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Biomedical subjects

Edwin A Deitch

Publications and source records attributed to Edwin A Deitch.

At least 19 recordsLinked to original sources
PubMed2007

Glucose-6-phosphate dehydrogenase deficiency and the inflammatory response to endotoxin and polymicrobial sepsis.

OBJECTIVE: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common human genetic polymorphism. The deficiency protects against malaria but was shown to worsen the clinical course after severe trauma. This study tested whether the deficiency is associated with altered cytokine responses in vitro and in vivo and affects survival after endotoxemia or polymicrobial sepsis (cecal ligation and puncture). DESIGN: Genotyping of animals was carried out using a novel and improved allele-specific polymerase chain reaction assay. Macrophage and splenocyte responses in vitro and ex vivo were compared using gene array analyses and enzyme-linked immunosorbent assays and flow cytometry under both baseline and lipopolysaccharide-stimulated conditions. Endotoxemia- or sepsis-induced mortality was compared under a variety of treatment and resuscitation protocols. SETTINGS: Medical school research laboratories. SUBJECTS: Litter mates of wild-type and G6PD-mutant mice that display a degree of G6PD deficiency similar to that observed in the African-type human deficiency (20% of normal). MEASUREMENTS AND MAIN RESULTS: Lipopolysaccharide in vivo (lipopolysaccharide from Escherichia coli, 10-35 mg/kg body weight intraperitoneally) resulted in greater interleukin-1beta, interleukin-6, and interleukin-10 levels in serum and peritoneal lavage in G6PD-deficient mice compared with wild type. Prevailing doses of lipopolysaccharide in vivo increased mortality in G6PD-deficient animals (40-70%) as compared with wild type (5-40%). In contrast, mortality after cecal ligation and puncture-induced sepsis was similar in G6PD-deficient and wild-type animals either in saline-resuscitated or antibiotic-treated animals. Splenic and blood phagocytes from septic G6PD-deficient and wild-type animals displayed attenuated ex vivo lipopolysaccharide responsiveness. CONCLUSIONS: This study demonstrates that G6PD deficiency augments cytokine responses after inflammatory challenges. The deficiency is disadvantageous as reflected in increased mortality after hyperinflammation caused by acute endotoxemia. However, the deficiency may not manifest worsened survival after the immunosuppressed condition associated with severe sepsis.

Animals↗
PubMed2006

Shaping of monocyte and macrophage function by adenosine receptors.

Adenosine is an endogenous purine nucleoside that, following its release into the extracellular space, binds to specific adenosine receptors expressed on the cell surface. Adenosine appears in the extracellular space under metabolically stressful conditions, which are associated with ischemia, inflammation, and cell damage. There are 4 types of adenosine receptors (A(1), A(2A), A(2B) and A(3)) and all adenosine receptors are members of the G protein-coupled family of receptors. Adenosine receptors are expressed on monocytes and macrophages and through these receptors adenosine modulates monocyte and macrophage function. Since monocytes and macrophages are activated by the same danger signals that cause accumulation of extracellular adenosine, adenosine receptors expressed on macrophages represent a sensor system that provide monocytes and macrophages with information about the stressful environment. Adenosine receptors, thus, allow monocytes and macrophages to fine-tune their responses to stressful stimuli. Here, we review the consequences of adenosine receptor activation on monocyte/macrophage function. We will detail the effect of stimulating the various adenosine receptor subtypes on macrophage differentiation/proliferation, phagocytosis, and tissue factor (TF) expression. We will also summarize our knowledge of how adenosine impacts the production of extracellular mediators secreted by monocytes and macrophages in response to toll-like receptor (TLR) ligands and other inflammatory stimuli. Specifically, we will delineate how adenosine affects the production of superoxide, nitric oxide (NO), tumor necrosis factor-alpha, interleukin (IL)-12, IL-10, and vascular endothelial growth factor (VEGF). A deeper insight into the regulation of monocyte and macrophage function by adenosine receptors should assist in developing new therapies for inflammatory diseases.

Adenosine↗
PubMed2006

Amiloride moderates increased gut permeability and diminishes mesenteric lymph-mediated priming of neutrophils in trauma/hemorrhagic shock.

