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Peter A Ward

Publications and source records attributed to Peter A Ward.

72 records · Page 4Linked to original sources
PubMed2002

C5a receptor and thymocyte apoptosis in sepsis.

In sepsis, apoptosis occurs in many different organs. The mediators responsible for induction of apoptosis are not clearly known, although there are some suggestions that C5a and the C5a receptor (C5aR) might be directly linked to apoptosis. In the cecal ligation/puncture (CLP) model of sepsis in rats, apoptosis occurs early in a variety of organs, especially in the thymus. We demonstrate that thymocytes from normal rats show specific, saturable, and high affinity binding of 125I-labeled recombinant rat C5a. C5a binding to thymocytes was significantly increased 3 h after CLP and also when thymocytes from normal rats were first incubated in vitro with lipopolysaccharide (LPS) or IL-6. The expression of C5aR mRNA in thymocytes was markedly increased 3, 6, and 12 h after CLP and increased similarly when normal thymocytes were first exposed to LPS or IL-6 in vitro. Thymocytes obtained 2 or 3 h after CLP and exposed in vitro to C5a, but not normal thymocytes, underwent increased apoptosis, as demonstrated by annexin-V binding, coinciding with increased activation of caspases 3, 6, and 8. These data provide the first direct evidence that in the early onset of sepsis, increased expression of C5aR occurs in thymocytes, which increases their susceptibility to C5a-induced apoptosis.

Animals↗
PubMed2002

Expression and function of the C5a receptor in rat alveolar epithelial cells.

Although alveolar epithelial cells (AEC) form an important barrier for host defenses in the lung, there is limited information about ways in which AEC can directly participate in the lung inflammatory response. In the current studies, primary cultures of rat AEC (RAEC) have been shown to specifically bind recombinant rat C5a at high affinity and in a saturable manner. This binding was enhanced in a time-dependent manner by pre-exposure of RAEC to LPS, IL-6, or TNF-alpha, the increased binding of C5a being associated with increased levels of mRNA for the C5a receptor (C5aR). Exposure of RAEC to C5a also caused increased expression of mRNA for C5aR. As compared with exposure of RAEC to LPS or to C5a alone, exposure to the combination caused enhanced production of TNF-alpha, macrophage inflammatory protein-2, and cytokine-induced neutrophil chemoattractant-1, as well as increased intracellular levels of IL-1beta. These data indicate that RAEC, when activated, have enhanced binding of C5a in association with increased mRNA for C5aR. The functional outcome is enhanced release of proinflammatory mediators. These data underscore the phlogistic potential of RAEC and the ability of C5a to enhance the phlogistic responses of RAEC.

Animals↗
PubMed2002

Regulatory role of IL-10 in experimental obliterative bronchiolitis in rats.

Obliterative bronchiolitis (OB) affects over half of all chronic human survivors following lung or heart-lung transplantation. Respiratory epithelial cell injury, peribronchial inflammation, and proliferation of fibrovascular connective tissue causing airway occlusion characterize this lesion. Using a rat model of experimental OB, tracheas and mainstem bronchi from Brown-Norway or Lewis (LEW) rats were transplanted subcutaneously into LEW recipients. At 7 days, airway lumens of allografts showed minimal luminal obstruction but significant respiratory epithelial loss. By 14 days, allografts demonstrated marked peribronchial inflammation, nearly complete loss of respiratory epithelium, and extensive intraluminal proliferation of fibrovascular connective tissue, with a mean 58% reduction in airway cross-sectional diameter. However, isografts showed only limited peribronchial inflammation and no loss of airway lumen. When recipients of allotransplants were treated with anti-IL-10, OB developed more rapidly. As early as 7 days, there was marked histologic evidence of OB and a 43% reduction in mean cross-sectional area. Allograft animals that received 5 microg/day of recombinant IL-10 as a constant infusion on day 14 showed almost complete preservation of respiratory epithelium and only mild peribronchial inflammation with only a 15% reduction in airway cross-sectional area. These findings suggest that endogenous IL-10 plays a regulatory role in the development of experimental OB.

Animals↗
PubMed2002

Anti-c5a ameliorates coagulation/fibrinolytic protein changes in a rat model of sepsis.

