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The Importance of CXCL1 in the Physiological State and in Noncancer Diseases of the Oral Cavity and Abdominal Organs. Int J Mol Sci 2022; 23:ijms23137151. [PMID: 35806156 PMCID: PMC9266754 DOI: 10.3390/ijms23137151] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 06/23/2022] [Accepted: 06/25/2022] [Indexed: 02/06/2023] Open
Abstract
CXCL1 is a CXC chemokine, CXCR2 ligand and chemotactic factor for neutrophils. In this paper, we present a review of the role of the chemokine CXCL1 in physiology and in selected major non-cancer diseases of the oral cavity and abdominal organs (gingiva, salivary glands, stomach, liver, pancreas, intestines, and kidneys). We focus on the importance of CXCL1 on implantation and placentation as well as on human pluripotent stem cells. We also show the significance of CXCL1 in selected diseases of the abdominal organs, including the gastrointestinal tract and oral cavity (periodontal diseases, periodontitis, Sjögren syndrome, Helicobacter pylori infection, diabetes, liver cirrhosis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), HBV and HCV infection, liver ischemia and reperfusion injury, inflammatory bowel disease (Crohn’s disease and ulcerative colitis), obesity and overweight, kidney transplantation and ischemic-reperfusion injury, endometriosis and adenomyosis).
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Herrlich A. Interorgan crosstalk mechanisms in disease: the case of acute kidney injury-induced remote lung injury. FEBS Lett 2021; 596:620-637. [PMID: 34932216 DOI: 10.1002/1873-3468.14262] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 12/08/2021] [Accepted: 12/09/2021] [Indexed: 11/07/2022]
Abstract
Homeostasis and health of multicellular organisms with multiple organs depends on interorgan communication. Tissue injury in one organ disturbs this homeostasis and can lead to disease in multiple organs, or multiorgan failure. Many routes of interorgan crosstalk during homeostasis are relatively well known, but interorgan crosstalk in disease still lacks understanding. In particular, how tissue injury in one organ can drive injury at remote sites and trigger multiorgan failure with high mortality is poorly understood. As examples, acute kidney injury can trigger acute lung injury and cardiovascular dysfunction; pneumonia, sepsis or liver failure conversely can cause kidney failure; lung transplantation very frequently triggers acute kidney injury. Mechanistically, interorgan crosstalk after tissue injury could involve soluble mediators and their target receptors, cellular mediators, in particular immune cells, as well as newly identified neuro-immune connections. In this review, I will focus the discussion of deleterious interorgan crosstalk and its mechanistic concepts on one example, acute kidney injury-induced remote lung injury.
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Affiliation(s)
- Andreas Herrlich
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, MO, USA
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Frydas S, Papaioannou N, Papazahariadou M, Hatzistilianou M, Karagouni E, Trakatelli M, Brellou G, Petrarca C, Castellani ML, Conti P, Riccioni G, Patruno A, Grilli A. Inhibition of MCP-1 and MIP-2 Chemokines in Murine Trichinellosis: Effect of the Anti-Inflammatory Compound L-Mimosine. Int J Immunopathol Pharmacol 2016; 18:85-94. [PMID: 15698514 DOI: 10.1177/039463200501800110] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Mimosine, is a plant amino-acid which has been reported to block DNA replication in mammalian cells and to arrest cells reversibly towards the end of the G1 phase or at the beginning of the S phase. In this study, 42 mice were infected with T. spiralis, a nematode parasite, and treated with the anti-inflammatory compound L-mimosine, to determine if any alteration in the chronic inflammatory state occurred, by investigating the host's immunological response. MCP-1, a C-C chemokine and MIP-2, a C-X-C chemokine were tested and measured in the sera of infected animals, after 1, 10, 20, 30, 40, 50 and 60 days postinfection, by ELISA method. The diaphragm/muscle and the masseters of the infected mice, were tested for inflammatory response. We found that MCP-1 was partially inhibited by L-mimosine, while MIP-2 was totally inhibited. Moreover, in sections of the diaphragm and masseters, the infiltration of inflammatory cells such as macrophages, lymphocytes and eosinophils were more intense in untreated animals compared to those treated with L-mimosine. These findings show, that L-mimosine may have an inhibitory effect on MCP-1 and MIP-2 serum levels in Trichinellosis and may influence the recruitment of inflammatory cells and the intensity of the inflammatory reaction in this parasitic disease.
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Affiliation(s)
- S Frydas
- Parasitology Dept. Veterinary Faculty, Aristotelian University of Thessaloniki, Greece.
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Organ cross talk and remote organ damage following acute kidney injury. Int Urol Nephrol 2014; 46:2337-45. [DOI: 10.1007/s11255-014-0766-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Accepted: 06/10/2014] [Indexed: 10/25/2022]
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6
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Lentsch AB. Regulatory mechanisms of injury and repair after hepatic ischemia/reperfusion. SCIENTIFICA 2012; 2012:513192. [PMID: 24278708 PMCID: PMC3820555 DOI: 10.6064/2012/513192] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Accepted: 09/12/2012] [Indexed: 06/02/2023]
Abstract
Hepatic ischemia/reperfusion injury is an important complication of liver surgery and transplantation. The mechanisms of this injury as well as the subsequent reparative and regenerative processes have been the subject of thorough study. In this paper, we discuss the complex and coordinated responses leading to parenchymal damage after liver ischemia/reperfusion as well as the manner in which the liver clears damaged cells and regenerates functional mass.
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Affiliation(s)
- Alex B. Lentsch
- Department of Surgery, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, ML 0558, Cincinnati, OH 45267-0558, USA
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Altmann C, Andres-Hernando A, McMahan RH, Ahuja N, He Z, Rivard CJ, Edelstein CL, Barthel L, Janssen WJ, Faubel S. Macrophages mediate lung inflammation in a mouse model of ischemic acute kidney injury. Am J Physiol Renal Physiol 2011; 302:F421-32. [PMID: 22114207 DOI: 10.1152/ajprenal.00559.2010] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Serum IL-6 is increased in acute kidney injury (AKI) and inhibition of IL-6 reduces AKI-mediated lung inflammation. We hypothesized that circulating monocytes produce IL-6 and that alveolar macrophages mediate lung inflammation after AKI via chemokine (CXCL1) production. To investigate systemic and alveolar macrophages in lung injury after AKI, sham operation or 22 min of renal pedicle clamping (AKI) was performed in three experimental settings: 1) systemic macrophage depletion via diphtheria toxin (DT) injection to CD11b-DTR transgenic mice, 2) DT injection to wild-type mice, and 3) alveolar macrophage depletion via intratracheal (IT) liposome-encapsulated clodronate (LEC) administration to wild-type mice. In mice with AKI and systemic macrophage depletion (CD11b-DTR transgenic administered DT) vs. vehicle-treated AKI, blood monocytes and lung interstitial macrophages were reduced, renal function was similar, serum IL-6 was increased, lung inflammation was improved, lung CXCL1 was reduced, and lung capillary leak was increased. In wild-type mice with AKI administered DT vs. vehicle, serum IL-6 was increased. In mice with AKI and alveolar macrophage depletion (IT-LEC) vs. AKI with normal alveolar macrophage content, blood monocytes and lung interstitial macrophages were similar, alveolar macrophages were reduced, renal function was similar, lung inflammation was improved, lung CXCL1 was reduced, and lung capillary leak was increased. In conclusion, administration of DT in AKI is proinflammatory, limiting the use of the DTR-transgenic model to study systemic effects of AKI. Mice with AKI and either systemic mononuclear phagocyte depletion or alveolar macrophage depletion had reduced lung inflammation and lung CXCL1, but increased lung capillary leak; thus, mononuclear phagocytes mediate lung inflammation, but they protect against lung capillary leak after ischemic AKI. Since macrophage activation and chemokine production are key events in the development of acute lung injury (ALI), these data provide further evidence that AKI may cause ALI.
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Van Sweringen HL, Sakai N, Tevar AD, Burns JM, Edwards MJ, Lentsch AB. CXC chemokine signaling in the liver: impact on repair and regeneration. Hepatology 2011; 54:1445-53. [PMID: 21626524 PMCID: PMC3175305 DOI: 10.1002/hep.24457] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2011] [Accepted: 05/17/2011] [Indexed: 01/12/2023]
Abstract
The process of liver repair and regeneration following hepatic injury is complex and relies on a temporally coordinated integration of several key signaling pathways. Pathways activated by members of the CXC family of chemokines play important roles in the mechanisms of liver repair and regeneration through their effects on hepatocytes. However, little is known about the signaling pathways used by CXC chemokine receptors in hepatocytes. Here we review our current understanding of the pathways involved in both CXC chemokine receptor signaling in other cell types, most notably neutrophils, and similar pathways operant during hepatocyte proliferation/liver regeneration to formulate a basis for the function of CXC chemokine receptor signaling in hepatocytes.
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Perry BC, Soltys D, Toledo AH, Toledo-Pereyra LH. Tumor Necrosis Factor-α in Liver Ischemia/Reperfusion Injury. J INVEST SURG 2011; 24:178-88. [DOI: 10.3109/08941939.2011.568594] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Ypsilantis P, Lambropoulou M, Anagnostopoulos C, Tsigalou C, Vasiliadis C, Kortsaris A, Papadopoulos N, Simopoulos C. Pringle maneuver exacerbates systemic inflammatory response and multiple-organ injury induced by extended liver radiofrequency ablation. Hum Exp Toxicol 2011; 30:1855-64. [PMID: 21382910 DOI: 10.1177/0960327111401438] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
AIM To assess the systemic inflammatory response (SIR) and the multi-organ damage after large-volume liver radiofrequency ablation (RFA) with or without concurrent Pringle maneuver. METHODS Wistar rats were subjected to 30% liver RFA (group RFA), liver RFA under 30-min Pringle maneuver (group RFA + P), Pringle only (group P) or sham operation (group S). Serum levels of interleukin-1α (IL-1α), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), serum biochemical profile, multiple-organ pathology and the activity of nuclear factor-κB (NF-κB) in the liver were assessed post-operatively. RESULTS The levels of IL-6 and TNF-α were increased from 1h up to 1w and 6h, respectively, in both RFA groups, while IL-6 was only mildly increased at 3 h in group P. IL-6 was higher in group RFA + P compared to group RFA. Serum biochemical profile was altered more intensely in group RFA + P compared to RFA. There was tissue injury in the non-ablated liver portion as well as in adjacent and remote organs with lesions being more severe in group RFA + P. At 1 h, NF-κB was equally activated in all study groups. CONCLUSIONS Extended liver RFA causes SIR and multi-organ injury, which are exacerbated when a concurrent Pringle maneuver is applied.