BACKGROUND: Amiloride, an inhibitor of Na+/H+ exchangers and Na+ channels has been shown recently to ameliorate both gut and lung injury in rats subjected to a combined insult of trauma and hemorrhagic shock (T/HS). We have shown previously that mesenteric lymph duct ligation prevents T/HS-induced lung endothelial injury and neutrophil activation, suggesting that toxic inflammatory factors originating from the gut and carried in the lymph are responsible for the lung injury observed after T/HS. This study investigates whether the protective effect of amiloride against T/HS-induced lung injury was associated with decreased lymph toxicity and gut permeability. METHODS: Male rats subjected to trauma (laparotomy) plus hemorrhagic shock (mean arterial pressure, 30 mm Hgx90 min) (T/HS) or trauma plus sham shock (T/SS) and treated with amiloride or its vehicle had their mesenteric lymph duct catheterized. Mesenteric lymph collected before and after shock was assayed for biologic activity on endothelial cells (cytotoxicity and permeability) and neutrophils (respiratory burst activity). Gut permeability was assessed by monitoring plasma concentrations of the fluorescent dye FITC-dextran after its injection into the ileum. RESULTS: Amiloride administration reduced the capacity of post-shock mesenteric lymph to prime neutrophils for an increased respiratory burst. Amiloride failed to decrease the ability of mesenteric lymph to kill endothelial cells or increase their permeability. Amiloride decreased gut permeability. CONCLUSIONS: The mechanisms of the lung protective effect of amiloride in rats undergoing T/HS may be secondary to decreased neutrophil activation, diminished gut permeability, or an effect on the end organ.

Amiloride↗
PubMed2006

Adenosine A2A receptor inactivation increases survival in polymicrobial sepsis.

The mechanisms governing the impairment of bacterial clearance and immune function in sepsis are not known. Adenosine levels are elevated during tissue hypoxia and damage associated with sepsis. Adenosine has strong immunosuppressive effects, many of which are mediated by A(2A) receptors (A(2A)R) expressed on immune cells. We examined whether A(2A)R are involved in the regulation of immune function in cecal ligation and puncture-induced murine polymicrobial sepsis by genetically or pharmacologically inactivating A(2A)R. A(2A)R knockout (KO) mice were protected from the lethal effect of sepsis and had improved bacterial clearance compared with wild-type animals. cDNA microarray analysis and flow cytometry revealed increased MHC II expression in A(2A)-inactivated mice, suggesting improved Ag presentation as a mechanism of protection. Apoptosis was attenuated in the spleen of A(2A) KO mice indicating preserved lymphocyte function. Levels of the immunosuppressive cytokines IL-10 and IL-6 were markedly lower following A(2A)R blockade. Similar to observations with A(2A)R KO mice, an A(2A)R antagonist increased survival even when administered in a delayed fashion. These studies demonstrate that A(2A)R blockade may be useful in the treatment of infection and sepsis.

Adenosine A2 Receptor Antagonists↗
PubMed2006

Neutrophil activation is modulated by sex hormones after trauma-hemorrhagic shock and burn injuries.

Recent literature indicates that females are more resistant to shock-, trauma-, and sepsis-induced immune dysfunction and organ injury than are males. Consequently, using trauma-hemorrhagic shock (T/HS) and burn models, we tested whether the neutrophil response to trauma occurred in a sexually dimorphic fashion and, if so, the role of sex hormones. Neutrophil activation, as reflected by CD11b expression and respiratory burst activity, was increased to a greater extent in male rats than in female rats after T/HS or burn injury. Testosterone appeared to potentiate neutrophil activation, because castration reduced neutrophil activation, whereas ovariectomy had little effect. Mechanistically, this sexually dimorphic neutrophil response appeared to be due to both cellular and humoral factors. Evidence for a cellular difference between male and female neutrophils is based on the observation that naive female neutrophils were more resistant to activation by burn or T/HS plasma and lymph than naive male neutrophils and that this resistance varied over the estrus cycle. Additionally, the humoral environment was more neutrophil activating in male rats, because burn and T/HS plasma and lymph from male rats activated naive male neutrophils to a greater extent than comparable samples from females. Last, on the basis of in vitro experiments examining the effects of estrogen on calcium signaling, it appears that estrogen limits trauma-induced neutrophil activation, at least in part, by limiting the entry of calcium into the cell via store-operated calcium entry mechanisms. In conclusion, there is a striking sexual dimorphism in neutrophil responses after trauma, and these changes reflect both cellular resistance to activation as well as a less activating humoral environment.

