Jon Walsh

Borgess Medical Center

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Luis H. Toledo‐Pereyra

Michigan State University

Roberto Anaya‐Prado

Tecnológico de Monterrey

Peter A. Ward

University of Michigan–Ann Arbor

Fernando López-Neblina

Universidad Autónoma de Baja California

Jayne S. Reuben

Texas College

Alexander H. Toledo

University of North Carolina at Chapel Hill

Edwin W. Lai

Azienda Ospedaliero-Universitaria Cagliari

Ruipeng Guo

Medizinische Hochschule Hannover

J. Ricardo Ramos-Kelly

Universidad de Tijuana

Ruilin Guo

First Affiliated Hospital of Chongqing Medical University

Cooperative Institutions

University of Michigan–Ann Arbor

Borgess Medical Center

Michigan State University

Mexican Social Security Institute

Western Michigan University

Secretaría de Salud de Jalisco

Inflarx (Germany)

University of North Carolina at Chapel Hill

Texas College

Gaston College

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Molecular signaling pathways in ischemia/reperfusion.

PubMed (2004)

Luis H. Toledo‐Pereyra Alexander H. Toledo Jon Walsh Fernando López-Neblina

Ischemia and reperfusion (I/R) is an important pathologic phenomenon that has not been completely defined from the perspective of the molecular signaling pathways developed immediately at its inception to minutes and hours thereafter. From the practical point of view, we have divided I/R into 3 phases: phase I, which occurs seconds to minutes after the injury and is associated with changes dependent on the activation of phospholipases, intracellular calcium, eicosanoids, other lipid molecules, protein kinases, inducible nitric oxide synthase, and the expression of preformed adhesion molecules like P-selectin; phase II, which occurs minutes to hours after I/R injury and is associated with the active transcription of protein synthesis of molecules like inflammatory cytokines (mainly tumor necrosis factor-alpha and interleukin 1) starting their signaling downstream from the membrane into the cytoplasm where kinases will be activated and send signals to the nucleus for the activation of transcription factors and further continuing with the inflammatory event; and phase III, which occurs several hours to days after I/R and is associated with the appearance of molecular chronic mechanisms of protection like the presence of anti-inflammatory cytokines of the IL-10 type, late adhesion molecules, and other growth factors such as TGF-beta. This completes the whole molecular event related to I/R injury.

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Exogenous Nitric Oxide Donor and Related Compounds Protect Against Lung Inflammatory Response After Hemorrhagic Shock and Resuscitation

Journal of Trauma and Acute Care Surgery (2004)

Roberto Anaya‐Prado Luis H. Toledo‐Pereyra Jon Walsh Ruilin Guo Jayne S. Reuben

Background: Resuscitation from hemorrhagic shock triggers an inflammatory response characterized by upregulation of cytokine and adhesion molecule expression, increased leukocyte activity, and accumulation of polymorphonuclear neutrophils in a variety of tissues. This study investigated the capability of an exogenous nitric oxide (NO) donor, sodium nitroprusside (NP); a NO substrate, L-arginine; and an inducible NO synthase inhibitor, L-N6-(1-iminoethyl)lysine (L-NIL) to reduce lung injury in an animal model of mixed controlled and uncontrolled hemorrhagic shock. Methods: For this study, 72 Sprague–Dawley rats weighing 250 to 300 g were subjected to a model of uncontrolled hemorrhagic shock for 150 minutes. Six groups of animals were included in this study (12 per group): sham–saline, sham–NP, shock–saline, shock–NP, shock–L-arginine, and shock–L-N6-(1-iminoethyl)lysine. After the period of hemorrhagic shock, resuscitation of the groups was accomplished using normal saline (groups 1 and 3), NP (0.5 mg/kg) (groups 2 and 4), L-arginine (300 mg/kg) (group 5), or L-NIL (50 mg/kg) (group 6). The following indices were evaluated: fluid requirements for resuscitation, mean arterial pressure (MAP), arterial po2, pco2, and pH, lung wet-to-dry weight ratio, lung histology and cytokine (interleukin [IL]-1α, IL-β1, tumor necrosis factor-β [TNFβ], IL-3, IL-4, IL-5, IL-6, IL-10, TNFα, IL-2, interferon-γ [IFNγ]), and mRNA expression in the lung by a ribonuclease protection assay (RPA). Results: Sodium nitroprusside significantly increased MAP and reduced fluid requirements during resuscitation after hemorrhage. There also was a significant improvement in lung function, as expressed by improvements in po2, pco2, and pH, and reduction of the wet-to-dry weight ratio. In addition, a significant reduction in acute lung injury was observed in the histologic studies. Furthermore, the expression of cytokines was reduced by NP treatment. The use of L-arginine and L-NIL offered similar protective results for the injured lung. Conclusions: These data suggest that limiting inducible NO synthase–generated NO availability with the exogenous NO donor, sodium nitroprusside, may reduce lung injury after severe hemorrhage, possibly, among other effects, by downregulating the expression of inflammatory cytokines. L-arginine and L-NIL also had a beneficial effect on lung function and structure.