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Affiliation(s)
- Petros Ypsilantis
- Laboratory of Experimental Surgery and Surgical Research, School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.
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Klune JR, Tsung A. Molecular biology of liver ischemia/reperfusion injury: established mechanisms and recent advancements. Surg Clin North Am 2010; 90:665-77. [PMID: 20637940 DOI: 10.1016/j.suc.2010.04.003] [Citation(s) in RCA: 147] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Hepatic ischemia/reperfusion (I/R) injury occurs in a variety of clinical contexts, including transplantation, liver resection surgery, trauma, and hypovolemic shock. The mechanism of organ damage after I/R has been studied extensively and consists of complex interactions of multiple inflammatory pathways. The major contributors to I/R injury include production of reactive oxygen species, release of proinflammatory cytokines and chemokines, and activation of immune cells to promote inflammation and tissue damage. Recent research has focused on the mechanisms by which these immune responses are initially activated through signaling molecules and their cellular receptors. Thorough understanding of the pathophysiology of liver I/R may yield novel therapeutic strategies to reduce I/R injury and lead to improved clinical outcomes.
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Affiliation(s)
- John R Klune
- Department of Surgery, F675 UPMC Presbyterian Hospital, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA
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Iida A, Yoshidome H, Shida T, Takano S, Takeuchi D, Kimura F, Shimizu H, Ohtsuka M, Miyazaki M. Hepatocyte nuclear factor-kappa beta (NF-kappaB) activation is protective but is decreased in the cholestatic liver with endotoxemia. Surgery 2010; 148:477-89. [PMID: 20227101 DOI: 10.1016/j.surg.2010.01.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2009] [Accepted: 01/18/2010] [Indexed: 12/30/2022]
Abstract
BACKGROUND Obstructive jaundice (OJ) is an important clinical consideration associated with a high risk of bacteremia. Hepatocyte nuclear factor-kappa B (NF-kappaB) activation confers an antiapoptotic function. Although the occurrence of hepatocyte apoptosis has been shown in OJ, the activation and role of NF-kappaB over the time course of OJ in conjunction with endotoxemia have not yet been well defined. We hypothesized that NF-kappaB activation may be decreased over the time course of OJ and endotoxemia, which leads to severe liver injury. The aim of the current study was to examine whether NF-kappaB activation can decrease hepatocyte apoptosis and liver injury over the time course of OJ in response to lipopolysaccharide (LPS) administration. METHODS Male C57BL/6 mice were subjected to bile duct ligation and were administered LPS intravenously at 3 days (OJ3) or 14 days (OJ14) after bile duct ligation. NF-kappaB activation; protein expressions of NF-kappaB p65, IkappaB-alpha, Ikappabeta-b, and Pin1; immunohistochemistry of poly adenosine diphosphate (ADP)-ribose polymerase p85 fragment (PARP); and serum alanine transaminase (ALT) levels were examined. RESULTS Hepatocyte NF-kappaB activation was observed during OJ. After LPS administration, the hepatic NF-kappaB activation defined by electrophoretic mobility shift assay was decreased in the OJ14 group compared with the OJ3 group, which is consistent with a decrease in NF-kappaB p65 protein expression. Changes in phosphorylated Ikappa-B-beta but not phosphorylated IkappaB-alpha mirrored these results. Significant hepatocyte apoptosis defined by PARP immunohistochemistry was observed in the LPS-treated OJ14 relative to the LPS-treated OJ3. Hepatic expressions of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in the LPS OJ14 mice were upregulated relative to those in the LPS OJ3. Serum ALT levels increased significantly in the LPS OJ14 relative to other mice. The survival rate was significantly less in the LPS OJ14 relative to other mice. CONCLUSION After prolonged OJ, exposure to endotoxemia was associated with a decrease in hepatocyte NF-kappaB activation and an increase in hepatocyte apoptosis and secondary necrosis, thus resulting in liver dysfunction.
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Affiliation(s)
- Ayako Iida
- Department of General Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
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Takeuchi D, Yoshidome H, Kurosawa H, Kimura F, Shimizu H, Ohtsuka M, Kato A, Yoshitomi H, Furukawa K, Miyazaki M. Interleukin-18 exacerbates pulmonary injury after hepatic ischemia/reperfusion in mice. J Surg Res 2010; 158:87-93. [PMID: 19394645 DOI: 10.1016/j.jss.2008.08.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2008] [Revised: 07/30/2008] [Accepted: 08/06/2008] [Indexed: 11/15/2022]
Abstract
BACKGROUND Hepatic ischemia/reperfusion has been shown to cause both local hepatic and distant organ (such as lung) injury caused by accumulation of neutrophils in the local and distant organs, leading to neutrophil-dependent organ injury. Interleukin (IL) -18 is required for facilitating neutrophil-dependent local hepatic injury by suppressing anti-inflammatory cytokine expression, but less is known about the involvement of this cytokine in distant organ injury. The objective of this study was to determine whether IL-18 contributes to pulmonary injury induced by hepatic ischemia/reperfusion. METHODS C57BL/6 mice and IL-18 knockout mice (C57BL/6 background) were subjected to 90 min of partial hepatic ischemia and subsequent reperfusion. Neutrophil accumulation in the lung was assessed by pulmonary myeloperoxidase contents. Pulmonary expressions of keratinocyte derived chemokine (KC, CXCL1), macrophage chemoattractant protein-1 (MCP-1, CCL2), tumor necrosis factor-alpha, interferon-gamma, IL-4, and IL-10 were measured by tissue enzyme-linked immunosorbent assay (ELISA). Lung edema was quantified by the pulmonary wet to dry weight ratios. RESULTS Hepatic ischemia/reperfusion caused significant increases in pulmonary neutrophil recruitment and lung edema. Also, pulmonary expression of KC and MCP-1 were up-regulated. In the IL-18 knockout mice, hepatic ischemia/reperfusion-induced increases in pulmonary neutrophil recruitment, lung injury defined by lung edema, and pulmonary chemokine expression were attenuated. Furthermore, pulmonary expression of an anti-inflammatory cytokine IL-4 and systemic IL-10 expression were significantly up-regulated in the IL-18 knockout mice. CONCLUSIONS The data suggested that IL-18 plays an important role in the development of pulmonary injury after hepatic ischemia/reperfusion by up-regulating proinflammatory mediators and possibly suppressing anti-inflammatory cytokine expression.
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Affiliation(s)
- Dan Takeuchi
- Department of General Surgery, Chiba University Graduate School of Medicine, Chiba-Shi, Chiba, Japan
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Wang BY, Li QX, Li J, Xie XF, Ao Y, Ai YX. Hepatotoxicity and gene expression down-regulation of CYP isozymes caused by renal ischemia/reperfusion in the rat. ACTA ACUST UNITED AC 2009; 61:169-76. [PMID: 19230630 DOI: 10.1016/j.etp.2008.12.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2008] [Revised: 11/25/2008] [Accepted: 12/30/2008] [Indexed: 11/29/2022]
Abstract
Renal ischemia/reperfusion (I/R) occurs in many clinical scenarios, including trauma, elective surgery, and transplantation. Events initiated by this process can lead to inflammation in the kidneys, culminating in local injury as well as distant organ dysfunction. The objectives of this study were to investigate the changes in the functions of the liver and the regulation of gene expression of cytochrome P450 (CYP) isozymes after renal I/R. Hepatoxocity was assessed by serum alanine aminotransferase (sALT), serum aspartate aminotransferase (sAST) and liver glutathione-S-transferase (GST) activities, liver glutathione (GSH) level, and histopathological examination. Hepatic cytochrome P4503A1 (CYP3A1) and cytochrome P4502E1 (CYP2E1) activities were measured by erythromycin N-demethylase (ERD) and aniline hydroxylase (ANH) activities, respectively. CYP3A1 and CYP2E1 mRNA expression was determined by RT-PCR. Results showed that activities of sALT and sAST were significantly increased, while hepatic CYP3A1and CYP2E1 activities as well as their respective mRNA levels were significantly decreased after renal I/R. Moreover, hepatic tissue congestion, degeneration, and local necrosis were observed in rats after 1, 4, and 8h renal reperfusion following 2h renal ischemia. In conclusion, the present study suggests that renal I/R can cause hepatotoxicity and gene expression down-regulation of CYP isozymes in rats.
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Affiliation(s)
- Bao-Ying Wang
- Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan, China
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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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Interleukin-6 mediates lung injury following ischemic acute kidney injury or bilateral nephrectomy. Kidney Int 2008; 74:901-9. [PMID: 18596724 DOI: 10.1038/ki.2008.314] [Citation(s) in RCA: 203] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Patients with acute kidney injury frequently have pulmonary complications. Similarly ischemic acute kidney injury or bilateral nephrectomy in rodents causes lung injury characterized by pulmonary edema, increased pulmonary capillary leak and interstitial leukocyte infiltration. Interleukin-6 is a pro-inflammatory cytokine that is increased in the serum of patients with acute kidney injury and predicts mortality. Here we found that lung neutrophil infiltration, myeloperoxidase activity, the neutrophil chemokines KC and MIP-2 and capillary leak all increased within 4 h following acute kidney injury in wild-type mice. These pathologic factors were reduced in interleukin-6-deficient mice following acute kidney injury or bilateral nephrectomy. The lungs of mutant mice had reduced KC but MIP-2 was similar to that of wild type mice. Wild-type mice, treated with an interleukin-6 inactivating antibody, had decreased lung myeloperoxidase activity and KC levels following acute kidney injury. Our study shows that interleukin-6 contributes to lung injury following acute kidney injury.