Animals↗
PubMed2006

Role of the gut in the development of injury- and shock induced SIRS and MODS: the gut-lymph hypothesis, a review.

It has long been recognized that major trauma, shock, or burn injury can lead to an acute systemic inflammatory state (SIRS) as well as the multiple organ dysfunction syndrome (MODS). Because of the high mortality rate associated with the development of MODS, for over two decades an intense effort has been devoted towards trying to unravel the underlying mechanisms of this complex syndrome. Although the gut has been implicated in the development of SIRS and MODS experimentally and clinically, its exact role in the pathogenesis of SIRS and MODS remains controversial. However, based on recent experimental evidence, it appears that unique gut-derived factors carried in the intestinal lymph, but not the portal vein, lead to acute injury- and shock-induced SIRS and MODS. These observations have led to the gut-lymph hypothesis of MODS, where gut-derived factors present in intestinal (mesenteric) lymph serve as the triggers that initiate the systemic inflammatory and tissue injurious responses observed after major trauma or episodes of shock.

Animals↗
PubMed2006

Adenosine A2A receptor activation reduces lung injury in trauma/hemorrhagic shock.

OBJECTIVE: Hemorrhagic shock and resuscitation trigger a global ischemia/reperfusion phenomenon, in which various inflammatory processes critically contribute to the ensuing tissue damage. Adenosine is an endogenous nucleoside that is released during shock. Activation of adenosine A(2A) receptors can broadly inactivate inflammatory cascades. The current study was designed to evaluate the effect of A(2A) receptor activation on organ injury and inflammation in the setting of global ischemia/reperfusion elicited by trauma/hemorrhagic shock and resuscitation. DESIGN: Prospective animal study with concurrent control. SETTING: Small animal laboratory. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: The rats were subjected to a laparotomy (trauma) and 90 mins of hemorrhagic shock or trauma/sham shock. The selective A(2A) receptor agonist CGS-21680 (2-p-(2-carboxyethyl) phenethylamino-5'-N-ethyl-carboxamidoadenosine; 0.5 mg/kg) or its vehicle was injected 30 mins before shock or immediately after resuscitation. At 3 hrs following resuscitation, animals were killed and tissue was harvested for analysis. Lung permeability and pulmonary myeloperoxidase levels were used to quantitate lung injury. Intestinal injury was determined by histologic analysis of terminal ileum. Red blood cell deformability was measured by a laser-assisted ektacytometer. In this assay, a decrease in the elongation index is a marker of decreased red blood cell deformability. MEASUREMENTS AND MAIN RESULTS: Pretreatment with CGS-21680 protected the lung but not the gut against shock-induced injury and prevented the shock-induced decrease in red blood cell deformability. Posttreatment with CGS-21680 ameliorated shock-induced lung injury but failed to prevent gut injury and preserve red blood cell deformability. CONCLUSION: A(2A) receptor agonists may represent a novel therapeutic approach in preventing organ injury following trauma/hemorrhagic shock.

Adenosine↗
PubMed2006

Intensive care unit management of the trauma patient.

