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Background We have recently shown that inhibition of peptidylarginine deiminase (PAD) improves survival in a rodent model of lethal cecal ligation and puncture. The roles of PAD inhibitors in hemorrhagic shock (HS), however, are largely unknown. The goal of this study was to investigate the effects of YW3-56, a novel PAD inhibitor, on survival after severe HS. Methods Mouse macrophages were exposed to hypoxic conditions followed by reoxygenation in the presence or absence of YW3-56. Enzyme-linked immunosorbent assay (ELISA) was performed to measure levels of secreted tumor necrosis factor α and interleukin-6 in the culture medium. Cell viability was determined by methyl thiazolyl tetrazolium assay. In the survival experiment, anesthetized male Wistar–Kyoto rats ( n = 10/group) were subjected to 55% blood loss, and treated with or without YW3-56 (10 mg/kg, intraperitoneally). Survival was monitored for 12 h. In the nonsurvival experiment, morphologic changes of the lungs were examined. Levels of circulating cytokine-induced neutrophil chemoattractant 1 (CINC-1) and myeloperoxidase (MPO) in the lungs were measured by ELISA. Expression of lung intercellular adhesion molecules-1 (ICAM-1) was also determined by Western blotting. Results Hypoxia/reoxygenation (H/R) insult induced tumor necrosis factor α and interleukin-6 secretion from macrophages, which was significantly attenuated by YW3-56 treatment. YW3-56 treatment also increased cell viability when macrophages were exposed to H/R up to 6/15 h and improved survival rate from 20% to 60% in lethal HS rat model. Compared to the sham groups, pulmonary MPO activity and ICAM-1 expression in the HS group were significantly increased, and acute lung injury was associated with a higher degree of CINC-1 levels in serum. Intraperitoneal delivery of YW3-56 significantly reduced pulmonary MPO and ICAM-1 expression and attenuated acute lung injury. Conclusions Our results demonstrate for the first time that administration of YW3-56, a novel PAD inhibitor, can improve survival in a rat model of HS and in a cell culture model of H/R. The survival advantage is associated with an attenuation of local and systemic pro-inflammatory cytokines and the protection against acute lung injury after hemorrhage. Thus, PAD inhibition may represent a novel and promising therapeutic strategy for severe HS. [ABSTRACT FROM AUTHOR]

Disturbance of immunity is an important factor to modulate inflammatory responses after severe shock. Post-shock mesenteric lymph (PSML) return plays an adverse role in multiple organ injuries induced by the hemorrhagic shock, and the inflammatory factors are involved in this process. However, whether the PSML can exacerbate immune dysfunctions that modulate inflammatory response to the hemorrhagic shock remains unknown. In the present study, the effects of PSML drainage on the distribution of T lymphocyte subgroup, the release of inflammatory factors, and apoptosis of thymocytes were investigated; the effect of PSML on the specific parameters of cellular immune function was also determined. Results showed that PSML drainage reduced the increased levels of CD3+, CD3 + CD4+, CD4 + CD25+ lymphocytes, IFN-γ, and the ratios of CD3 + CD4+/CD3 + CD4− in blood of the shocked rats at 3 h after resuscitation; PSML drainage also abolished the decreased IL-4 level and restored the higher ratio of IFN-γ/IL-4 to normal levels. Tissue injury, including enlarged intermembrance space and edema with congestion in the medulla, increased apoptotic cells and bax expression, decreased number of cells in the S phase, and bcl-2 expression were observed in the thymus after hemorrhagic shock. PSML drainage reversed these effects. In particular, PSML drainage increased the proliferation index and decreased p53 expression of thymocytes. These results suggest that hyperimmunity occurred at early stages of hemorrhagic shock with resuscitation and that PSML drainage could markedly improve cellular immune function that is responsible for the reduced inflammatory responses. [ABSTRACT FROM AUTHOR]