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Abstract
The development of respiratory failure in patients with AKI is a particularly devastating consequence that greatly increases patient mortality. When respiratory failure and AKI occur together, the mortality is greater than 80%. A clear understanding of the mechanisms leading to respiratory failure is of great clinical relevance to patients with AKI in order to prevent and treat this life-threatening complication. Pulmonary edema leading to respiratory failure has been a recognized complication of kidney failure since 1901. Remarkably, the pathogenesis of this complication remains elusive, despite over 100 years of clinical and experimental debate in the literature. A review of this literature suggests that there are 4 causes of pulmonary edema leading to respiratory failure in patients with AKI: (1) volume overload (cardiogenic edema), (2) left ventricular dysfunction (cardiogenic edema), (3) increased lung capillary permeability (noncardiogenic edema), and (4) acute lung injury (noncardiogenic edema with inflammation). In this review, these mechanisms are presented in historical context including the original descriptions of pathology and pathophysiology, recent epidemiologic data, and experimental studies in animals. Although volume overload is a well-accepted mechanism of pulmonary edema in patients with AKI, the purpose of this review was to highlight the evidence showing that noncardiogenic edema and acute lung injury also occur. By recognizing that the pulmonary complications of AKI are not simply from volume overload, specific treatment strategies may be discovered and used to improve outcomes in patients with the ominous and life threatening combination of AKI and respiratory failure.
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Murphy CG, Chen G, Winter DC, Bouchier-Hayes DJ. Glutamine preconditioning protects against tourniquet-induced local and distant organ injury in a rodent ischemia-reperfusion model. Acta Orthop 2007; 78:559-66. [PMID: 17966012 DOI: 10.1080/17453670710014220] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Ischemia-reperfusion (IR) injury is a common surgical event, with tourniquet use being a recognized cause in orthopedic surgery. Preconditioning is a highly evolutionarily conserved endogenous protective mechanism, but finding a clinically safe, acceptable method of induction has proven difficult. Glutamine, a known inducer of the heat shock protein response, offers pharmacological modulation of injury through clinically acceptable preconditioning. Our aim was to test the hypothesis that glutamine preconditioning protects against tourniquet-induced regional and remote IR injury in a rodent model. ANIMALS AND METHODS 40 adult male Sprague-Dawley rats were randomized into 4 groups: control, IR injury, normal saline-pretreated and IR injury, and glutamine-pretreated and IR injury. Pretreated groups received either normal saline or glutamine by intravenous bolus 24 h before injury. A bilateral hindlimb tourniquet model was used. Blood samples were analyzed, bronchioalveolar lavage (BAL) performed, and skeletal muscle and lung harvested for evaluation. RESULTS The glutamine-pretreated group showed significantly lower muscle myeloperoxidase (MPO) content and creatine kinase levels than the untreated or saline-pretreated injury groups. Lung tissue showed reduced MPO content and a significantly reduced neutrophil count by BAL fluid microscopy. INTERPRETATION These data suggest that preconditioning with glutamine offers local and distant organ protection in the setting of tourniquet-induced IR injury.
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Affiliation(s)
- Colin G Murphy
- Department of Surgery, RCSI Research and Education Centre, Beaumont Hospital, Dublin.
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Hoke TS, Douglas IS, Klein CL, He Z, Fang W, Thurman JM, Tao Y, Dursun B, Voelkel NF, Edelstein CL, Faubel S. Acute renal failure after bilateral nephrectomy is associated with cytokine-mediated pulmonary injury. J Am Soc Nephrol 2006; 18:155-64. [PMID: 17167117 DOI: 10.1681/asn.2006050494] [Citation(s) in RCA: 211] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Clinical studies demonstrate that acute renal failure (ARF) is associated with increased mortality, which may be due to pulmonary complications. ARF may affect the lung via increased renal production or impaired clearance of mediators of lung injury, such as proinflammatory cytokines. Bilateral nephrectomy is a method to examine directly the deleterious systemic effects of absent renal clearance in ARF without the confounding effects that are associated with ischemia-reperfusion injury (e.g., ischemic ARF) or systemic toxicity (e.g., cisplatin-induced ARF). This study contrasts the effects of ischemic ARF and bilateral nephrectomy on serum cytokines and lung injury. It demonstrates that the acute absence of kidney function after both ischemic ARF and bilateral nephrectomy is associated with an increase in multiple serum cytokines, including IL-6 and IL-1beta, and that the cytokine profiles were distinct. Lung injury after ischemic ARF and bilateral nephrectomy was similar and was characterized by pulmonary vascular congestion and neutrophil infiltration. For investigation of the role of proinflammatory cytokines in pulmonary injury after ARF, the anti-inflammatory cytokine IL-10 was administered before bilateral nephrectomy. IL-10 treatment improved pulmonary architecture and was associated with a reduction in inflammatory markers, including bronchoalveolar lavage fluid total protein, pulmonary myeloperoxidase activity (a biochemical marker of neutrophils), and the chemokine macrophage inflammatory protein 2. These data demonstrate for the first time that the acute absence of kidney function results in pulmonary injury independent of renal ischemia and highlight the critical role of the kidney in the maintenance of serum cytokine balance and pulmonary homeostasis.
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Affiliation(s)
- Thomas S Hoke
- Department of Medicine, University of Colorado at Denver and Health Sciences Center, Denver, CO80262, USA
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Gray KD, Simovic MO, Blackwell TS, Christman JW, May AK, Parman KS, Chapman WC, Stain SC. Activation of nuclear factor kappa B and severe hepatic necrosis may mediate systemic inflammation in choline-deficient/ethionine-supplemented diet-induced pancreatitis. Pancreas 2006; 33:260-7. [PMID: 17003648 DOI: 10.1097/01.mpa.0000240599.95817.34] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES We hypothesized that hepatic injury is associated with severe acute pancreatitis (SAP) and may result in lung injury through nuclear factor kappa B (NF-kappaB)-dependent inflammatory mediators. The study characterizes the timing and determines the involvement of selected cytokines and chemokines in the pathogenesis of hepatocellular injury associated with SAP. METHODS The SAP was induced in C57BL/6 mice by feeding a choline-deficient/ethionine-supplemented diet. The mice were killed at 12-hour intervals for 96 hours. Terminal deoxynucleotidyl transferase-mediated nick-end labeling staining was used to determine the extent of hepatic apoptosis. The NF-kappaB activation in nuclear protein extracts from liver tissue was measured using a sensitive RelA enzyme-linked immunoadsorbent assay. Tumor necrosis factor alpha, interleukin 6, macrophage inflammatory protein (MIP) 2, and keratinocyte-derived chemokine (KC) levels in homogenates of liver and lung tissues were measured by enzyme-linked immunoadsorbent assay. The SAP-associated neutrophil lung inflammation was measured as tissue myeloperoxidase activity. RESULTS The SAP and subsequent liver injury were confirmed by histological analysis and rises in plasma amylase and transaminase levels. Severe hepatocellular apoptosis was detected at 36 and 48 hours after the diet initiation by terminal deoxynucleotidyl transferase-mediated nick-end labeling staining (P < 0.05) and subsequently progressed to hepatic necrosis. Liver NF-kappaB activation was detected at 36 hours (P < 0.05) and followed by a sharp increase in hepatocellular levels of interleukin 6, MIP-2, and KC at 72 hours and thereafter (P < 0.05). Levels of MIP-2 and KC in lung tissue were also elevated at 72 hours (P < 0.05) and closely correlated with increased myeloperoxidase activity and increased inflammatory cell infiltrate in the lung. CONCLUSIONS Choline-deficient/ethionine-supplemented diet-induced SAP is accompanied with hepatocellular apoptosis and eventual necrosis. This injury is associated with the hepatic NF-kappaB activation leading to the production of NF-kappaB-dependent cytokines and chemokines in the liver, which may mediate the lung injury.
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Affiliation(s)
- Keith D Gray
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
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Villeneuve PJ, Sundaresan S. Complications of Pulmonary Resection: Postpneumonectomy Pulmonary Edema and Postpneumonectomy Syndrome. Thorac Surg Clin 2006; 16:223-34. [PMID: 17004550 DOI: 10.1016/j.thorsurg.2006.05.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Bassed on the authors' review of the unusual variants of PPS and the body of published experience, a revision of the current classification scheme for PPS into a more comprehensive form is justified as follows: (1) by the nature of obstruction; and (2) by the time of onset. This classification encompasses early and late symptom onset, as well as considering both airway and vascular compression. This scheme argues in favor of an expanded cardiac work-up in addition to the measures outlined previously for airway assessment. Althought PPS remains a rare clinical entity, the refinement in the understanding of this condition and the evolution of treatment options have vastly improved patient outcomes. A careful evaluation of the patient must be done before embarking on treatment owing to the numerous etiologies for progressive dyspnea in the pneumonectomy patient.