OBJECTIVE: The goal of this concise review is to provide an overview of some of the most important intensive care unit issues and approaches that are unique to trauma patients as compared with the general intensive care unit population. STUDY SELECTION: Clinical trials in trauma patients focusing on hemorrhage control, issues in resuscitation, staged operative repair of multiple injuries, the diagnosis and therapy of the abdominal compartment syndrome, and the treatment of traumatic brain injury were identified on PubMed. CONCLUSIONS: The intensive care unit care of the trauma patient differs from that of other intensive care unit patients in many ways, one of the most important being the need to continuously integrate operative and nonoperative therapy. Although progress in the care of the injured has been made, death due to uncontrolled bleeding, severe head injury, or the development of multiple organ dysfunction syndrome remains all too common in this patient population. Furthermore, due to the potential nature of the injuries, the conundrum not infrequently arises that the optimal treatment for one injury or organ system, such as preoperative permissive hypotension in actively bleeding patients, may result in suboptimal or even deleterious therapy in the presence of another injury, such as traumatic brain injury. LEARNING OBJECTIVES: On completion of this article, the reader should be able to:Dr. Deitch has disclosed that he is/was the recipient of grant/research funds from Celgene. Dr. Dayal has disclosed that she has no financial relationships with or interests in any commercial companies pertaining to this educational activity. Lippincott CME Institute, Inc., has identified and resolved all faculty conflicts of interest regarding this educational activity. Visit the Critical Care Medicine Web site (www.ccmjournal.org) for information on obtaining continuing medical education credit.

Abdomen↗
PubMed2006

Bone marrow failure in male rats following trauma/hemorrhagic shock (T/HS) is mediated by mesenteric lymph and modulated by castration.

Bone marrow (BM) suppression occurs following trauma/hemorrhagic shock (T/HS) in experimental animals as well as following severe injury in humans. Although the pathophysiology of BM suppression remains poorly understood, mesenteric lymph is thought to play an important role in T/HS-induced BM suppression; however, the direct effect of mesenteric lymph on BM in vitro has never been studied. In addition, recent studies in rats have also shown that female and castrated male rats are protected against T/HS-induced BM failure. We therefore hypothesized that mesenteric lymph is a source of factor(s) causing direct BM suppression and that the effects of mesenteric lymph are gender dependent. To test this hypothesis, we subjected noncastrated (NC) and castrated (C) male and proestrus female rats to T/HS or trauma sham shock (T/SS). Mesenteric lymph collected 3 h postshock was plated (4% v/v) with BM cells collected from unmanipulated male or female rats for granulocyte-macrophage colony-forming units (CFU-GM) and erythroid burst-forming units (BFU-E) colony growth. The T/HS lymph collected from NC-male rats but not from female rats caused a 50% inhibition of CFU-GM and BFU-E colony growth compared with cells cultured without lymph (P < 0.05 versus all other groups (ANOVA + Tukey). T/HS lymph collected from C-male rats also caused no significant inhibition of CFU-GM and BFU-E colony growth compared with cells cultured without lymph. Female and male BM progenitor cells had a similar response to mesenteric lymph from all groups tested. These results show that mesenteric lymph from NC-male rats suppresses CFU-GM and BFU-E progenitor growth in vitro, whereas the lymph from C-male and female rats did not. The effects of mesenteric lymph were the same regardless of whether the target BM was from male or female rats. The results therefore indicate that BM failure in male rats is directly mediated by factors present within the mesenteric lymph that appear to be modulated by castration, and protection against BM failure in female rats occurs at a systemic rather than a local level. Further studies are needed to elucidate potential therapeutic effects of lymph manipulation in hematopoiesis after injury.

Animals↗
PubMed2006

Lymph from a primate baboon trauma hemorrhagic shock model activates human neutrophils.

We have reported that toxic factors in intestinal lymph are responsible for acute lung injury and bone marrow suppression and that they contribute to a systemic inflammatory state based on studies in rodent models of trauma-hemorrhagic shock. Rodent models may not completely reflect the responses of injured patients. Thus, it is important to confirm these findings in primates before applying them to injured human patients with trauma. Thus, we have recently established baboon trauma-hemorrhagic shock (T/HS) and trauma-sham shock (T/SS) models that showed that gut-derived factors carried in the lymph potentiates lung injury and causes human endothelial dysfunction and suppresses human bone marrow progenitor cell growth. Here, we further investigated the effects of these primate lymph samples on human neutrophils. We hypothesized that toxic factors in baboon lymph may prime and/or activate human polymorphonuclear leukocyte (PMN) leading to overproduction of superoxide, thereby contributing to the development of adult respiratory distress syndrome and multiple organ failure. To this effect, we have examined the priming effect of baboon T/HS and T/SS lymph on PMN respiratory burst and expression of adhesion molecule in human neutrophils. The results of these studies indicate that PMN treated with baboon T/HS lymph showed significantly induced respiratory burst responses compared with PMN treated with T/SS lymph or medium when phorbol myristate acetate PMA was applied after lymph pretreatment. Secondly, we found that the expression of CD11b adhesion molecule was increased by incubation with T/HS lymph. These results suggest that baboon lymph from T/HS models can increase respiratory burst and adhesion molecule expression in human PMN, thereby potentially contributing to PMN-mediated organ injury.