Sepsis and trauma are the two most common causes of disseminated intravascular coagulation and multiple organ dysfunction syndrome. Both disseminated intravascular coagulation and the systemic inflammatory response syndrome often lead to multiple organ dysfunction syndrome. The current studies have evaluated the relationship between the anaphylatoxin, C5a, and changes in the coagulation/fibrinolytic systems during the cecal ligation and puncture (CLP) model of sepsis in rats. CLP animals treated with anti-C5a had a much improved number of survivors (63%) compared to rats treated with pre-immune IgG (31%). In CLP rats treated with pre-immune IgG there was clearly increased procoagulant activity with prolongation of the activated partial thromboplastin time and prothrombin time, reduced platelet counts, and increased levels of plasma fibrinogen. Evidence for thrombin formation was indicated by early consumption of factor VII:C, subsequent consumption of factors XI:C and IX:C and anti-thrombin and increased levels of the thrombin-anti-thrombin complex and D-dimer. Limited activation of fibrinolysis was indicated by reduced plasma levels of plasminogen and increased levels of tissue plasminogen activator and plasminogen activator inhibitor. Most of these parameters were reversed in CLP rats that had been treated with anti-C5a. Production of C5a during sepsis may directly or indirectly cause hemostatic defects that can be reduced by blockade of C5a.

Animals↗
PubMed2002

Activator protein-1 activation in acute lung injury.

The role of activator protein-1 (AP-1) in inflammation is primarily unknown. AP-1 was evaluated in nuclear extracts from alveolar macrophages and whole lung nuclear extracts during acute lung injury after deposition of IgG immune complexes. AP-1 activation occurred in macrophages and in whole lung extracts, but with distinctly different time courses. Low levels of constitutive AP-1 were observed in normal rat lung as determined by the electrophoretic mobility shift assay. Increased AP-1 was detected 2 hours after initiation of the inflammatory response in lung with a further increase by 4 hours, while AP-1 activation was found in alveolar macrophages 0.5 hour after onset of the inflammatory response. mRNAs and proteins for c-fos, c-jun, jun-B, and jun-D were all up-regulated in whole lung tissues and in alveolar macrophages during acute lung injury induced by IgG immune complex deposition. Depletion of lung macrophages sharply reduced AP-1 activation, as did anti-tumor necrosis factor-alpha, whereas complement depletion showed no effect on lung AP-1 activation. The data suggest that activation of AP-1 occurs in both alveolar macrophages and in the lung, and this activation process is macrophage- and tumor necrosis factor-alpha-dependent.

Acute Disease↗
PubMed2002

Generation of C5a by phagocytic cells.

The complement activation product, C5a, is a powerful phlogistic factor. Using antibodies to detect human or rat C5a, incubation at pH 7.4 of human blood neutrophils or rat alveolar macrophages (AMs) with C5 in the presence of phorbol 12-myristate 13-acetate (PMA) led to generation of C5a. Rat AMs activated with lipopolysaccharide also generated C5a from C5. With activated neutrophils, extensive cleavage of C5 occurred, whereas activated macrophages had much more selective proteolytic activity for C5. Peripheral blood human or rat mononuclear cells and rat alveolar epithelial cells when stimulated with phorbol ester all failed to demonstrate an ability to cleave C5, suggesting a specificity of C5 cleavage by phagocytic cells. With rat AMs, C5a generation was time-dependent and was blocked if AMs were pretreated with inhibitors of transcription or protein synthesis (actinomycin D or cycloheximide). Similar treatment of activated human polymorphonuclear leukocytes only partially reduced C5a generation after addition of C5. C5a generated by activated AMs was biologically (chemotactically) active. This generation was sensitive to serine protease inhibitors but not to other classes of inhibitors. These data indicate that phagocytic cells, especially lung macrophages, can generate C5a from C5. In the context of the lung, this may represent an important C5a-generating pathway that is independent of the plasma complement system.

Animals↗
PubMed2002

Protection of innate immunity by C5aR antagonist in septic mice.

Innate immune functions are known to be compromised during sepsis, often with lethal consequences. There is also evidence in rats that sepsis is associated with excessive complement activation and generation of the potent anaphylatoxin C5a. In the presence of a cyclic peptide antagonist (C5aRa) to the C5a receptor (C5aR), the binding of murine 125I-C5a to murine neutrophils was reduced, the in vitro chemotactic responses of mouse neutrophils to mouse C5a were markedly diminished, the acquired defect in hydrogen peroxide (H2O2) production of C5a-exposed neutrophils was reversed, and the lung permeability index (extravascular leakage of albumin) in mice after intrapulmonary deposition of IgG immune complexes was markedly diminished. Mice that developed sepsis after cecal ligation/puncture (CLP) and were treated with C5aRa had greatly improved survival rates. These data suggest that C5aRa interferes with neutrophil responses to C5a, preventing C5a-induced compromise of innate immunity during sepsis, with greatly improved survival rates after CLP.