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Affiliation(s)
- P James Villeneuve
- Division of General Surgery, Department of Surgery, The Ottawa Hospital, Ontario, Canada
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22
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Takamatsu Y, Shimada K, Yamaguchi K, Kuroki S, Chijiiwa K, Tanaka M. Inhibition of inducible nitric oxide synthase prevents hepatic, but not pulmonary, injury following ischemia-reperfusion of rat liver. Dig Dis Sci 2006; 51:571-9. [PMID: 16614969 DOI: 10.1007/s10620-006-3172-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2005] [Accepted: 07/12/2005] [Indexed: 12/15/2022]
Abstract
The aim of this study was to investigate the contribution of inducible nitric oxide synthase (iNOS)-derived nitric oxide on the liver and lung injury following hepatic ischemia-reperfusion (I/R) using a novel and potent iNOS inhibitor, ONO-1714. Rats were subjected to 90 min of partial hepatic ischemia followed by 3, 6, 12, and 24 hr of reperfusion. Expression of iNOS mRNA peaked at 3 hr of reperfusion in the liver and lung. Plasma nitric oxide levels were increased fourfold at 24 hr of reperfusion and plasma ALT was increased, reaching a peak at 12 hr of reperfusion; both were significantly inhibited by ONO-1714. Histological examination revealed extensive liver damage, whereas this was not seen in the ONO-1714 group. Lung injury was not significantly changed in groups with versus without ONO-1714. Nitrotyrosine expression was seen in regions similar to those of the histological injuries of the liver, while this staining was absent in the ONO-1714 group. These data show that generation of peroxynitrite could be involved in the pathogenesis of liver injury but not lung injury after hepatic I/R. Inhibition of iNOS could be applied for attenuation of liver injury following hepatic I/R.
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Affiliation(s)
- Yuji Takamatsu
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Toledo-Pereyra LH, Lopez-Neblina F, Reuben JS, Toledo AH, Ward PA. Selectin inhibition modulates Akt/MAPK signaling and chemokine expression after liver ischemia-reperfusion. J INVEST SURG 2005; 17:303-13. [PMID: 15764497 DOI: 10.1080/08941930490884706] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Tissue damage after ischemia and reperfusion (I/R) is largely caused by the sequelae of neutrophil infiltration. This inflammatory process can be initiated as the result of stroke, coronary ischemia, trauma, and other related conditions. The infiltration of neutrophils is facilitated by the expression of adhesion molecules on the surface of endothelial cells. Particularly important are the selectin family of adhesion molecules at the onset of neutrophil-mediated injury. The aim of this study was to determine the role of selectin inhibition in the modulation of chemokine expression and Akt/MAPK signaling after liver I/R. In addition, we evaluated the optimal dose and time of administration of a small molecule selectin inhibitor, TBC-1269. Mice subjected to 90 min of partial (70-80%) hepatic ischemia followed by 3 h of reperfusion were divided into 15 groups (n = 4/group); sham, ischemic control, and 10, 20, and 40 mg/kg dose groups for the antiselectin molecule were studied at 3 times of drug administration: 1 h before reperfusion (but after ischemia), at the time of reperfusion, and at 15 min after reperfusion. The parameters measured after 3 h of reperfusion included liver function tests (ALT and AST), histopathology, and tissue myeloperoxidase (MPO). Chemokine expression (MIP-1alpha, MIP-1beta, MIP-2 and KC), Akt, MAPK (p44/p42), and RSK expressions were also measured in liver tissue by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis, respectively. It was demonstrated that the small molecule multi-selectin inhibitor (TBC-1269) offered the most significant protection for the ischemic liver when given at 40 mg/kg at the time ofreperfusion. AST significantly differed between the control group and the group receiving 40 mg/kg at the time of reperfusion (p = .01). MPO levels in the liver tissue of the ischemic controls were significantly increased when compared to the levels of this enzyme in the TBC-1269 group at 40 mg/kg. Histological examination reflected the same results, with a significant difference (p = .02) between these same two groups. The chemokine profile also showed that the same treatment group had a downregulation of MIP-lalpha, MIP-1beta, MIP-2, and KC, as well as a lower expression of Akt, MAPK(p44/42), and RSK when compared to the control group. Thus, we demonstrated that the small molecule selectin inhibitor, TBC-1269, offered significant functional and structural protection of the ischemic liver when given at 40 mg/kg at the time of reperfusion. Lower doses and different times of administration did not show as prominent a drug effect. This selectin inhibition modulated the expression of Akt, MAPK (p44/42), and RSK, as well as MIP-1alpha, MIP-1beta, MIP-2, and KC chemokines. These alterations in cellular signaling and chemokine expression represent potential mechanisms or pathways of inflammatory response in I/R.
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Affiliation(s)
- Luis H Toledo-Pereyra
- Borgess Research Institute, Michigan State University/Kalamazoo Center for Medical Studies, Kalamazoo, Michigan 49048, USA.
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Fallsehr C, Zapletal C, Kremer M, Demir R, von Knebel Doeberitz M, Klar E. Identification of differentially expressed genes after partial rat liver ischemia/reperfusion by suppression subtractive hybridization. World J Gastroenterol 2005; 11:1303-16. [PMID: 15761968 PMCID: PMC4250677 DOI: 10.3748/wjg.v11.i9.1303] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [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 identify potential diagnostic target genes in early reperfusion periods following warm liver ischemia before irreversible liver damage occurs.
METHODS: We used two strategies (SSH suppression subtractive hybridization and hybridization of cDNA arrays) to determine early changes in gene expression profiles in a rat model of partial WI/R, comparing postischemic and adjacent nonischemic liver lobes. Differential gene expression was verified (WI/R; 1 h/2 h) and analyzed in more detail after warm ischemia (1 h) in a reperfusion time kinetics (0, 1, 2 and 6 h) and compared to untreated livers by Northern blot hybridizations. Protein expression was examined on Western blots and by immunohistochemistry for four differentially expressed target genes (Hsp70, Hsp27, Gadd45a and IL-1rI).
RESULTS: Thirty-two individual WI/R target genes showing altered RNA levels after confirmation by Northern blot analyzes were identified. Among them, six functionally uncharacteristic expressed sequences and 26 known genes (12 induced in postischemic liver lobes, 14 with higher transcriptional expression in adjacent nonischemic liver lobes). Functional categories of the verified marker genes indicate on the one hand cellular stress and tissue damage but otherwise activation of protective cellular reactions (AP-1 transcription factors, apoptosis related genes, heat shock genes). In order to assign the transcriptional status to the biological relevant protein level we demonstrated that Hsp70, Hsp27, Gadd45a and IL-1rI were clearly up-regulated comparing postischemic and untreated rat livers, suggesting their involvement in the WI/R context.
CONCLUSION: This study unveils a WI/R response gene set that will help to explore molecular pathways involved in the tissue damage after WI/R. In addition, these genes especially Hsp70 and Gadd45a might represent promising new candidates indicating WI/R liver damage.
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Affiliation(s)
- Christine Fallsehr
- Institute of Molecular Pathology, University of Heidelberg, Heidelberg, Germany
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Takamatsu Y, Shimada K, Chijiiwa K, Kuroki S, Yamaguchi K, Tanaka M. Role of leukotrienes on hepatic ischemia/reperfusion injury in rats. J Surg Res 2004; 119:14-20. [PMID: 15126076 DOI: 10.1016/j.jss.2003.07.004] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2003] [Indexed: 11/15/2022]
Abstract
BACKGROUND Leukotrienes (LT), composed of cysteinyl LT (cLT; LTC(4), LTD(4), and LTE(4)) and LTB(4), are potent lipid mediators enhancing the vascular permeability and recruitment of neutrophils, which are common features of hepatic ischemia/reperfusion (I/R) injury. The aim of this study was to investigate whether LT can mediate the liver and lung injuries following hepatic I/R. MATERIALS AND METHODS Sprague-Dawley rats were subjected to 90 min of partial hepatic ischemia followed by 3, 12, and 24 h of reperfusion. In the hepatic and pulmonary tissues, LT content and the mRNA expression of LT-synthesis enzymes, 5-lypoxygenase (5-LO), LTC(4) synthase (LTC(4)-S), and LTA(4) hydrolase (LTA(4)-H) were measured. Tissue injuries were assessed by plasma ALT, histological examination, and wet-to-dry tissue weight ratios. RESULTS The cLT content in the hepatic tissue after 12 and 24 h reperfusion was increased 4- to 5-fold compared to controls and this was accompanied by the enhancement of hepatic edema and plasma ALT elevation. There were no significant changes in the mRNA expression of LT-synthesis enzymes in both tissues. LTB(4) levels were not increased despite a significant neutrophil infiltration in both tissues. CONCLUSIONS These data suggest that cLT are generated in the liver during the reperfusion period and may contribute to the development of hepatic edema and exert cytotoxicity. Factors other than LTB(4) may contribute to neutrophil infiltration.
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Affiliation(s)
- Yuji Takamatsu
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
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26
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Maheshwari A, Christensen RD, Calhoun DA, Dimmitt RA, Lacson A. Circulating CXC-chemokine concentrations in a murine intestinal ischemia-reperfusion model. Fetal Pediatr Pathol 2004; 23:145-57. [PMID: 15768860 DOI: 10.1080/15227950490523781] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
BACKGROUND CXC-chemokines bearing the glutamic acid-leucine-arginine (ELR) motif (ELR+ CXC chemokines) are potent neutrophil chemoattractants and hence may play a role in mucosal injury seen with intestinal ischemia-reperfusion (I/R). METHODS Serum concentrations of ELR+ CXC chemokines (keratinocyte-derived chemokine(KC) / CXC ligand (CXCL) 1, macrophage inflammatory protein (MIP)-2/CXCL 2/3, lipopolysaccharide-induced CXC chemokine (LIX) / CXCL5, and lungkine/CXCL15) were measured in a murine intestinal I/R model. Fifteen 4-week-old wild-type mice were studied in three subgroups: sham, ischemia (superior mesenteric artery [SMA] clamping for 60 min) and ischemia-reperfusion (SMA clamping for 60 min followed by reperfusion for 90 min). RESULTS Concentrations of KC/CXCL1 and MIP-2/CXCL2/3 in sham-treated animals (145 +/- 123 and 107 +/- 55 pg/mL, respectively) and the ischemia subgroup (646 +/- 413 and 226 +/- 129 pg/mL) were similar, but concentrations were signifcantly higher with reperfusion (6398 +/- 2297, p < .001 and 874 +/- 790 pg/mL, p = .04). LIX/CXCL5 and lungkine/CXCL15 concentrations did not change significantly with ischemia or following I/R. KC/CXCL1 and MIP-2/CXCL2/3 concentrations correlated positively with the severity of mucosal injury and with each other, whereas a negative relationship was observed between LIX/CXCL5 concentrations and microscopic injury scores. CONCLUSIONS Development of mucosal injury in intestinal I/R is associated with increased serum concentrations of KC/CXCL1 and MIP-2/CXCL2/3, but not with those of LIX/CXCL5 and lungkine/CXCL15.
