI. METHODS Male C57Bl/6 mice were subjected to 45 min of bilateral renal ischemia, followed by 4, 6, 12, 24 and 48 h of reperfusion. Blood was collected to measure serum creatinine and cytokine concentrations. Bronchoalveolar lavage fluid (BALF) was collected to determine the number of cells and PGE(2) concentration. Expressions of iNOS and COX-2 in lung were determined by Western blot. Gene analyses were quantified by real time PCR. RESULTS Serum creatinine increased in the IRI group compared to sham mainly at 24 h after IRI (2.57 +/- 0.16 vs. 0.43 +/- 0.07, p < 0.01). The total number of cells in BAL fluid was higher in the IRI group in comparison with sham, 12 h (100 x 10(4) +/- 15.63 vs. 18.1 x 10(4) +/- 10.5, p < 0.05) 24 h (124 x 10(4) +/- 8.94 vs. 23.2 x 10(4) +/- 3.5, p < 0.05) and 48 h (79 x 10(4) +/- 15.72 vs. 22.2 x 10(4) +/- 4.2, p < 0.05), mainly by mononuclear cells and neutrophils. Pulmonary COX-2 and iNOS were up-regulated in the IRI group. TNF-alpha, IL-1beta, MCP-1, KC and IL-6 mRNA expression were up-regulated in kidney and lungs 24 h after renal IRI. ICAM-1 mRNA was up-regulated in lungs 24 h after renal IRI. Serum TNF-alpha, IL-1beta and MCP-1 and BALF PGE(2) concentrations were increased 24 h after renal IRI. CONCLUSION Renal IRI induces an increase of cellular infiltration, up-regulation of COX-2, iNOS and ICAM-1, enhanced chemokine expression and a Th1 cytokine profile in lung demonstrating that the inflammatory response is indeed systemic, possibly leading to an amplification of renal injury.
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Local and remote tissue injury upon intestinal ischemia and reperfusion depends on the TLR/MyD88 signaling pathway. Med Microbiol Immunol 2009; 199:35-42. [DOI: 10.1007/s00430-009-0134-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2009] [Indexed: 01/01/2023]
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Nitric oxide mediates lung vascular permeability and lymph-borne IL-6 after an intestinal ischemic insult. Shock 2009; 32:55-61. [PMID: 18838940 DOI: 10.1097/shk.0b013e31818bb7a1] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Acute lung injury following intestinal I/R depends on neutrophil-endothelial cell interactions and on cytokines drained from the gut through the lymph. Among the mediators generated during I/R, increased serum levels of IL-6 and NO are also found and might be involved in acute lung injury. Once intestinal ischemia itself may be a factor of tissue injury, in this study, we investigated the presence of IL-6 in lymph after intestinal ischemia and its effects on human umbilical vein endothelial cells (HUVECs) detachment. The involvement of NO on the increase of lung and intestinal microvascular permeability and the lymph effects on HUVEC detachment were also studied. Upon anesthesia, male Wistar rats were subjected to occlusion of the superior mesenteric artery during 45 min, followed by 2-h intestinal reperfusion. Rats were treated with the nonselective NO synthase (NOS) inhibitor L-NAME (N(omega)-nitro-L-arginine methyl ester) or with the selective inhibitor of iNOS aminoguanidine 1 h before superior mesenteric artery occlusion. Whereas treatment with L-NAME during ischemia increased both IL-6 levels in lymph and lung microvascular permeability, aminoguanidine restored the augmented intestinal plasma extravasation due to ischemia and did not induce IL-6 in lymph. On the other hand, IL-6 and lymph of intestinal I/R detached the HUVECs, whereas lymph of ischemic rats upon L-NAME treatment when incubated with anti-IL-6 prevented HUVEC detachment. It is shown that the intestinal ischemia itself is sufficient to increase intestinal microvascular permeability with involvement of iNOS activation. Intestinal ischemia and absence of constitutive NOS activity leading to additional intestinal stress both cause release of IL-6 and increase of lung microvascular permeability. Because anti-IL-6 prevented the endothelial cell injury caused by lymph at the ischemia period, the lymph-borne IL-6 might be involved with endothelial cell activation. At the reperfusion period, this cytokine does not seem to be modulated by NO.