Animals↗
PubMed2006

Gut-lymph hypothesis of systemic inflammatory response syndrome/multiple-organ dysfunction syndrome: validating studies in a porcine model.

BACKGROUND: Trauma-hemorrhagic shock (T/HS) mesenteric lymph from rats has multiple biological properties and appears to cause organ injury via the activation of neutrophils and endothelial cells. As the next step in testing the potential clinical relevance of these rodent studies, we utilized a swine T/HS model to determine whether the intestinal lymph results observed in the rodent could be replicated in swine. A porcine model was chosen because the pig and human cardiovascular and gastrointestinal physiology are similar. METHODS: Male pigs were subjected to T/HS and a major intestinal lymph duct was cannulated. Hemorrhagic shock (mean arterial pressure, 40 mm Hg) was performed by withdrawing blood, for 3 hours or until the base deficit reached -5. Animals were then resuscitated in two stages to mimic the prehospital and hospital phases of resuscitation. Mesenteric lymph was collected hourly throughout the experiment and its biological activity was tested on neutrophils (respiratory burst) and endothelial cells (monolayer permeability and cytotoxicity). RESULTS: T/HS lymph but not trauma-sham shock lymph (T/SS) increased neutrophil activation as reflected by an augmented respiratory burst. Likewise T/HS lymph collected at all time points up to 5 hours postshock significantly increased endothelial cell permeability by twofold or greater (p < 0.05), whereas T/HS lymph produced during the first 2 hours postshock was cytotoxic for endothelial cells (viability 70%, p < 0.05 vs. preshock). In contrast, T/SS lymph had no effect on the endothelial cells. CONCLUSION: This large animal model validates rodent studies showing that the shock-injured gut releases biologically active factors into the mesenteric lymph and these factors activate neutrophils and injure endothelial cells.

Animals↗
PubMed2005

Adenosine augments IL-10 production by macrophages through an A2B receptor-mediated posttranscriptional mechanism.

Adenosine receptor ligands have anti-inflammatory effects and modulate immune responses by up-regulating IL-10 production by immunostimulated macrophages. The adenosine receptor family comprises G protein-coupled heptahelical transmembrane receptors classified into four types: A1, A2A, A2B, and A3. Our understanding of the signaling mechanisms leading to enhanced IL-10 production following adenosine receptor occupancy on macrophages is limited. In this study, we demonstrate that adenosine receptor occupancy increases IL-10 production by LPS-stimulated macrophages without affecting IL-10 promoter activity and IL-10 mRNA levels, indicating a posttranscriptional mechanism. Transfection experiments with reporter constructs containing sequences corresponding to the AU-rich 3'-untranslated region (UTR) of IL-10 mRNA confirmed that adenosine receptor activation acts by relieving the translational repressive effect of the IL-10 3'-UTR. By contrast, adenosine receptor activation failed to liberate the translational arrest conferred by the 3'-UTR of TNF-alpha mRNA. The IL-10 3'-UTR formed specific complexes with proteins present in cytoplasmic extracts of RAW 264.7 cells. Adenosine enhanced binding of proteins to a region of the IL-10 3'-UTR containing the GUAUUUAUU nonamer. The stimulatory effect of adenosine on IL-10 production was mediated through the A(2B) receptor, because the order of potency of selective agonists was 5'-N-ethylcarboxamidoadenosine (NECA) > N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) > 2-chloro-N6-cyclopentyladenosine (CCPA) = 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethyl-carboxamidoadenosine (CGS-21680). Also, the selective A2B antagonist, alloxazine, prevented the effect of adenosine. Collectively, these studies identify a novel pathway in which activation of a G protein-coupled receptor augments translation of an anti-inflammatory gene.