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Affiliation(s)
- Akhil Maheshwari
- Department of Pediatrics, University of South Florida College of Medicine, Florida, USA.
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Ley K. Weird and weirder: how circulating chemokines coax neutrophils to the lung. Am J Physiol Lung Cell Mol Physiol 2004; 286:L463-4. [PMID: 14761870 DOI: 10.1152/ajplung.00386.2003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Jiang Y, Gu XP, Qiu YD, Sun XM, Chen LL, Zhang LH, Ding YT. Ischemic preconditioning decreases C-X-C chemokine expression and neutrophil accumulation early after liver transplantation in rats. World J Gastroenterol 2003; 9:2025-9. [PMID: 12970899 PMCID: PMC4656667 DOI: 10.3748/wjg.v9.i9.2025] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Polymorphonuclear neutrophil (PMN) plays a major role in liver ischemia/reperfusion injury. Protective effect of ischemic preconditioning (IP) has been confirmed in liver ischemia/reperfusion injury. The purpose of this study was to investigate the effect of IP on C-X-C chemokine expression and PMNs recruitment early after liver transplantation.
METHODS: Male Sprague-Dawley rats were used as donors and recipients of orthotopic liver transplantation (OLT). The donor liver was stored 24 h in University of Wisconsin (UW) solution at 4 °C pre-implantation. IP was done by clamp of the portal vein and hepatic artery of the donor liver for 10 minutes followed by reperfusion for 10 minutes before harvesting. The neutrophilic infiltration in liver was quantified using a myeloperoxidase (MPO) assay. Intragraft expression of macrophage inflammatory protein-2 (MIP-2) mRNA was investigated with in situ hybridization. The serum levels of MIP-2 and tumor necrosis factor (TNF)-α were also monitored.
RESULTS: After liver transplantation without IP, the hepatic MPO increased significantly compared with sham operated group. In IP group, PMN in liver indicated by MPO was reduced significantly. In situ hybridization showed no MIP-2 mRNA in sham group but dramatic expression in hepatocytes in non-IP group. In IP group, MIP-2 mRNA was significantly down-regulated. Similarly, serum MIP-2 and TNF-α levels were significantly elevated in non-IP group and both were reduced in IP group.
CONCLUSION: IP might protect graft liver from preservation-reperfusion injury after OLT through down-regulating C-X-C chemokine expression of hepatocytes, and alleviating PMNs recruitment after reperfusion.
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Affiliation(s)
- Yong Jiang
- Department of Hepatobiliary Surgery, Gulou Hospital, Medical Department of Nanjing University, Jiangsu Province, China.
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29
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Chung YJ, Yang GH, Islam Z, Pestka JJ. Up-regulation of macrophage inflammatory protein-2 and complement 3A receptor by the trichothecenes deoxynivalenol and satratoxin G. Toxicology 2003; 186:51-65. [PMID: 12604170 DOI: 10.1016/s0300-483x(02)00605-4] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The trichothecenes are a group of mycotoxins that target leukocytes and have a wide range of immunomodulatory effects. Differential display analysis was applied to assess the effects of the trichothecenes deoxynivalenol (vomitoxin, DON) and satratoxin G (SG), on mRNA in the RAW 264.7 macrophage cell line. Cells were incubated with DON (1 microg/ml) or SG (5 ng/ml) for 2 h and total RNA then subjected to RT-PCR with a set of oligo(dT) primers. Resultant cDNA was amplified using an oligo (dT) downstream primer and an arbitrary decanucleotide upstream primer to make 35S-labeled PCR products. After separation of the products in denaturing polyacrylamide gel, 23 differentially expressed cDNA fragments were isolated and sequenced. Two of these were identified as known genes, namely, macrophage inflammatory protein-2 (MIP-2), a potent neutrophil chemoattractant involved in tissue injury and inflammation, and complement 3a receptor (C3aR), a proinflammatory mediator. Both MIP-2 and C3aR mRNAs were up-regulated by DON while only MIP-2 mRNA was induced by SG. Using commercially available antibodies, MIP-2 protein was also found to be induced by both DON and SG in RAW 264.7 cell cultures. When mice were treated with DON (12.5 mg/kg), splenic MIP-2 mRNA and serum MIP-2 levels were increased. MIP-2 mRNA and serum MIP-2 levels were synergistically increased when mice were co-treated with DON and LPS. Up-regulation of MIP-2 and C3aR are consistent with previous reports of trichothecene-induced inflammatory gene up-regulation and suggest that the specific genes affected may depend on trichothecene structures.
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Affiliation(s)
- Yong-Joo Chung
- Department of Food Science and Human Nutrition, 234 G M Trout Building, Michigan State University, East Lansing, MI 48824-1224, USA
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DeVries ME, Hosiawa KA, Cameron CM, Bosinger SE, Persad D, Kelvin AA, Coombs JC, Wang H, Zhong R, Cameron MJ, Kelvin DJ. The role of chemokines and chemokine receptors in alloantigen-independent and alloantigen-dependent transplantation injury. Semin Immunol 2003; 15:33-48. [PMID: 12495639 DOI: 10.1016/s1044-5323(02)00126-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Transplantation injury and rejection involves the interplay of innate and acquired immune responses. Immune-related injury manifests itself in three temporal phases: early innate immune driven alloantigen-independent injury, acquired immune driven alloantigen-dependent injury, and chronic injury. Sequential waves of chemokine expression play a central role in regulating graft injury through the recruitment of phagocytes shortly after transplantation and activated lymphocytes and phagocytes in the weeks and years following transplantation. This review focuses on recent studies demonstrating the role of chemokines in transplantation.
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Affiliation(s)
- Mark E DeVries
- Department of Immunology, Division of Experimental Therapeutics, University of Toronto, University Health Network, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4
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Li Q, Park PW, Wilson CL, Parks WC. Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell 2002; 111:635-46. [PMID: 12464176 DOI: 10.1016/s0092-8674(02)01079-6] [Citation(s) in RCA: 594] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The influx of inflammatory cells to sites of injury is largely directed by signals from the epithelium, but how these cells form chemotactic gradients is not known. In matrilysin null mice, neutrophils remained confined in the interstitium of injured lungs and did not advance into the alveolar space. Impaired transepithelial migration was accompanied by a lack of both shed syndecan-1, a heparan sulfate proteoglycan, and KC, a CXC chemokine, in the alveolar fluid. KC was bound to shed syndecan-1, and it was not detected in the lavage of syndecan-1 null mice. In vitro, matrilysin cleaved syndecan-1 from the surface of cells. Thus, matrilysin-mediated shedding of syndecan-1/KC complexes from the mucosal surface directs and confines neutrophil influx to sites of injury.
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Affiliation(s)
- Qinglang Li
- Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO 63110, USA
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Peralta C, Perales JC, Bartrons R, Mitchell C, Gilgenkrantz H, Xaus C, Prats N, Fernández L, Gelpí E, Panés J, Roselló-Catafau J. The combination of ischemic preconditioning and liver Bcl-2 overexpression is a suitable strategy to prevent liver and lung damage after hepatic ischemia-reperfusion. THE AMERICAN JOURNAL OF PATHOLOGY 2002; 160:2111-22. [PMID: 12057915 PMCID: PMC1850813 DOI: 10.1016/s0002-9440(10)61160-1] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The present study evaluates the effectiveness of ischemic preconditioning and Bcl-2 overexpression against the liver and lung damage that follow hepatic ischemia-reperfusion and investigates the underlying protective mechanisms. Preconditioning and Bcl-2, respectively, reduced the increased tumor necrosis factor (TNF) and macrophage inflammatory protein-2 (MIP)-2 levels observed after hepatic reperfusion. Bcl-2 overexpression or anti-MIP-2 pretreatment seems to be more effective than preconditioning or anti-TNF pretreatment against inflammatory response, microcirculatory disorders, and subsequent hepatic ischemia-reperfusion injury. Furthermore, each one of these strategies individually was unable to completely inhibit hepatic injury. The combination of preconditioning and Bcl-2 overexpression as well as the combined anti-TNF and anti-MIP-2 pretreatment totally prevented hepatic injury, whereas the benefits of preconditioning and Bcl-2 were abolished by TNF and MIP-2. In contrast to preconditioning, Bcl-2 did not modify lung damage induced by hepatic reperfusion. This could be explained by the differential effect of both treatments on TNF release. Anti-TNF therapy or preconditioning, by reducing TNF release, reduced pulmonary inflammatory response, whereas the benefits of preconditioning on lung damage were abolished by TNF. Thus, the induction of both Bcl-2 overexpression in liver and preconditioning, as well as pharmacological strategies that simulated their benefits, such as anti-TNF and anti-MIP-2 therapies, could be new strategies aimed to reduce lung damage and inhibit the hepatic injury associated with hepatic ischemia-reperfusion.
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Affiliation(s)
- Carmen Peralta
- Department of Medical Bioanalysis, Instituto de Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, CSIC-IDIBAPS, Barcelona, Spain
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Tsujimoto H, Ono S, Mochizuki H, Aosasa S, Majima T, Ueno C, Matsumoto A. Role of macrophage inflammatory protein 2 in acute lung injury in murine peritonitis. J Surg Res 2002; 103:61-7. [PMID: 11855919 DOI: 10.1006/jsre.2001.6325] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND Acute lung injury is a frequent extraabdominal complication of bacterial peritonitis, and neutrophil plays an important role in this lung damage. Macrophage inflammatory protein 2 (MIP-2) serves the same chemotactic function as IL-8 which is a potent neutrophil chemotactic factor in humans, and we investigated the role of MIP-2 associated with neutrophil recruitment in the lung of murine peritonitis. METHODS Cecal ligation and puncture (CLP) were performed on mice. MIP-2 levels in blood and lung tissue, MIP-2 mRNA expression in lung tissue and bronchoalveolar lavage fluid (BALF), and CD11b expression on peripheral blood neutrophil and BALF cells were determined after CLP. In addition, we investigated the effect of anti-MIP-2 antibody on the lung injury associated with peritonitis. RESULTS MIP-2 mRNA expression was observed in lung tissue after CLP and numerous neutrophils were accumulated in the lung under those conditions. Anti-MIP-2 antibody contributed to the inhibition of the CD11b expression and chemotaxis of pulmonary neutrophils, lung edema, and thus the reduction in peritonitis-related mortality. CONCLUSIONS MIP-2 plays a pivotal role in neutrophil recruitment in the lung following peritonitis, and control of neutrophil accumulation in the lung by neutralizing MIP-2 is recommended as a new therapeutic approach to the lung damage associated with peritonitis.