Sodium nitroprusside

Mean arterial pressure

10.1097/01.ta.0000135354.72494.8d

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The Role of MAP Kinases in Trauma and Ischemia–Reperfusion

Journal of Investigative Surgery (2004)

Edwin W. Lai Luis H. Toledo‐Pereyra Jon Walsh Fernando López-Neblina Roberto Anaya‐Prado

Mitogen-activated protein kinases (MAPKs) have been the focus of a number of studies, as these compounds are involved in a number of important inflammatory cell signaling mechanisms. Recent studies have further elucidated the role of MAPKs in the inflammatory response, as a result of trauma and/or ischemia-reperfusion (I/R) injury. There are three major classes of MAPKs that may be involved in the inflammatory response: extracellular signal-regulated kinases (ERKs), stress-activated protein kinases (SAPKs)/c-Jun NH(2)-terminal kinases (JNKs), and p38 MAPKs (p38). This is clinically relevant, because these pathways may be a possible target for anti-inflammatory drug intervention. This review studies the role of MAPKs in trauma and/or I/R.

Inflammatory response

10.1080/ivs.17.1.45.53

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Multiple Selectin Blockade With a Small-Molecule Selectin Inhibitor Does Not Affect Survival After a Second Inflammatory Challenge With Nonlethal LPS

Journal of Investigative Surgery (2002)

Roberto Anaya‐Prado J. Ricardo Ramos-Kelly Luis H. Toledo‐Pereyra Jon Walsh Peter A. Ward

The effects of anti-adhesion molecule antibodies on the blockade of leukocyte-endothelial interactions have the potential of decreasing survival through possibly increased infection vulnerability. The aim of this study was to determine the effect of a small-molecule selectin inhibitor (TBC-1269) on both liver response and survival to a nonlethal lipopolysaccharide (LPS) challenge after hemorrhagic shock. Ninety-six Sprague-Dawley rats were subjected to a model of uncontrolled hemorrhagic shock. Six groups of animals were included in this study ( n = 16 per group): sham/saline, sham/LPS, shock/saline, shock/LPS, shock/TBC1269, and shock/TBC-1269/LPS. Experimental design consisted of the development of hemorrhagick shock (3 mL/100 g) in a 15-min period, tail amputation and drug administration at 30 min, and subsequent resuscitation to maintain mean arterial pressure at 70mm Hg. A septic challenge was produced with 0.1 mg/kg of LPS ( Escherichia coli type 78H4086; Sigma Chemical, St. Louis, MO) given intravenously via penile vein at 20 h. Liver injury tests (alanine aminotransferase, ALT), liver myeloperoxidase, liver histology, and 21-day survival were evaluated. Statistical analysis included the Bartlett test for equality of variance, a two-way analysis of variance (ANOVA), and overall followed by pairwise log-rank test for survival. Significant improvements in liver function and histology were observed in animals treated with TBC-1269 with or without a nonlethal septic challenge. Neutrophil infiltration, as evidenced by liver myeloperoxidase (MPO) was significantly decreased in animals treated with TBC-1269 alone and those having LPS administration after TBC-1269 treatment. We conclude that TBC-1269, multisectin blocker, was effective in reducing liver damage even with the addition of a second inflammatory insult as the nonlethal LPS challenge used in this study.

10.1080/08941930290085921

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The Role of MAP Kinases in Trauma and Ischemia–Reperfusion

Journal of Investigative Surgery (2004)

Edwin W. Lai Luis H. Toledo‐Pereyra Jon Walsh Fernando López-Neblina Roberto Anaya‐Prado

Mitogen-activated protein kinases (MAPKs) have been the focus of a number of studies, as these compounds are involved in a number of important inflammatory cell signaling mechanisms. Recent studies have further elucidated the role of MAPKs in the inflammatory response, as a result of trauma and/or ischemia–reperfusion (I/R) injury. There are three major classes of MAPKs that may be involved in the inflammatory response: extracellular signal-regulated kinases (ERKs), stress-activated protein kinases (SAPKs)/c-Jun NH2-terminal kinases (JNKs), and p38 MAPKs (p38). This is clinically relevant, because these pathways may be a possible target for anti-inflammatory drug intervention. This review studies the role of MAPKs in trauma and/or I/R.