Animals↗
PubMed2002

Role of nitric oxide in acute lung inflammation: lessons learned from the inducible nitric oxide synthase knockout mouse.

OBJECTIVE: Acute lung inflammation is characterized by complex interactions among cytokines, chemokines, adhesion molecules, leukocytes, and other mediators. Proinflammatory cytokines have been implicated in the up-regulation of the inducible form of nitric oxide synthase (iNOS), which produces large amounts of nitric oxide (NO). Conversely, in some systems, NO regulates the expression of cytokines to affect leukocyte recruitment. Thus, the role of NO both exogenously administered and endogenously produced by iNOS in acute lung inflammation has not been fully elucidated. The current studies suggest a proinflammatory role for inhaled NO in a compartmentalized model of lung injury, whereas blocking of iNOS afforded protection. These results and other previous investigations have been complicated by the use of nonselective blockers of the iNOS isoform. MEASUREMENTS AND MAIN RESULTS: In an attempt to circumvent this, we examined the response of the lung to direct endotoxin challenge in mice in which iNOS had been genetically deleted (iNOS-/-). We observed a significant decrease in the inflammatory response in the iNOS-/- mice compared with wild-type mice as characterized by decreases in neutrophil accumulation and cytokine expression. Additionally, the lung cytokine response in the iNOS-/- mice was characterized by a significant increase in interleukin-12 and an inability to up-regulate interleukin-10. CONCLUSIONS: Induction of NO may be a key mediator in driving the cytokine response to endotoxin toward an increased type-2 (interleukin-10) response and a diminished type-1 (interleukin-12) response.

Animals↗
PubMed2002

Increased C5a receptor expression in sepsis.

Excessive production of the complement activation product C5a appears to be harmful during the development of sepsis in rodents. Little is known about the role of the C5a receptor (C5aR) and its presence in different organs during sepsis. Using the cecal ligation/puncture (CLP) model in mice, we show here that C5aR immunoreactivity was strikingly increased in lung, liver, kidney, and heart early in sepsis in both control and neutrophil-depleted mice. C5aR mRNA expression in these organs was also significantly increased during sepsis. Immunohistochemical analysis revealed patterns of increased C5aR expression in parenchymal cells in all four organs following CLP. Mice injected at the start of CLP with a blocking IgG to C5aR (alphaC5aR) showed dramatically improved survival when compared with animals receiving nonspecific IgG, as did mice injected with alphaC5a. In alphaC5aR-treated mice, serum levels of IL-6 and TNF-alpha and bacterial counts in various organs were significantly reduced during CLP when compared with control CLP animals. These studies demonstrate for the first time that C5aR is upregulated in lung, liver, kidney, and heart during the early phases of sepsis and that blockade of C5aR is highly protective from the lethal outcome of sepsis.

Animals↗
PubMedDate not supplied

Attenuation of half sulfur mustard gas-induced acute lung injury in rats.

Airway instillation into rats of 2-chloroethyl ethyl sulfide (CEES), the half molecule of sulfur mustard compound, results in acute lung injury, as measured by the leak of plasma albumin into the lung. Morphologically, early changes in the lung include alveolar hemorrhage and fibrin deposition and the influx of neutrophils. Following lung contact with CEES, progressive accumulation of collagen occurred in the lung, followed by parenchymal collapse. The co-instillation with CEES of liposomes containing pegylated (PEG)-catalase (CAT), PEG-superoxide dismutase (SOD), or the combination, greatly attenuated the development of lung injury. Likewise, the co-instillation of liposomes containing the reducing agents, N-acetylcysteine (NAC), glutathione (GSH), or resveratrol (RES), significantly reduced acute lung injury. The combination of complement depletion and airway instillation of liposomes containing anti-oxidant compounds maximally attenuated CEES-induced lung injury by nearly 80%. Delayed airway instillation of anti-oxidant-containing liposomes (containing NAC or GSH, or the combination) significantly diminished lung injury even when instillation was delayed as long as 1 h after lung exposure to CEES. These data indicate that CEES-induced injury of rat lungs can be substantially diminished by the presence of reducing agents or anti-oxidant enzymes delivered via liposomes.

Acute Disease↗
PubMedDate not supplied

Protection from half-mustard-gas-induced acute lung injury in the rat.