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Affiliation(s)
- Hironori Tsujimoto
- Department of Surgery I, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan
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Araya J, Tsuruma T, Hirata K, Yagihashi A, Watanabe N. TCV-116, an angiotensin II type 1 receptor antagonist, reduces hepatic ischemia-reperfusion injury in rats. Transplantation 2002; 73:529-34. [PMID: 11889423 DOI: 10.1097/00007890-200202270-00006] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
BACKGROUND In Pringle's maneuver during liver surgery and liver transplantation, ischemia-reperfusion (I/R) is an unavoidable process, and protection against hepatic I/R injury is a major unresolved problem. Therefore, various pharmacologic approaches to prevent hepatic I/R injury are currently under trial. In this study, we investigated whether TCV-116, an angiotensin II type 1 receptor antagonist, can reduce this injury. METHODS The rats were pretreated either with TCV-116 (group 1) or with the vehicle alone (group 2). The rats in group 3 were not pretreated. Thereafter, they were subjected to partial hepatic I/R. RESULTS After reperfusion, the mean peak plasma concentrations of aspartate aminotransferase, alanine aminotransferase, lactic dehydrogenase, and creatine kinase were lower in group 1 than in groups 2 and 3. The magnitude of hepatic injury was reduced in group 1 compared with that in groups 2 and 3. The mean peak plasma concentrations of tumor necrosis factor-alpha, cytokine-induced neutrophil chemoattractants-1, and interleukin-6 were lower in group 1 than in groups 2 and 3. The number of neutrophils infiltrating the liver was also lower in group 1 than in groups 2 and 3. The mean peak plasma concentration of hepatocyte growth factor (HGF) was higher in group 1 than in groups 2 and 3. CONCLUSIONS TCV-116 reduced the hepatic I/R injury by inhibiting inflammatory cytokine production and by enhancing HGF production.
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Affiliation(s)
- Jun Araya
- Department of Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan 060-0061
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Faouzi S, Burckhardt BE, Hanson JC, Campe CB, Schrum LW, Rippe RA, Maher JJ. Anti-Fas induces hepatic chemokines and promotes inflammation by an NF-kappa B-independent, caspase-3-dependent pathway. J Biol Chem 2001; 276:49077-82. [PMID: 11602613 DOI: 10.1074/jbc.m109791200] [Citation(s) in RCA: 175] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Agonistic antibodies against the Fas receptor, when administered to mice in vivo, cause significant apoptosis in the liver. In this study we show that anti-Fas antibody not only causes apoptosis of liver cells but also provokes hepatic inflammation. Two hours after injection of anti-Fas, when mice displayed evidence of caspase-3 activation and apoptosis, we found significant hepatic induction of the CXC chemokines macrophage inflammatory protein-2 and KC. Coincident with the chemokine induction was infiltration of the hepatic parenchyma by neutrophils. Neutralization experiments identified that chemokines were the cause of Fas-induced hepatic inflammation, with KC having the predominant effect. Chemokine induction in the livers of anti-Fas-treated mice was not associated with activation of NF-kappa B. Instead, it coincided with nuclear translocation of activator protein-1 (AP-1). AP-1 activation in liver was detected 1-2 h after anti-Fas treatment, suggesting a connection to the onset of apoptosis. When apoptosis was prevented by pretreating mice with a caspase-3 inhibitor, AP-1 activation and hepatic chemokine production were both significantly reduced. Hepatic inflammation was also reduced by 70%. Taken together, these findings indicate that Fas ligation can induce inflammation in the liver in vivo. Inflammation does not arise from Fas-mediated signaling through NF-kappa B; rather, it represents an indirect effect, requiring activation of caspase-3 and nuclear translocation of AP-1.
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Affiliation(s)
- S Faouzi
- Liver Center and the Department of Medicine, University of California, San Francisco, California 94110, USA
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Miura M, Fu X, Zhang QW, Remick DG, Fairchild RL. Neutralization of Gro alpha and macrophage inflammatory protein-2 attenuates renal ischemia/reperfusion injury. THE AMERICAN JOURNAL OF PATHOLOGY 2001; 159:2137-45. [PMID: 11733364 PMCID: PMC1850606 DOI: 10.1016/s0002-9440(10)63065-9] [Citation(s) in RCA: 173] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Previous studies have provided strong evidence for a role for neutrophils in mediating pathology during reperfusion of ischemic tissues. CXC chemokines including interleukin-8, KC/Gro alpha, and macrophage inflammatory protein (MIP)-2, direct neutrophils to tissue sites of inflammation. In the current study we tested the efficacy of antibodies to KC/Gro alpha and MIP-2 in inhibiting neutrophil infiltration into kidneys during reperfusion after 1 hour of warm ischemia using a mouse model. KC mRNA and protein were produced within 3 hours after reperfusion of the ischemic kidneys. MIP-2 mRNA and protein were twofold to fourfold lower than KC and were at low levels until 9 hours after reperfusion. Only 60% of mice subjected to ischemia/reperfusion injury survived to day 3 after reperfusion. Treatment with rabbit neutralizing antibodies to both KC and MIP-2 inhibited neutrophil infiltration into ischemic kidneys during reperfusion, restored renal function as assessed by decreased serum creatinine and urea nitrogen levels to near normal levels, and resulted in complete survival of treated animals. Finally, treatment with both antibodies significantly reduced histologically graded pathology of kidneys subjected to ischemia/reperfusion injury. Collectively, the results indicate the efficacy of neutralizing the chemokines directing neutrophils into ischemic kidneys during reperfusion to inhibit this infiltration and attenuate the resulting pathology.
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Affiliation(s)
- M Miura
- Urological Institute and the Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
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Wakai A, Winter DC, Street JT, O'Sullivan RG, Wang JH, Redmond HP. Inosine attenuates tourniquet-induced skeletal muscle reperfusion injury. J Surg Res 2001; 99:311-5. [PMID: 11469903 DOI: 10.1006/jsre.2001.6192] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND Adenosine attenuates skeletal muscle reperfusion injury, but its short half-life in vivo limits potential therapeutic benefits. The aim of this study was to ascertain whether inosine, a stable adenosine metabolite, modulates skeletal muscle reperfusion injury. MATERIALS AND METHODS C57BL/6 mice were randomized (8-10 per group) to six groups: time controls; inosine (100 mg/kg) before anesthesia; 2 h of bilateral tourniquet hindlimb ischemia; I/R (2 h of bilateral tourniquet hindlimb ischemia, 3 h of reperfusion); inosine (100 mg/kg) before I/R; drug vehicle before I/R. Serum tumor necrosis factor (TNF)-alpha and macrophage inflammatory protein (MIP)-2 were measured before ischemia and at the end of reperfusion. Tissue edema was determined by wet/dry weight ratios. Tissue leucosequestration was assessed by the myeloperoxidase (MPO) content. RESULTS At the end of reperfusion, inosine pretreatment resulted in lower MPO levels in muscle (P = 0.02) and lung (P = 0.0002) than saline pretreatment. Similarly, muscle (P = 0.04) and lung (P = 0.02) wet/dry ratios were significantly reduced with inosine but not with saline pretreatment. At the end of reperfusion, serum proinflammatory cytokine levels (TNF-alpha and MIP-2) were significantly reduced (P < 0.05) compared to preischemia levels following inosine pretreatment but not saline pretreatment. Ischemia alone did not alter any of the parameters assessed. CONCLUSIONS These findings demonstrate that pretreatment with inosine attenuates the local and systemic proinflammatory responses associated with skeletal muscle reperfusion injury.
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Affiliation(s)
- A Wakai
- Department of Academic Surgery, Cork University Hospital, Cork, Republic of Ireland
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Johnson JL, Wallace BH, Mareen CD, Graves DB, Ferrer TJ, Robertson RD, Cone JB. Intraperitoneal blood exacerbates the remote inflammatory response to murine peritonitis. THE JOURNAL OF TRAUMA 2001; 51:253-9; discussion 259-60. [PMID: 11493781 DOI: 10.1097/00005373-200108000-00006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND This study investigated the effects of intra-abdominal blood on the systemic response to peritonitis using a murine model of hemorrhage, peritonitis, and multiple organ dysfunction syndrome. METHODS The model used male ICR mice subjected to hemorrhage and intraperitoneal zymosan. Half of the mice received intraperitoneal blood. Outcome measures included lung myeloperoxidase, lung edema, lung injury score, and plasma and lung tissue chemokine production. RESULTS Peritoneal blood (in association with peritoneal inflammation) increased lung neutrophil sequestration (myeloperoxidase) (2.56 +/- 1.42 vs. 1.45 +/- 0.49 U/left lung, p = 0.04) and lung weight (0.11 +/- 0.04 vs. 0.07 +/- 0.02 g/left lung, p = 0.02), and was associated with significantly higher chemokine levels in plasma (KC and MCP-1) and lung tissue (KC, MIP-2, and MCP-1). Both plasma and lung tissue neutrophil chemoattractants KC and MIP-2 were significantly linearly correlated with myeloperoxidase (p < 0.009), and lung tissue KC (a neutrophil chemokine) and MCP-1 and MIP-1alpha (mononuclear cell chemokines) correlated with lung injury score (p < 0.003). CONCLUSION Although blood alone in the peritoneal cavity was well tolerated, in conjunction with inflammation, it was synergistic in amplifying the systemic inflammatory response. The amplified lung injury in this model was associated with significant increases in circulating and lung tissue chemokine concentrations.