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Kinross J, Warren O, Basson S, Holmes E, Silk D, Darzi A, Nicholson JK. Intestinal ischemia/reperfusion injury: defining the role of the gut microbiome. Biomark Med 2009; 3:175-92. [DOI: 10.2217/bmm.09.11] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Intestinal ischemia/reperfusion (I/R) injury initiates a systemic inflammatory response syndrome with a high associated mortality rate. Early diagnosis is essential for reducing surgical mortality, yet current clinical biomarkers are insufficient. Metabonomics is a novel strategy for studying intestinal I/R, which may be used as part of a systems approach for quantitatively analyzing the intestinal microbiome during gut injury. By deconvolving the mammalian–microbial symbiotic relationship systems biology thus has the potential for personalized risk stratification in patients exposed to intestinal I/R. This review describes the mechanism of intestinal I/R and explores the essential role of the intestinal microbiota in the initiation of systemic inflammatory response syndrome. Furthermore, it analyzes current and future approaches for elucidating the mechanism of this condition.
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Affiliation(s)
- James Kinross
- Department of Biomolecular Medicine, SORA, Imperial College London
| | - Oliver Warren
- Department of Biomolecular Medicine, SORA, Imperial College London
| | | | - Elaine Holmes
- Department of Biomolecular Medicine, SORA, Imperial College London
| | - David Silk
- Department of Biomolecular Medicine, SORA, Imperial College London
| | - Ara Darzi
- Department of Biomolecular Medicine, SORA, Imperial College London
| | - Jeremy K Nicholson
- Professor of Biological Chemistry, Head of Department of Biomolecular Medicine, SORA, Imperial College, 6th Floor, Sir Alexander Fleming Building, South Kensington Campus, London, SW7 2AZ, UK
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Li JY, Yin HZ, Gu X, Zhou Y, Zhang WH, Qin YM. Melatonin protects liver from intestine ischemia reperfusion injury in rats. World J Gastroenterol 2008; 14:7392-6. [PMID: 19109875 PMCID: PMC2778125 DOI: 10.3748/wjg.14.7392] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [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 protective effect of melatonin on liver after intestinal ischemia-reperfusion injury in rats.
METHODS: One hundred and fifty male Wistar rats, weighing 190-210 g, aged 7 wk, were randomly divided into melatonin exposure group, alcohol solvent control group and normal saline control group. Rats in the melatonin exposure group received intraperitoneal (IP) melatonin (20 mg/kg) 30 min before intestinal ischemia-reperfusion (IR), rats in the alcohol solvent control group received the same concentration and volume of alcohol, and rats in the normal saline control group received the same volume of normal saline. Serum samples were collected from each group 0.5, 1, 6, 12, and 24 h after intestinal IR. Levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured with an auto-biochemical analyzer. Serum TNF-α was tested by enzyme-linked immunosorbent assay (ELISA). Malondialdehyde (MDA) in liver was detected by colorimetric assay. Pathological changes in liver and immunohistochemical straining of ICAM-1 were observed under an optical microscope.
RESULTS: The levels of ALT measured at various time points after intestinal IR in the melatonin exposure group were significantly lower than those in the other two control groups (P < 0.05). The serum AST levels 12 and 24 h after intestinal IR and the ICAM-1 levels (%) 6, 12 and 24 h after intestinal IR in the melatonin exposure group were also significantly lower than those in the other two control groups (P < 0.05).
CONCLUSION: Exotic melatonin can inhibit the activity of ALT, AST and TNF-α, decrease the accumulation of MDA, and depress the expression of ICAM-1 in liver after intestinal IR injury, thus improving the liver function.