Abstract: Background: Large-volume, rapid crystalloid infusion may increase endothelial cell damage and induce shear stress, potentially leading to multiple-organ dysfunction syndrome. Limited guideline data for fluid administration are currently available, especially for the aging population. The aim of the present study was to compare the degree of organ damage in conscious aging rats when different resuscitation speeds were used during the treatment of hemorrhagic shock (HS). Methods: Eighteen aging male Wistar-Kyoto rats were randomly divided into the following three groups: the control group, 30-min rapid resuscitation group, and 12-h slow resuscitation group. To mimic HS, 40% of the total blood volume was withdrawn. Fluid resuscitation (1:3) was given at 30 min after the blood withdrawal. Blood biochemical parameters including glucose, lactic acid, and lactate dehydrogenase (LDH) were measured along with the levels of serum and bronchoalveolar lavage fluid, tumor necrosis factor alpha (TNF-α), and interleukin 10 by enzyme-linked immunosorbent assay. The lungs were examined for pathologic changes, and the injury score at 24 h after HS was calculated. Results: Compared with slow-rate resuscitation, initially rapid and immediate resuscitation significantly increased the serum levels of glucose, LDH, and proinflammatory cytokines (TNF-α and interleukin 10), and bronchoalveolar lavage fluid levels of white blood cells, TNF-α, and LDH as well as produced pathologic changes in the organ. The lung injury scores were higher after induced HS in aging rats. Conclusions: The slow and continuous (12 h) fluid resuscitation rate ameliorated HS-induced organ damage in conscious aging rats. [Copyright &y& Elsevier]

Abstract: Background: Hemorrhagic shock activates cellular stress signals and can lead to systemic inflammatory response, organ injury, and death. Mitogen-activated protein kinase (MAPK) acts as a sensor of tissue injury in models of ischemia-reperfusion injury. Lipoxins are endogenous lipid mediators with potent anti-inflammatory and pro-resolving actions. We hypothesized that BML-111 (a lipoxin A4-receptor agonist) attenuates hemorrhagic shock-induced acute lung injury (ALI) through inhibiting activation of the MAPK pathway. Methods: We randomized Sprague-Dawley rats into four groups: sham, hemorrhagic shock–resuscitation (HS), HS plus BML-111 (BML-111), and HS plus BML-111 and BOC-2 (BOC-2). Two hours after resuscitation, we collected samples of lung. We obtained bronchoalveolar lavage fluid for neutrophil count. We performed optical microscopy to examine pathologic changes in lungs. Wet/dry ratios, myeloperoxidase expression, interleukin (IL)-1β and IL-6 levels in lung were measured. We evaluated MAPK activation and the DNA binding activity of activator protein-1 in lung. Results: Treatment with BML-111 reduced the lung damage and wet/dry ratio, neutrophil count in bronchoalveolar lavage fluid, expression of myeloperoxidase, and production of IL-1β and IL-6 in lung. Phosphorylation of MAPK was also decreased by BML-111 in lung. Furthermore, the DNA binding activity of activator protein-1 was blocked by BML-111. An antagonist of the lipoxin A4-receptor, BOC-2, reversed the protective effect of BML-111 on ALI induced by hemorrhagic shock. Conclusions: This study indicates that BML-111 attenuated hemorrhagic shock-induced ALI via the MAPK/activator protein-1 signaling pathway. Therefore, BML-111 may have therapeutic potential for hemorrhagic shock-induced ALI. [Copyright &y& Elsevier]

Hemorrhagic shock and resuscitation induces pulmonary inflammation that leads to acute lung injury. Biliverdin, a metabolite of heme catabolism, has been shown to have potent cytoprotective, anti-inflammatory, and anti-oxidant effects. This study aimed to examine the effects of intravenous biliverdin administration on lung injury induced by hemorrhagic shock and resuscitation in rats. Biliverdin or vehicle was administered to the rats 1 h before sham or hemorrhagic shock-inducing surgery. The sham-operated rats underwent all surgical procedures except bleeding. To induce hemorrhagic shock, rats were bled to achieve a mean arterial pressure of 30 mmHg that was maintained for 60 min, followed by resuscitation with shed blood. Histopathological changes in the lungs were evaluated by histopathological scoring analysis. Inflammatory gene expression was determined by Northern blot analysis, and oxidative DNA damage was assessed by measuring 8-hydroxy-2′ deoxyguanosine levels in the lungs. Hemorrhagic shock and resuscitation resulted in prominent histopathological damage, including congestion, edema, cellular infiltration, and hemorrhage. Biliverdin administration prior to hemorrhagic shock and resuscitation significantly ameliorated these lung injuries as judged by histopathological improvement. After hemorrhagic shock and resuscitation, inflammatory gene expression of tumor necrosis factor-α and inducible nitric oxide synthase were increased by 18- and 8-fold, respectively. Inflammatory gene expression significantly decreased when biliverdin was administered prior to hemorrhagic shock and resuscitation. Moreover, after hemorrhagic shock and resuscitation, lung 8-hydroxy-2' deoxyguanosine levels in mitochondrial DNA expressed in the pulmonary interstitium increased by 1.5-fold. Biliverdin administration prior to hemorrhagic shock and resuscitation decreased mitochondrial 8-hydroxy-2' deoxyguanosine levels to almost the same level as that in the control animals. We also confirmed that biliverdin administration after hemorrhagic shock and resuscitation had protective effects on lung injury. Our findings suggest that biliverdin has a protective role, at least in part, against hemorrhagic shock and resuscitation-induced lung injury through anti-inflammatory and anti-oxidant mechanisms. [ABSTRACT FROM AUTHOR]