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Affiliation(s)
- J L Johnson
- Department of Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA
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Martinez-Mier G, Toledo-Pereyra LH, McDuffie JE, Warner RL, Ward PA. Neutrophil depletion and chemokine response after liver ischemia and reperfusion. J INVEST SURG 2001; 14:99-107. [PMID: 11396626 DOI: 10.1080/08941930152024228] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Abstract
Neutrophils play a major role in the hepatic microvasculature following liver ischemia and reperfusion (I/R). Leukocyte cytokine chemoattractants (chemokines) are produced by neutrophils and cause neutrophil activation in I/R injury. We examined the role of neutrophils in the production of chemokines in the liver and lung inflammatory response following liver I/R. C57BL/6 mice were subjected to partial liver ischemia for 90 min. Four groups of animals were included: sham group, sham group with neutrophil depletion, ischemic control group, and ischemic control with neutrophil depletion. We evaluated at 3 h liver injury measurements, serum macrophage inflammatory protein-2 (MIP-2) and macrophage inflammatory protein-1 alpha (MIP-1alpha) chemokines, liver and lung tissue myeloperoxidase (MPO), and liver and lung histology. Statistical analysis included analysis of variance (ANOVA), and Student-Newman-Keuls and Kruskal-Wallis multiple comparison Z-value tests. Ischemic controls showed a significant increase in liver enzyme levels along with statistically significant higher liver and lung MPO activity values than the rest of the other groups (p < .05). MIP-2 values were higher in the ischemic control group when compared to the ischemic neutrophil depleted group. MIP-1alpha levels showed opposite results, being significantly lower (p < .05) in the ischemic control as compared to the neutrophil-depleted group. Improved liver and lung histopathological features were observed in the ischemic neutrophil depleted group when compared to the ischemic control group. Our study confirmed the key role of neutrophils in liver I/R injury and appeared to suggest some relationship between neutrophils and the production of certain chemokines, such as MIP-1alpha, which had an inverse relationship in the absence of neutrophils. Further studies will confirm the validity of these preliminary observations.
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Affiliation(s)
- G Martinez-Mier
- Surgery Research Sciences and Molecular Biology, Borgess Research Institute, Kalamazoo, Michigan 49001, USA
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Matuschak GM, Henry KA, Johanns CA, Lechner AJ. Liver-lung interactions following Escherichia coli bacteremic sepsis and secondary hepatic ischemia/reperfusion injury. Am J Respir Crit Care Med 2001; 163:1002-9. [PMID: 11282780 DOI: 10.1164/ajrccm.163.4.2003020] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
We hypothesized that ischemia/reperfusion (I/R) injury of the liver during normotensive gram-negative bacteremic sepsis alters the kinetics of circulating endotoxin, tumor necrosis factor-alpha (TNF-alpha), and coinduced mediators, thereby exacerbating sepsis-induced lung inflammation. Liver and lung dysfunction were studied after hematogenous infection of Sprague-Dawley rats with 10(9) Escherichia coli serotype O55:B5 (EC) and 90 min of secondary hepatic ischemia in EC + I/R and saline-infused (normal saline NS) x I/R rats, followed by brief (1 h) or longer reperfusion (24 h). TNF- alpha:leukotriene interactions in this model were examined using the 5-lipoxygenase-activating protein inhibitor MK-886. Compared with sham-operated EC + Sham animals, peak serum endotoxin, TNF-alpha, alanine aminotransferase, interleukin-6 (IL-6), and hepatic neutrophil (PMN) influx were higher in EC + I/R rats through 24 h (p < 0.05) despite comparable arterial pressure. Lung PMN influx and wet/dry weight ratios were likewise enhanced in EC + I/R versus EC + Sham or NS + I/R rats. MK-886 attenuated TNF-alpha concentrations and ischemic liver injury but not mortality. Thus, focal hepatic I/R augments circulating endotoxin, TNF-alpha, and postbacteremic lung inflammation early after normotensive E. coli bacteremic sepsis.
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Affiliation(s)
- G M Matuschak
- Division of Pulmonary, Critical Care, and Occupational Medicine, Saint Louis University Health Sciences Center, St. Louis, Missouri 63110-0250, USA.
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Wrightson WR, Edwards MJ, McMasters KM. The Role of the Ultrasonically Activated Shears and Vascular Cutting Stapler in Hepatic Resection. Am Surg 2000. [DOI: 10.1177/000313480006601111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
Hemorrhage and liver failure are the two greatest concerns for patients undergoing major liver resection. Inflow occlusion (Pringle maneuver) is often used to minimize blood loss, but hepatic ischemia results in an increased risk of postoperative hepatic dysfunction. We report our experience with the Harmonic Scalpel ultrasonically activated shears (UAS; Ethicon Endo-Surgery, Cincinnati, OH) and a vascular stapler for hepatic resection as technological advances that aid in minimizing blood loss and thereby reduce the need for inflow occlusion. We retrospectively reviewed liver resections performed from September 1997 through July 1998, in which the UAS and articulating vascular endoscopic linear cutting stapler were used. The vascular stapler was used to divide the appropriate portal vein branch and hepatic vein(s) before parenchymal transection. Parenchymal dissection was performed with UAS to a depth of approximately 2 to 3 cm, and the remainder of the liver parenchyma was divided by a clamp crush and clip and suture ligate technique. Patients underwent segmental resection (n = 12), lobectomy (n = 13), or extended lobectomy (n = 11). Resection was performed for metastatic disease, primary liver tumors, or benign disease in 21, 8, and 7 patients, respectively. A Pringle maneuver was performed in 7 of 36 patients (mean clamp time, 8 minutes). The median required intraoperative blood transfusion was 0 units of packed red blood cells. Major and minor complications occurred in 12 and 3 patients, respectively. Two deaths were related to pneumonia and abdominal infection. The vascular stapler safely and securely divides portal vein branches and hepatic veins. The UAS initiates parenchymal transection with minimal blood loss. These two technologies facilitate the surgeon's aim of liver resection without blood transfusion or Pringle maneuver.
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Affiliation(s)
- William R. Wrightson
- Division of Surgical Oncology, Department of Surgery, University of Louisville School of Medicine, and the James Graham Brown Cancer Center, Louisville, Kentucky
| | - Michael J. Edwards
- Division of Surgical Oncology, Department of Surgery, University of Louisville School of Medicine, and the James Graham Brown Cancer Center, Louisville, Kentucky
| | - Kelly M. McMasters
- Division of Surgical Oncology, Department of Surgery, University of Louisville School of Medicine, and the James Graham Brown Cancer Center, Louisville, Kentucky
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Martinez-Mier G, Toledo-Pereyra LH, McDuffie JE, Warner RL, Ward PA. P-selectin and chemokine response after liver ischemia and reperfusion. J Am Coll Surg 2000; 191:395-402. [PMID: 11030245 DOI: 10.1016/s1072-7515(00)00360-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND P-selectin plays a major role in the earliest phase of polymorphonuclear neutrophil recruitment in the hepatic microvasculature after liver ischemia and reperfusion. Leukocyte cytokine chemoattractants (chemokines) cause polymorphonuclear neutrophil activation in ischemia and reperfusion injury. In this study, we examined the role of P-selectin in the production of chemokines in the liver and lung inflammatory response after 90 minutes of warm ischemia. STUDY DESIGN Thirty-six C57BL/6 mice were subjected to partial liver ischemia for 90 minutes. Three groups of animals were included (n = 12 per group): the sham group, the ischemic control group, and the P-selectin-deficient gene targeted mice group. After 3 hours, we evaluated liver injury measurements, serum chemokines (MIP[macrophage inflammatory protein]-1alpha and MIP-2), liver and lung tissue myeloperoxidase, and liver and lung histology. Statistical analysis included ANOVA, Student-Newman-Keuls', and Kruskal-Wallis Multiple Comparison Z-value tests. RESULTS P-selectin-deficient mice showed significant decreases in liver enzyme levels (p < 0.05) and marked decreases in serum MIP-1alpha and MIP-2 chemokine determinations (p < 0.05) when compared with ischemic controls. Neutrophil infiltration was significantly ameliorated in the liver (p < 0.05) and markedly decreased in the lung, as reflected by decreased MPO levels. Improved histopathologic features in the liver and lung were observed in the P-selectin-deficient mice group compared with ischemic controls. CONCLUSIONS Our study confirms the key role of P-selectin in the pathogenesis of liver ischemia and reperfusion and the production of chemokines. P-selectin-deficient animals had improved liver function, decreased neutrophil infiltration, and decreased MIP- 1alpha and MIP-2 responses.
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Affiliation(s)
- G Martinez-Mier
- Borgess Research Institute, Department of Surgery Research Sciences, Kalamazoo, MI 49001, USA
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Martinez-Mier G, Toledo-Pereyra LH, McDuffie E, Warner RL, Ward PA. L-Selectin and chemokine response after liver ischemia and reperfusion. J Surg Res 2000; 93:156-62. [PMID: 10945958 DOI: 10.1006/jsre.2000.5954] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND L-selectin plays an important role in the early phase of PMNs recruitment in the hepatic microvasculature following liver ischemia and reperfusion (I/R). Leukocyte cytokine chemoattractants (chemokines) cause polymorphonuclear neutrophil (PMN) activation in I/R injury. In this study, we examined the role of L-selectin in the production of chemokines in the liver and lung inflammatory response following 90 min of warm ischemia. STUDY DESIGN Thirty-six C57BL/6 mice were subjected to partial liver ischemia for a period of 90 min. Three groups of animals were included (n = 12 per group)-sham group, ischemic control, and the ischemic group receiving monoclonal antibody against L-selectin. We evaluated at 3 h: liver injury measurements, serum chemokines (MIP-2 and MIP-1alpha), liver and lung tissue myeloperoxidase (MPO), and liver and lung histology. Statistical analysis included ANOVA, Student-Newman-Keuls', and Kruskal-Wallis multiple comparison Z-value tests. RESULTS The ischemic group treated with anti-L-selectin showed significant decreases in liver enzyme levels and a marked decrease in serum MIP-2 (P < 0.05) when compared to ischemic controls. No reduction in serum MIP-1alpha was noted; however, neutrophil infiltration was significantly ameliorated in the liver and in the lung, as reflected by decreased MPO levels (P < 0.05). Improved histopathological features were observed in the anti-L-selectin-treated group compared to ischemic controls in the liver and the lung. CONCLUSIONS Our study suggests an important role for L-selectin in the pathogenesis of liver I/R and the production of chemokines. Anti-L-selectin treatment resulted in improved liver function, decreased neutrophil infiltration, and decreased MIP-2 chemokine response.