3' Untranslated Regions↗
PubMed2005

Non-specific effects of 4-chloro-m-cresol may cause calcium flux and respiratory burst in human neutrophils.

We examined the effects of 4-chloro-m-cresol (4-CmC, a potent and specific activator of ryanodine receptors) on Ca(2+)-release/influx and respiratory burst in freshly isolated human PMN as well as HL60 cells. 4-CmC induces Ca(2+) store-depletion in a dose-dependent manner at concentrations between 400muM and 3mM, however no dose-dependent effect on Ca(2+)-influx was found. 4-CmC depleted Ca(2+) stores that were shared with the GPC agonists such as fMLP and PAF, and therefore 4-CmC presumably depletes Ca(2+) from ER. Since the authentic ligand for RyR is cyclic ADP-ribose (cADPR), we assessed the functional relevance of RyR in PMN by studying the presence and function of membrane-bound ADP-ribosyl cyclase (CD38) in PMN. First, expression of CD38 was confirmed by RT-PCR using cDNA from HL60 cells. Second, PMN from trauma patients showed significantly enhanced CD38 expression than those from healthy volunteers. In addition, although no chemotaxis effect was detected by 4-CmC, it stimulated respiratory burst in PMN in a dose-dependent manner. Our findings suggest that RyRs exist in human PMN and that RyR pathway may play an active role in inflammatory PMN calcium signaling. 8-Br-cADPR and cyclic 3-deaza-ADP did not have inhibitory effects either on 4-CmC-induced Ca(2+) store-depletion or on respiratory burst, on the other hand, PLC inhibitor, U73122, completely attenuated both 4-CmC-induced Ca(2+) store-depletion and respiratory burst. Although it has been used as a specific activator of RyR, 4-CmC has non-specific effects which cause Ca(2+) store-depletion and respiratory burst at least in human PMN.

Calcium↗
PubMed2005

Dual effects of mesenteric lymph isolated from rats with burn injury on contractile function in rat ventricular myocytes.

Gut-derived factors in intestinal lymph have been shown to trigger myocardial contractile dysfunction. However, the underlying cellular mechanisms remain unclear. We examined the effects of physiologically relevant concentrations of mesenteric lymph collected from rats with 40% burn injury (burn lymph) on excitation-contraction coupling in rat ventricular myocytes. Burn lymph (0.1-5%), but not control mesenteric lymph from sham-burn animals, induced dual positive and negative inotropic effects depending on the concentrations used. At lower concentrations (<0.5%), burn lymph increased the amplitude of myocyte contraction (1.6 +/- 0.3-fold; n = 12). At higher concentrations (>0.5%), burn lymph initially enhanced myocyte contraction, which was followed by a block of contraction. These effects were partially reversible on washout. The initial positive inotropic effect was associated with a prolongation of action potential duration (measured at 90% repolarization, 2.5 +/- 0.6-fold; n = 10), leading to significant increases in the net Ca2+ influx (1.7 +/- 0.1-fold; n = 8). There were no significant changes in the resting membrane potential. The negative inotropic effect was accompanied by a decrease in the action potential plateau (overshoot decrease by 69 +/- 10%; n = 4) and membrane depolarization. Voltage-clamp experiments revealed that the positive inotropic effects of burn lymph were due to an inhibition of the transient outward K+ currents that prolong action potential duration, and the inhibitory effects were due to a concentration-dependent inhibition of Ca2+ currents that lead to a reduction of action potential plateau. These burn lymph-induced changes in cardiac myocyte Ca2+ handling can contribute to burn-induced contractile dysfunction and ultimately to heart failure.

Action Potentials↗
PubMed2005

Albumin peptide: a molecular marker for trauma/hemorrhagic-shock in rat mesenteric lymph.