The chemical warfare agent analog, 2-chloroethyl ethyl sulfide, known as 'half-mustard gas' (HMG), is less toxic and less of an environmental hazard than the full molecule and has been shown to produce an acute lung injury in rats when instilled via intrapulmonary injection. This injury is characterized by massive, localized hemorrhage and edema into the alveolar compartment and can be quantitated by measuring extravasation of (125)I-bovine serum albumin into the extravascular compartment. Employing this rat model of HMG-induced lung injury, we observed significant attenuation of the pulmonary injury when experimental animals were complement or neutrophil depleted prior to HMG challenge. Significant protection also was provided by the use of antioxidants such as catalase, dimethyl sulfoxide, dimethyl thiourea, resveratrol and N-acetyl-L-cysteine (NAC). The last compound showed protection from lung injury as high as 70% and was still effective even when given up to 90 min after exposure of the lungs to HMG. These data suggest that acute lung injury caused by exposure to HMG may be related partially to complement mediated pathways and the generation by neutrophils of toxic oxygen species The data indicate that NAC is an effective antidote against HMG-induced acute lung injury in the rat.

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.

Animals↗
PubMedDate not supplied

Selectin inhibition modulates Akt/MAPK signaling and chemokine expression after liver ischemia-reperfusion.

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.

Alanine Transaminase↗
PubMedDate not supplied

Selectin inhibition modulates NF-kappa B and AP-1 signaling after liver ischemia/reperfusion.

The infiltration of neutrophils after ischemia and reperfusion (I/R) is facilitated by the expression of adhesion molecules on the surface of both leukocytes and endothelial cells. Adhesion molecules of the selectin family are of particular importance at the onset of neutrophil mediated injury, as demonstrated by the occurrence of many cellular interactions with the final extravasation of inflammatory leukocytes at the site of I/R damage. Previous studies demonstrated a prevention of neutrophil extravasation and protection of ischemic damage when a small anti-selectin molecule was used. In this study, we tested a new small anti-selectin compound (OC-229) in a murine model of partial hepatic I/R. The aim of this study was to determine the effect of OC-229 on liver function and histology after I/R and to evaluate its role in the modulation of the inflammatory molecular signaling pathways of NF-kappa B and AP-1 under the same experimental condition. Mice subjected to 90 min of partial (70-80%) hepatic ischemia and 3 h of reperfusion were divided into three groups (n = 9/group): sham, ischemic control, and treated group, which received 25 mg/kg of the anti-selectin small molecule OC-229. These groups were studied when the treatment was given at the time of reperfusion (no pretreatment was given). The parameters measured at 3 h of reperfusion included liver function tests (ALT and AST), liver histology, and liver tissue electrophoretic mobility shift assay (EMSA) for NF-kappa B and AP-1. It was demonstrated that the multiselectin inhibitor OC-229 offered significant protection for the ischemic liver when given at 25 mg/kg at the time of reperfusion. ALT and AST serum levels significantly decreased when the ischemic control and the group receiving OC-229 were compared (p = .01). Treated animals demonstrated better histological findings as well. The EMSA showed dissociation of NF-kappa B and AP-1 activity in the liver nuclear extracts after selectin inhibition treatment. A reduction in the activity of AP-1 and an increment in NF-kappa B activation was seen. In this work, we obtained evidence that the small-molecule selectin inhibitor OC-229 offered functional and histological protection of the ischemic liver when given at 25 mg/kg at the time for reperfusion. There was dissociation in the activation signals of NF-kappa B and AP-1. Increase in NF-kappa B and reduction of the activation of AP-1 were noted at 3 h of reperfusion.

Alanine Transaminase↗
PubMedDate not supplied

Endogenous regulation of the acute inflammatory response.

The acute inflammatory response has been triggered in rat lungs by deposition of IgG immune complexes. The inflammatory reaction triggered is highly tissue damaging and requires activation of NF-kappaB with ensuing generation of chemokines and cytokines. Endogenous generation of IL- 10 and IL- 13 as well as secretory leukocyte protease inhibitor (SLPI), significantly regulates this inflammatory response. IL-10 and IL-13 attenuate NF-kappaB activation by interfering with breakdown of IkappaBalpha, while SLPI likewise suppresses NF-kappaB activation, but by interfering with breakdown of IkappaBbeta. Antibody induced blockade of IL-10, IL-13 or SLPI enhances NF-KB activation in lung and exacerbates the lung inflammatory response and injury. These data indicate that endogenous IL-10, IL-13 and SLPI are important regulators of the inflammatory response by reducing gene activation with resultant generation of peptide mediators/cytokines and chemokines.

Acute Disease↗
PubMedDate not supplied

The attenuation of hemorrhage-induced liver injury by exogenous nitric oxide, L-arginine, and inhibition of inducible nitric oxide synthase.

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.

Animals↗