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Luis H Toledo-Pereyra

Publications and source records attributed to Luis H Toledo-Pereyra.

At least 19 recordsLinked to original sources
PubMed2006

Phosphoregulation of signal transduction pathways in ischemia and reperfusion.

Ischemia/reperfusion (I/R) injury triggered by pathogenic processes, such as organ transplant dysfunction, stroke, myocardial infarction, and shock, stimulate both immune and inflammatory pathways. Inflammatory cell activation and cytotoxic cytokine expression are associated with reperfusion injury. The activation of these inflammatory mediators initiates several interconnected downstream cascades regulated by phosphorylation and dephosphorylation reactions. These complex phosphorylation-dependent signal transduction pathways ultimately initiate nuclear transcription of inflammatory as well as anti-inflammatory genes to repair and assist in the recovery of damaged cells. Radical oxygen species (ROS) production, under ischemic conditions, initiates a cascade of events regulated by phosphorylation/dephosphorylation reactions and inflammatory gene expression. This is a review of the current understanding of the phosphoregulatory mechanisms that mediate the complex processes of signal transduction secondary to I/R injury. The rationale for inhibiting or activating signaling pathways as a promising molecular target for ameliorating reperfusion injury in I/R-related diseases, such as stroke, myocardial infarction, and storage for transplantation, is discussed on the basis of a new understanding of the mechanisms modulating phosphoregulatory pathways. In addition, we present part of our ongoing research in this field with phosphoregulatory signal transduction and its potential application.

Animals↗
PubMed2004

Exogenous nitric oxide donor and related compounds protect against lung inflammatory response after hemorrhagic shock and resuscitation.

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]-1 alpha, IL-beta 1, tumor necrosis factor-beta [TNF beta], IL-3, IL-4, IL-5, IL-6, IL-10, TNF alpha, IL-2, interferon-gamma [IFN gamma]), 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.

Animals↗
PubMed2004

Reactive oxygen species and molecular biology of ischemia/reperfusion.

Ischemic reperfusion injury is a complex pathophysiological event associated with significant impairment of multiple vascular and cellular responses. Oxidative damage due to the presence of radical oxygen species is the essential step that initiates a wide range of intracellular stress signaling processes that culminate in excessive cytokine and chemokine response, adhesion molecule upregulation and nitric oxide overproduction. As we studied all the various mechanisms of injury, we began deciphering the best means to treat the ischemic insult by modulating those proteins or active mediators that are responsible for the lesion. In this manner, we have utilized free radical scavengers, calcium channel blockers, membrane stabilizers, vasodilators, exogenous nitric oxide and arginine, adhesion molecule blockers and small molecule selectin antagonists, in an effort to improve cell function and survival after ischemia and reperfusion. The continuous investigation of new and old compounds that mitigate the ischemic injury will permit us to advance this important field of medicine.

Animals↗
PubMed2004

Molecular signaling pathways in ischemia/reperfusion.

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.

Animals↗
PubMed2003

Xenotransplantation: a view to the past and an unrealized promise to the future.

Since the early 20th Century when Emerich Ullman transplanted a pig kidney into the arm of a woman (1902), Princeteau implanted portions of a rabbit kidney into the kidney of a child who was dying of renal insufficiency (1905), Jaboulay transplanted two kidneys from a pig and a goat as donor sources (1906), and Unger implanted a monkey kidney into a human (1910), xenotranplantation has made some strides, mostly related to advanced surgical techniques, improved knowledge of immunological principles, and to steps associated with the development of the most effective immunosuppressive therapy. Innovative surgical techniques were introduced by Alexis Carrel in the first decade of the 1900s, so that vascular anastomoses could be realized without a considerable amount of thrombotic/embolic problems, long before heparin times. Inasmuch as these advances were soundly characterized, it became evident that the results were far from expected and that the time was not ripe for xenotranplantation. It took 50 years (1963) before Keith Reemtsma transplanted 13 kidneys from chimpanzees into patients with kidney failure. Remarkably, one patient survived for 9 months before dying from electrolyte imbalance. In the ensuing years, Starzl (1964), Hardy (1964), Cooley (1968), Ross (1968), Barnard (1977), Bailey (1984) and a few others entered this new field with less than satisfactory accomplishments. The unsolvable barrier of hyperacute rejection required persistence and ingenuity. The recognition of xenoantibodies and their requirement for full depletion, through ex vivo porcine perfusion, plasmapheresis, immunoabsorption and complement inhibition, facilitated important advances in this field. The introduction of accommodation and molecular chimerism has further improved the knowledge of this newly conceived field. Advanced molecular engineering techniques have recently permitted the creation of the clonal Gal-deficient pig by eliminating the alpha-1, 3 galactosyltransferase gene. These discoveries together with better immunosuppression raise hope for the yet unrealized promise of xenotranplantation.

Animals↗
PubMedDate not supplied

Multiple selectin blockade with a small-molecule selectin inhibitor does not affect survival after a second inflammatory challenge with nonlethal LPS.

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.

Animals↗
PubMedDate not supplied

Exogenous nitric oxide downregulates MIP-2 and MIP-1alpha chemokines and MAPK p44/42 after ischemia and reperfusion of the rat kidney.

The mechanisms by which nitric oxide (NO) exerts its protective effect in the ischemia/reperfusion (I/R) injury of the kidney have not been fully determined. The hypothesis of this study was based on the assumption that I/R upregulates some chemokines (MIP-2 and MIP-1alpha) as well as certain protein kinases (MAPK p44/42), and therefore we aimed in this work at recognizing if an exogenous NO donor would downregulate these effects in rat ischemic kidneys at the same time that it would offer functional protection as measured by serum creatinine. Sprague-Dawley rats were subjected to renal warm ischemia (75 min) and contralateral nephrectomy. Animals were divided into 3 groups (n = 8 per group): sham, ischemic control, and ischemic group treated with sodium nitroprusside (NaNP 5 mg/kg) given 15 min prior to reperfusion. Serum creatinine (SCr), serum chemokines (MIP-2 and MIP-1alpha), kidney tissue MAPK p44/42, kidney neutrophil infiltration determined by myeloperoxidase (MPO), and light histology were evaluated 4 h after reperfusion began. There were significant improvements in SCr and better histopathological features in the I/R-NaNP group compared with the I/R group. Similarly, the I/R-NaNP kidneys exhibited a downregulating effect of serum chemokines (MIP-2 and MIP-1alpha) and kidney tissue MAPK p44/42 that was not observed in the I/R group alone. The MPO levels were lower in the I/R-NaNP group compared with the I/R untreated group. We can conclude from these experiments that I/R of the rat kidney upregulated the production of MIP-2 and MIP-1alpha chemokines and the activation of MAPKp44/42. It also had a detrimental effect on the function and structure of the ischemic kidney. Exogenous NO had a temporal protective effect in organ function and histology and exerted a downregulating response in the production of MIP-2 and MIP-1alpha chemokines and the activation of MAPK p44/42 following I/R.

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