Vascular permeability and endothelial cell damage has been shown to occur in rats subjected to trauma with hemorrhagic-shock. Although the factors responsible for the endothelial cell injury are unknown, it has been hypothesized that toxic factors produced in response to hemorrhagic-shock originate in the gut and are absorbed into the mesenteric lymphatics. Consistent with this hypothesis, it has been shown that lymph collected from animals subjected to trauma with hemorrhagic-shock (T/HS) results in a marked decrease in endothelial cell viability both in vitro and in vivo. We therefore compared the lymph collected pre-T/HS to samples collected during, and up to 3h post-T/HS in order to identify a factor present or increased in post-T/HS lymph. This analysis revealed that a single cationic peptide band was significantly increased in post-T/HS lymph, but not in lymph from control animals subjected to trauma without hemorrhagic-shock (T/SS). This peptide was subsequently identified as the N-terminal 24 amino acids of rat serum albumin (RSA) by mass spectrometry and amino acid sequencing. Although the measured increase in the albumin peptide correlates with detectable shock lymph-induced endothelial cell toxicity, the peptide was not toxic to endothelial cells. We therefore propose that the significant increase in the albumin peptide is a marker for post-T/HS lymph-induced endothelial cell toxicity.

Animals↗
PubMed2005

Augmented IL-10 production and redox-dependent signaling pathways in glucose-6-phosphate dehydrogenase-deficient mouse peritoneal macrophages.

Glucose-6-phosphate dehydrogenase (G6PD) supports cellular antioxidant pathways. G6PD deficiency is associated with malaria protection but was shown to worsen the clinical course to injury. This study tested whether G6PD deficiency manifests in altered cytokine responses using peritoneal macrophages from a G6PD-deficient mouse model with a degree of defect similar to the common type A(-) human G6PD deficiency. Lipopolysaccharide (LPS)-induced interleukin (IL)-10 and IL-12 production was doubled in G6PD-deficient macrophages compared with wild-type (WT). Protein kinase C (PKC) activation by phorbol-ester prior to LPS resulted in a fivefold greater IL-10 production in G6PD-deficient macrophages compared with WT. Interferon-gamma treatment prior to LPS augmented IL-12 production in G6PD-deficient and WT macrophages and partially inhibited IL-10 production by G6PD-deficient macrophages. The antioxidants (N-acetyl-L-cysteine and glutathione ethyl-ester) blunted IL-10 and IL-12 production, indicating a role for oxidative stress in the observed response differences between deficient and WT macrophages. LPS-induced activation of nuclear factor-kappaB, cyclic adenosine monophosphate response element-binding protein, and specificity protein 3 was augmented in G6PD-deficient cells compared with WT. The PKCdelta inhibitor Rottlerin inhibited IL-10 and IL-12 production at different 50% effective-dose concentrations between deficient and WT macrophages, indicating elevated PKCdelta activity in deficient cells. This study reveals that activated G6PD-deficient macrophages display an augmented production of cytokines with a prominent impact on IL-10 production. The altered cytokine responses are associated with augmented activation of redox-dependent transcription factors and PKCdelta. Alterations in signaling pathways and associated changes in cytokine production may play a role in modulating the inflammatory responses following bacterial or malarial infections in G6PD deficiency.

Animals↗
PubMed2005

Mesenteric lymph duct ligation decreases red blood cell alterations caused by acute pancreatitis.

BACKGROUND: Both experimental and clinical studies have shown that acute pancreatitis (AP) causes a significant decrease in red blood cell (RBC) deformability. The mechanisms by which AP induces RBC injury are unknown. The purpose of this study was to test the hypothesis that factors carried in the mesenteric lymph after an attack of AP significantly contribute to the RBC injury observed in AP. METHODS: RBC deformability was determined by means of laser-assisted ektacytometry in mesenteric lymph duct-ligated and non-ligated rats subjected to AP and in sham-operated animals. RESULTS: AP was associated with significant alterations of RBC deformability indices, namely the elongation index and half maximal RBC elongation. Pancreatitis-induced RBC deformability changes were partially prevented by mesenteric lymph duct ligation. CONCLUSIONS: Mesenteric lymph in AP contains factors that cause RBC damage, which is manifested by decreased deformability. Interruption of the lymph flow from the injured gut into the bloodstream decreases these RBC alterations.

Animals↗