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Oliveira WRSD, Silva ID, Simões RS, Fuchs LFP, Oliveira-Filho RM, Oliveira-Júnior ISD. Effects of prone and supine position on oxygenation and inflammatory mediator in a hydrochloric acid-induced lung dysfunction in rats. Acta Cir Bras 2008; 23:451-5. [PMID: 18797691 DOI: 10.1590/s0102-86502008000500011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2008] [Accepted: 06/24/2008] [Indexed: 11/21/2022] Open
Abstract
PURPOSE To compare the effectiveness of mechanical ventilation of supine versus prone position in hydrochloric acid (HCl)-induced lung dysfunction. METHODS Twenty, adult, male, Wistar-EPM-1 rats were anesthetized and randomly grouped (n=5 animals per group) as follows: CS-MV (mechanical ventilation in supine position); CP-MV (mechanical ventilation in prone position); bilateral instillation of HCl and mechanical ventilation in supine position (HCl+S); and bilateral instillation of HCl and mechanical ventilation in prone position (HCl+P). All groups were ventilated for 180 minutes. The blood partial pressures of oxygen and carbon dioxide were measured in the time points 0 (zero; 10 minutes before lung injury for stabilization), and at the end of times acid injury, 60, 120 and 180 minutes of mechanical ventilation. At the end of experiment the animals were euthanized, and bronchoalveolar lavages (BALs) were taken to determine the contents of total proteins, inflammatory mediators, and lungs wet-to-dry ratios. RESULTS In the HCl+P group the partial pressure of oxygen increased when compared with HCl+S (128.0+/-2.9 mmHg and 111.0+/-6.7 mmHg, respectively) within 60 minutes. TNF-alpha levels in BAL do not differ significantly in the HCl+P group (516.0+/-5.9 pg/mL), and the HCl+S (513.0+/-10.6 pg/mL). CONCLUSION The use of prone position improved oxygenation, but did not reduce TNF-alpha in BAL upon lung dysfunction induced by HCl.
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Liu C, Wu Q, Li Q, Liu D, Su H, Shen N, Tai M, Lv Y. Mesenteric lymphatic ducts ligation decreases the degree of gut-induced lung injury in a portal vein occlusion and reperfusion canine model. J Surg Res 2008; 154:45-50. [PMID: 19201426 DOI: 10.1016/j.jss.2008.06.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2008] [Revised: 04/02/2008] [Accepted: 06/05/2008] [Indexed: 01/22/2023]
Abstract
BACKGROUND Whether the mesenteric lymphatic system could serve as a route of transport by which gut-derived inflammatory mediators contribute to the induction of remote organ injuries is uncertain. We therefore made a gut-induced lung injury canine model by portal vein occlusion and reperfusion (PV O/R) and studied the role of mesenteric lymphatic ducts ligation (ML) to gut-induced lung injury with this model. MATERIAL AND METHODS Eighteen mongrel dogs were divided into control, PV O/R, and PV O/R + ML groups. Cytokines and endotoxin levels in the portal vein and lymph from thoracic duct in different groups were tested. The permeability, myeloperoxidase activity, and histopathological investigation of intestine and lung were evaluated. RESULTS Cytokines and endotoxin levels in the portal vein were significantly increased in experimental groups compared with control group (P < 0.05), and that in the lymph from thoracic duct were significantly increased in PV O/R group compared with control and PV O/R + ML group (P < 0.05). Lung permeability and MPO activity in PV O/R group were significantly higher than those in control and PV O/R + ML group (P < 0.05); intestinal permeability in experimental groups were significantly higher with respect to control group. The lung injury score in PV O/R group was significantly higher than those in control and PV O/R + ML group (P < 0.05) and the intestinal injury scores in experimental groups were significantly higher than control group (P < 0.05). CONCLUSIONS The gut-induced lung injury canine model made by PV O/R is successful, and mesenteric lymphatic ducts ligation decreases the degree of gut-induced lung injury in this model.