Inflammatory response

10.1080/08941930490269646

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Citations (11)

Ryanodine Receptor Antagonism Protects the Ischemic Liver and Modulates TNF-α and IL-10

Journal of Surgical Research (2007)

Fernando López-Neblina Luis H. Toledo‐Pereyra Alexander H. Toledo Jon Walsh

10.1016/j.jss.2006.12.003

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Citations (21)

The Attenuation of Hemorrhage-Induced Liver Injury by Exogenous Nitric Oxide, L -Arginine, and Inhibition of Inducible Nitric Oxide Synthase

Journal of Investigative Surgery (2003)

Roberto Anaya‐Prado Luis H. Toledo‐Pereyra Ruipeng Guo Jayne S. Reuben Peter A. Ward

We investigated the role of nitric oxide (NO) in its ability to reduce liver injury in an animal model of hemorrhagic shock (HS). Ninety-six Sprague-Dawley rats weighing 250 to 300 g were divided in 6 groups ( n = 16 per group) that included treatment at the beginning of resuscitation with normal saline (groups 1, 3) sodium nitroprusside (NP) (0.5 mg/kg) (groups 2, 4) L -arginine (300 mg/kg) (group 5), and L - N 6 -(1-iminoethyl) lysine (L-NIL, 40 mg/kg) (group 6). The experimental model of HS consisted of the withdrawal of 3 mL blood per 100 g in a 15-min period, tail amputation (75%), and drug administration at 30 min. This was followed by fluid resuscitation (FR) with lactated Ringer's (LR) solution to reach a mean arterial pressure (MAP) of 40 mm Hg, then a hospital phase of 60 min with hemostasis and FR with LR solution to reach a MAP of 70 mm Hg with a 3-day observation phase. NP, L -Arginine, and L-NIL significantly reduced fluid requirements for resuscitation ( p = .0001) as well as significantly increased MAP after resuscitation from hemorrhage. We also observed an improved statistically significant difference ( p = .001) in tests demonstrating less hepatic injury and histology damage. The mRNA expression of cytokines in the liver (interleukin [IL]-1 f , IL- g 1, tumor necrosis factor [TNF] g , IL-3, IL-4, IL-5, IL-6, IL-10, TNF f , IL-2, interferon [IFN] n ) was reduced by NP treatment, L -arginine, and L-NIL. These data suggest that excess NO mediates hemorrhage-induced liver injury and that the suppression of inducible nitric oxide synthase (iNOS)-generated NO bioavailability with the NO donor sodium nitroprusside may reduce the pathophysiologic consequences of severe hemorrhage. This effect could be possibly related to the scavenging of to superoxide radicals (O 2 m ) or the blockade of the deleterious effects of TNF and other inflammatory cytokines. The protective action noted with L -arginine cannot be fully explained within the context of this article, although it could be most likely associated with the supplementation of eNOS-generated NO.

Sodium nitroprusside

Mean arterial pressure

10.1080/713829709

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Citations (2)

The Attenuation of Hemorrhage-Induced Liver Injury by Exogenous Nitric Oxide, L -Arginine, and Inhibition of Inducible Nitric Oxide Synthase

Journal of Investigative Surgery (2003)

Roberto Anaya‐Prado Luis H. Toledo‐Pereyra Ruru Guo Jayne S. Reuben Peter A. Ward

We investigated the role of nitric oxide (NO) in its ability to reduce liver injury in an animal model of hemorrhagic shock (HS). Ninety-six Sprague-Dawley rats weighing 250 to 300 g were divided in 6 groups (n = 16 per group) that included treatment at the beginning of resuscitation with normal saline (groups 1, 3) sodium nitroprusside (NP) (0.5 mg/kg) (groups 2, 4) L-arginine (300 mg/kg) (group 5), and L-N6-(1-iminoethyl) lysine (L-NIL, 40 mg/kg) (group 6). The experimental model of HS consisted of the withdrawal of 3 mL blood per 100 g in a 15-min period, tail amputation (75%), and drug administration at 30 min. This was followed by fluid resuscitation (FR) with lactated Ringer's (LR) solution to reach a mean arterial pressure (MAP) of 40 mm Hg, then a hospital phase of 60 min with hemostasis and FR with LR solution to reach a MAP of 70 mm Hg with a 3-day observation phase. NP, L-Arginine, and L-NIL significantly reduced fluid requirements for resuscitation (p =.0001) as well as significantly increased MAP after resuscitation from hemorrhage. We also observed an improved statistically significant difference (p =.001) in tests demonstrating less hepatic injury and histology damage. The mRNA expression of cytokines in the liver (interleukin [IL]-1alpha, IL-beta1, tumor necrosis factor [TNF]beta, IL-3, IL-4, IL-5, IL-6, IL-10, TNFalpha, IL-2, interferon [IFN]gamma) was reduced by NP treatment, L-arginine, and L-NIL. These data suggest that excess NO mediates hemorrhage-induced liver injury and that the suppression of inducible nitric oxide synthase (iNOS)-generated NO bioavailability with the NO donor sodium nitroprusside may reduce the pathophysiologic consequences of severe hemorrhage. This effect could be possibly related to the scavenging of to superoxide radicals (O2-) or the blockade of the deleterious effects of TNF and other inflammatory cytokines. The protective action noted with L-arginine cannot be fully explained within the context of this article, although it could be most likely associated with the supplementation of eNOS-generated NO.

Sodium nitroprusside

Mean arterial pressure

10.1080/08941930390230379

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Citations (16)