Abstract: Background: Therapeutic hypothermia has been proposed to be beneficial in an array of human pathologies including cardiac arrest, stroke, traumatic brain and spinal cord injury, and hemorrhagic shock. Burn depth progression is multifactorial but inflammation plays a large role. Because hypothermia is known to reduce inflammation, we hypothesized that moderate hypothermia will decrease burn depth progression. Methods: We used a second-degree 15% total body surface area thermal injury model in rats. Burn depth was assessed by histology of biopsy sections. Moderate hypothermia in the range of 31–33°C was applied for 4h immediately after burn and in a delayed fashion, starting 2h after burn. In order to gain insight into the beneficial effects of hypothermia, we analyzed global gene expression in the burned skin. Results: Immediate hypothermia decreased burn depth progression at 6h post injury, and this protective effect was sustained for at least 24h. Burn depth was 18% lower in rats subjected to immediate hypothermia compared to control rats at both 6 and 24h post injury. Rats in the delayed hypothermia group did not show any significant decrease in burn depth at 6h, but had 23% lower burn depth than controls at 24h. Increased expression of several skin-protective genes such as CCL4, CCL6 and CXCL13 and decreased expression of tissue remodeling genes such as matrix metalloprotease-9 were discovered in the skin biopsy samples of rats subjected to immediate hypothermia. Conclusions: Systemic hypothermia decreases burn depth progression in a rodent model and up-regulation of skin-protective genes and down-regulation of detrimental tissue remodeling genes by hypothermia may contribute to its beneficial effects. [Copyright &y& Elsevier]

OBJECTIVES The aim of this study was to assess the possible protective effect of montelukast against haemorrhagic shock-induced acute lung injury by interfering with inflammatory and oxidative pathways. Acute lung injury following haemorrhagic shock/resuscitation is an important contributor to late morbidity and mortality in trauma patients. Haemorrhagic shock (HS), followed by resuscitation, is considered to be an insult that frequently induces systemic inflammatory response syndrome and oxidative stress, resulting in multiple-organ dysfunction syndrome, including microvascular changes and microscopic damage termed acute lung paraynchymal injury. Montelukast is a cysteinyl leukotriene receptor antagonist that exerts an anti-inflammatory and antioxidant influence. METHODS Eighteen adult albino rats were assigned to three groups of six. In Group I, the ‘sham’ group, rats underwent all the surgical procedures but neither haemorrhagic shock nor resuscitation was carried out. Group II—the ‘HS’ induced, untreated group—was the control and underwent HS for one hour before being resuscitated with Ringer's lactate for one hour. Group III—the ‘montelukast’ group—underwent HS and treatment with montelukast (7 mg/kg i.p. injection) 30 min before the induction of HS, with the same dose repeated just before the reperfusion period. At the end of the experiment, two hours after completion of resuscitation, blood samples were collected for measurement of serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). The trachea was then isolated and bronchoalveolar lavage was carried out for measurement of leukotriene B4 (LTB4), leukotriene C4 (LTC4) and total protein. The lungs were harvested and the left lung was homogenized for measurement of malondialdehyde (MDA) and reduced glutathione (GSH) and the right lung was fixed in 10% formalin for histological examination. RESULTS Montelukast treatment (Group III) significantly reduced the total lung injury score, compared with the HS group (Group II) (P < 0.05). Montelukast also significantly decreased serum TNF-α and IL-6; lung MDA; bronchoalveolar lavage fluid (BALF) LTB4, LTC4 & total protein compared with the HS group (P < 0.05). Montelukast treatment significantly inhibited decrease in the lung GSH levels, compared with the HS group (P < 0.05). CONCLUSIONS The results of the present study reveal that montelukast may ameliorate lung injury in shocked rats by interfering with inflammatory and oxidative pathways, implicating the role of leukotrienes in the pathogenesis of haemorrhagic shock-induced lung inflammation. [ABSTRACT FROM AUTHOR]