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Affiliation(s)
- G Martinez-Mier
- Departments of Surgery Research Sciences and Molecular Biology, Borgess Research Institute, Kalamazoo, Michigan 49001, USA
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Lentsch AB, Kato A, Yoshidome H, McMasters KM, Edwards MJ. Inflammatory mechanisms and therapeutic strategies for warm hepatic ischemia/reperfusion injury. Hepatology 2000; 32:169-73. [PMID: 10915720 DOI: 10.1053/jhep.2000.9323] [Citation(s) in RCA: 342] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- A B Lentsch
- Department of Surgery, University of Louisville School of Medicine, Louisville, KY, USA.
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Ramos-Kelly JR, Toledo-Pereyra LH, Jordan J, Rivera-Chavez F, Rohs T, Holevar M, Dixon RA, Yun E, Ward PA. Multiple selectin blockade with a small molecule inhibitor downregulates liver chemokine expression and neutrophil infiltration after hemorrhagic shock. THE JOURNAL OF TRAUMA 2000; 49:92-100. [PMID: 10912864 DOI: 10.1097/00005373-200007000-00015] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND The purpose of this study was to investigate the regulatory effect of a small molecule selectin inhibitor in the liver by examining the functional, structural, and survival response of animals subjected to hemorrhagic shock and to determine the liver infiltration of neutrophils and the regulation of chemokine expression. Selectins play an important role in the development of the lesions associated with ischemia/reperfusion and hemorrhagic shock. Blocking individually the selectin family of adhesion molecules with monoclonal antibodies has resulted in better organ function and survival. To our knowledge, there are no studies demonstrating the beneficial effect of multiple selectin blockade with a small molecule inhibitor under conditions of hemorrhagic shock. METHODS Forty-eight Sprague-Dawley rats were subjected to hemorrhagic shock. Three groups of animals were included (n = 16/group), i.e., the sham, control, and treated groups, which received a small molecule selectin inhibitor (TBC-1269) at 25 mg/kg body weight after the bleeding began. The following parameters were evaluated: fluid requirements during resuscitation, liver injury tests (aspartate aminotransferase, alanine aminotransferase), liver histology and myeloperoxidase, and macrophage inflammatory protein-2 mRNA and cytokine-induced neutrophil chemoattractant mRNA in liver tissue, and animal survival at 3 days. Statistical analysis included Student's t test and analysis of variance when indicated. RESULTS Significant improvement in liver function and histology was noted in the treated group. Survival was also improved, although it is not known whether liver failure was the most proximate cause of lethality. Infiltration of neutrophils, measured by tissue myeloperoxidase, was significantly decreased in livers of treated animals. No significant changes were noted in fluid requirements. The small molecule selectin inhibitor group showed a down-regulating effect on liver macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant mRNA expression associated with less accumulation of neutrophils in the liver. CONCLUSION This study supports the role that selectins play in the pathogenesis of hemorrhagic shock. The mechanism of protection seen after multiple selectin blockade (TBC-1269) centered, in part, around the infiltration of liver neutrophils, probably dependent on the induction of macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant mRNA expression in liver tissue.
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Affiliation(s)
- J R Ramos-Kelly
- Borgess Research Institute, Surgery Research Sciences and Molecular Biology, Kalamazoo, Michigan, USA
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Fox-Robichaud A, Kubes P. Molecular mechanisms of tumor necrosis factor alpha-stimulated leukocyte recruitment into the murine hepatic circulation. Hepatology 2000; 31:1123-7. [PMID: 10796888 DOI: 10.1053/he.2000.6961] [Citation(s) in RCA: 82] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
To date, much of the adhesion work in the liver has been restricted to sinusoids and postsinusoidal venules. However, selectins have been localized on the portal (presinusoidal) venules and these vessels have been shown to be important in metastasis of tumors. The purpose of this study was to characterize the leukocyte-endothelial interactions within the 3 compartments of the hepatic microvasculature under baseline conditions and in response to tumor necrosis factor alpha (TNF-alpha). Mice deficient in P-selectin or both E- and P-selectin were compared with wild-type (C57Bl/6, wild type) mice. Animals were injected with murine TNF-alpha (15 microg/kg intraperitoneally [IP]) and the liver was examined by fluorescence intravital microscopy 4 hours later. Under baseline conditions, leukocyte flux in the portal venules was 1.42 +/- 0.42 cells/min. Leukocyte flux in the portal venules of wild-type mice increased 8-fold in response to 4 hours of TNF-alpha stimulation. This was reduced by 50% in the P-selectin-deficient mice but was not reduced further by either the addition of an E-selectin antibody (9A9, 100 microg intravenously [IV]) to these mice or in mice deficient in both E- and P-selectin. In P-selectin-deficient mice, the addition of an antibody against alpha(4)-integrin (R1-2, 75 microg IP) reduced rolling to baseline. But in the E- and P-double-selectin-deficient mice the addition of an antibody against L-selectin (Mel 14, 3 microg/kg IV) had no effect on TNF-alpha-induced recruitment. Similar responses were seen in the central venules, however, in the sinusoids the increased number of stationary leukocytes seen in response to 4 hours of TNF-alpha stimulation in the wild-type mice was not reduced in P-selectin-deficient mice with or without the alpha(4)-integrin antibody. These data suggest that leukocytes can use alpha(4)-integrin independent of the selectins in the venules. Within the sinusoids, however, inhibition of E-selectin, P-selectin, and alpha(4)-integrin was insufficient to reduce leukocyte recruitment.
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Affiliation(s)
- A Fox-Robichaud
- Immunology Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada
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Yoshidome H, Kato A, Edwards MJ, Lentsch AB. Interleukin-10 inhibits pulmonary NF-kappaB activation and lung injury induced by hepatic ischemia-reperfusion. THE AMERICAN JOURNAL OF PHYSIOLOGY 1999; 277:L919-23. [PMID: 10564176 DOI: 10.1152/ajplung.1999.277.5.l919] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Hepatic ischemia and reperfusion cause local and remote organ injury. This injury culminates from an integrated cascade of proinflammatory cytokines, chemokines, and adhesion molecules, many of which are regulated by the transcription factor nuclear factor-kappaB (NF-kappaB). The anti-inflammatory cytokine interleukin-10 (IL-10) has been shown to have inhibitory effects on NF-kappaB. The objective of the current study was to determine whether IL-10 could suppress pulmonary NF-kappaB activation and ensuing lung injury induced by hepatic ischemia-reperfusion. C57BL/6 mice underwent partial hepatic ischemia with or without intravenous administration of IL-10. Hepatic ischemia-reperfusion resulted in pulmonary NF-kappaB activation, increased mRNA expression of tumor necrosis factor-alpha (TNF-alpha), and macrophage inflammatory protein-2 (MIP-2), as well as increased pulmonary neutrophil accumulation and lung edema. Administration of IL-10 suppressed lung NF-kappaB activation, reduced TNF-alpha and MIP-2 mRNA expression, and decreased pulmonary neutrophil recruitment and lung injury. The data suggest that IL-10 protects against hepatic ischemia and reperfusion-induced lung injury by inhibiting lung NF-kappaB activation and the resulting pulmonary production of proinflammatory mediators.
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Affiliation(s)
- H Yoshidome
- Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA
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50
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Lentsch AB, Yoshidome H, Warner RL, Ward PA, Edwards MJ. Secretory leukocyte protease inhibitor in mice regulates local and remote organ inflammatory injury induced by hepatic ischemia/reperfusion. Gastroenterology 1999; 117:953-61. [PMID: 10500079 DOI: 10.1016/s0016-5085(99)70355-0] [Citation(s) in RCA: 64] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS This study identified and characterized the hepatic expression of secretory leukocyte protease inhibitor (SLPI) during hepatic ischemia and reperfusion in mice. In addition, the effects of exogenously administered and endogenous SLPI on liver and lung injury induced by hepatic ischemia and reperfusion were evaluated. METHODS C57BL/6 mice underwent 90 minutes of partial hepatic ischemia and 4 hours of reperfusion in the presence or absence of exogenous SLPI or neutralizing antibodies to SLPI. RESULTS Intravenous infusion of SLPI reduced liver and lung damage and diminished neutrophil accumulation in both organs. These effects were accompanied by reduced serum levels of tumor necrosis factor (TNF)-alpha and the CXC chemokine macrophage inflammatory protein (MIP)-2. SLPI also suppressed activation of the transcription factor NF-kappaB in liver. Hepatic ischemia and reperfusion caused increased expression of SLPI messenger RNA and SLPI protein, which was found in hepatocytes. Treatment of mice with anti-SLPI enhanced serum levels of TNF-alpha and MIP-2 and increased hepatic neutrophil accumulation and amount of liver injury. CONCLUSIONS These data indicate that SLPI has protective effects against hepatic ischemia/reperfusion injury and suggest that endogenous SLPI functions to regulate the hepatic inflammatory response.
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Affiliation(s)
- A B Lentsch
- Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky, USA.
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