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Affiliation(s)
- Chang Liu
- Department of Hepatobiliary Surgery, First Affiliated Hospital, School of Medicine, Xi'an Jiao Tong University, Xi'an, China
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Abstract
PURPOSE OF REVIEW Lymph flow will be discussed as part of the drainage and fluid balance of lung tissue and abdomen as well as a qualitative analysis of inflammatory processes. RECENT FINDINGS Measurement of lung lymph is still a technical challenge. Mechanical ventilation and positive end-expiratory pressure impede lung lymph flow by increased intrathoracic pressure and increased central venous pressure. Positive end-expiratory pressure may thus enhance edema formation of the lung. Inflammatory spread from abdomen to the lung via the lymphatic system has been shown in a number of experimental studies. Ligation or diversion of the thoracic duct has been proposed to blunt the effects of noxious stimuli mediated by lymphatics to the lungs. Lymphatics have a major role on abdominal fluid balance while draining extravascular fluid accumulation and edema, especially during sepsis. Mechanical ventilation with high airway pressure increases abdominal edema (ascites) and spontaneous breathing protects from edema formation. SUMMARY Lymph flow measurements are still a difficult task to perform; however, new results show an important function in the fluid balance of the lung and abdomen. Inflammatory spread may occur from the lung to the periphery by the blood stream and from the abdomen to the lung by lymph flow.
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Coelho FR, Cavriani G, Soares AL, Teixeira SA, Almeida PCL, Sudo-Hayashi LS, Muscará MN, Oliveira-Filho RM, Vargaftig BB, Tavares-de-Lima W. Lymphatic-borne IL-1beta and the inducible isoform of nitric oxide synthase trigger the bronchial hyporesponsiveness after intestinal ischema/reperfusion in rats. Shock 2008; 28:694-9. [PMID: 17607157 DOI: 10.1097/shk.0b013e318053621d] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Intestinal I/R (i-I/R) is an insult associated to further adult respiratory distress syndrome and multiple organ failure. This study was designed to evaluate the repercussions of i-I/R on bronchial reactivity to the cholinergic agent methacholine. Anesthetized rats were subjected to superior mesenteric artery occlusion (45 min) and killed after clamp release and defined intestinal reperfusion periods (30 min, 2, 4, or 24 h). Intestinal I/R caused a progressive bronchial hyporesponsiveness (BHR) that was maximal upon 2 h but reverted within 24 h of intestinal reperfusion. The BHR observed at 2-h i-I/R was prevented by NOS inhibitors (N-L-nitroarginine methyl ester and aminoguanidine) or the KATP channel blocker glibenclamide. Moreover, 2-h i-I/R increased the pulmonary iNOS mRNA expression, a fact prevented by lymphatic thoracic duct ligation. The methacholine reactivity of 2-h i-I/R bronchial segments incubated with NOS inhibitors or glibenclamide was similar to that of naive tissues. In vivo blockade of IL-1beta receptors or lymphatic duct ligation before 2-h i-I/R both abolished BHR. Incubation of naive bronchial segments with lymph collected from 2-h i-I/R rats determined BHR, an effect fully preventable by ex vivo blockade of IL-1beta receptors. Incubation of naive bronchial segments with IL-1beta, but not with IL-10 or TNF-alpha, significantly induced BHR that was prevented by N-L-nitroarginine methyl ester. Our data suggest that a gut ischemic insult generates IL-1beta that, upon reperfusion, travels through the lymph into the lungs. In this tissue, IL-1beta would stimulate the generation of NO that orchestrates the ensuing BHR for which the opening of KATP channels seems to play a pivotal role.
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Affiliation(s)
- Fernando Rodrigues Coelho
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
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Blei F. Literature watch. Blood and lymphatic endothelial cell-specific differentiation programs are stringently controlled by the tissue environment. Lymphat Res Biol 2007; 5:49-65. [PMID: 17508902 DOI: 10.1089/lrb.2007.5106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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WHAT'S NEW IN SHOCK, FEBRUARY 2007? Shock 2007. [DOI: 10.1097/shk.0b013e31802e45d4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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