Hemorrhagic shock (HS) following acute alcohol intoxication can increase proinflammatory cytokine production and induce marked immunosuppression. We investigated the effects of ethanol on physiopathology and cytokine levels following HS in acutely alcohol-intoxicated rats. Rats received an intravenous injection of 5 g/kg ethanol over 3 h followed by HS induced by withdrawal of 40% of total blood volume from a femoral arterial catheter over 30 min. Mean arterial pressure (MAP) and heart rate (HR) were monitored continuously for 48 h after the start of blood withdrawal. Biochemical parameters, including hemoglobin, ethanol, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), blood urea nitrogen (BUN), creatinine (Cre), lactic dehydrogenase (LDH), and creatine phosphokinase (CPK), were measured at 30 min before induction of HS and 0,1,3, 6, 9, 12,18,24, and 48 h after HS. Serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels were measured at 1 and 12 h after HS. The liver, kidneys, and lungs were removed for pathology at 48 h later. HS significantly increased HR, blood GOT, GPT, BUN, Cre, LDH, CPK, TNF-α, and IL-6 levels and decreased hemoglobin and MAP in rats. Acute ethanol intoxication further increased serum levels of GOT, GPT, BUN, Cre, LDH, CPK, TNF-α and IL-6 elevation following HS. Acutely intoxicated rats exacerbated the histopathologic changes in the liver, kidneys, and lungs following HS. [ABSTRACT FROM AUTHOR]

Although melatonin treatment following trauma-hemorrhage or ischemic reperfusion prevents organs from dysfunction and injury, the precise mechanism remains unknown. This study tested whether melatonin prevents liver injury following trauma-hemorrhage involved the protein kinase B (Akt)-dependent heme oxygenase (HO)-1 pathway. After a 5-cm midline laparotomy, male rats underwent hemorrhagic shock (mean blood pressure approximately 40 mmHg for 90 min) followed by fluid resuscitation. At the onset of resuscitation, rats were treated with vehicle, melatonin (2 mg/kg), or melatonin plus phosphoinositide 3-kinase (PI3K) inhibitor wortmannin (1 mg/kg). At 2 hr after trauma-hemorrhage, the liver tissue myeloperoxidase activity, malondialdehyde, adenosine triphosphate, serum alanine aminotransferase, and aspartate aminotransferase levels were significantly increased compared with sham-operated control. Trauma-hemorrhage resulted in a significant decrease in the Akt activation in comparison with the shams (relative density, 0.526 ± 0.031 versus 1.012 ± 0.066). Administration of melatonin following trauma-hemorrhage normalized liver Akt phosphorylation (0.993 ± 0.061), further increased mammalian target of rapamycin (mTOR) activation (5.263 ± 0.338 versus 2.556 ± 0.225) and HO-1 expression (5.285 ± 0.325 versus 2.546 ± 0.262), and reduced cleaved caspase-3 levels (2.155 ± 0.297 versus 5.166 ± 0.309). Coadministration of wortmannin abolished the melatonin-mediated attenuation of the shock-induced liver injury markers. Our results collectively suggest that melatonin prevents hemorrhagic shock-induced liver injury in rats through an Akt-dependent HO-1 pathway. [ABSTRACT FROM AUTHOR]

Introduction: Trauma patients are at high risk of complications and death from coagulopathy and inflammatory organ failure. Recent evidence implicates protein C (PC) as a key mediator of this process. We hypothesized that a mutation in the PC gene would ameliorate the inflammatory and coagulopathic response to hemorrhagic shock (HS) and resuscitation. Methods: FHH wild type and PC mutant rats underwent controlled hemorrhage for 120 min with 70% of blood volume removed. Rats were resuscitated with Ringers lactate (2x shed blood volume) and shed blood. Animals were sacrificed 4 h post-HS. Controls were untreated naïve rats. Results: AST and NFkB lung protein levels were elevated similarly in both WT and mutants compared with naïve rats. Plasma fibrinogen levels decreased significantly with progression of HS compared with baseline (BL) levels and returned towards normal 4 h after resuscitation. PC activity was similar in both groups at BL (0.5 ± 0.08 versus 0.6 ± 0.14; P = 0.14) and decreased from BL by 53% ± 24% in WT (P =0.08), by 67% ± 11% in mutants (P = 0.03) at sacrifice, and was not different between groups (P = 0.29). Conclusions: Our model of HS and resuscitation produced a hypocoaguable, hyperinflammatory state with increased levels of NFkB and decreased levels of fibrinogen and PC levels. The mutated PC did not appear to alter these responses in our model of HS and resuscitation. [Copyright &y& Elsevier]

Abstract: Background: The aim of the present study was to test the hypothesis that balanced crystalloid resuscitation would be better for the kidney than unbalanced crystalloid resuscitation in a rat hemorrhagic shock model. Methods: Male Wistar rats were randomly assigned to four groups (n =6/group): (1) time control; (2) hemorrhagic shock control; (3) hemorrhagic shock followed by unbalanced crystalloid resuscitation (0.9% NaCl); and (4) hemorrhagic shock followed by acetate and gluconate-balanced crystalloid resuscitation (Plasma Lyte). We tested the solutions for their effects on renal hemodynamics and microvascular oxygenation, strong-ion difference, systemic and renal markers of inflammation and oxidative stress including glycocalyx degradation as well as their effects on renal function. Results: The main findings of our study were that: (1) both the balanced and unbalanced crystalloid solutions successfully restored the blood pressure, but renal blood flow was only recovered by the balanced solution although this did not lead to improved renal microvascular oxygenation; (2) while unbalanced crystalloid resuscitation induced hyperchloremia and worsened metabolic acidosis in hemorrhaged rats, balanced crystalloid resuscitation prevented hyperchloremia, restored the acid–base balance, and preserved the anion gap and strong ion difference in these animals; (3) in addition balanced crystalloid resuscitation significantly improved renal oxygen consumption (increased VO2, decreased ); and (4) however neither balanced nor unbalanced crystalloid resuscitation could normalize systemic inflammation or oxidative stress. Functional immunohistochemistry biomarkers showed improvement in L-FABP in favor of balanced solutions in comparison to the hemorrhagic group although no such benefit was seen for renal tubular injury (measured by NGAL) by giving either unbalanced or balanced solutions. Conclusions: Although balanced crystalloid resuscitation seems superior to balanced crystalloid resuscitation in protecting the kidney after hemorrhagic shock and is certainly better than not applying fluid resuscitation, these solutions were not able to correct systemic inflammation or oxidative stress associated with hemorrhagic shock. [Copyright &y& Elsevier]

The article offers information on the study conducted by the authors related to fish oil that improves hemodynamic stabilization and inflammation after resuscitation in a rat model of hemorrhagic shock. It states that the study concluded that the fish oil pretreatment before fluid resuscitation showed a beneficial effect to the hemodynamic stabilization and inflammation reduction in a rat model.

Abstract: Aim of the study: Upregulation of pulmonary inflammatory molecules is crucial in mediating the development of acute lung injury induced by haemorrhagic shock. Dexmedetomidine and ketamine possess potent anti-inflammatory capacity. We sought to elucidate whether dexmedetomidine, ketamine, or dexmedetomidine–ketamine combination could mitigate acute lung injury in haemorrhagic shock rats. Methods: Fifty adult male Sprague–Dawley rats were randomized to the sham-instrumented, haemorrhagic shock (HS), HS plus dexmedetomidine (HS-D), HS plus ketamine (HS-K), or HS plus dexmedetomidine–ketamine (HS-D+K) group (n =10 in each group). Haemorrhagic shock was induced by blood withdrawing and the mean blood pressure was maintained at 40–45mmHg for 120min. Resuscitation was then performed by infusion of shed blood/saline mixtures. After monitoring for another 8h, rats were sacrificed. Results: Histology findings and lung injury score analysis revealed moderate lung injury in rats of the HS, HS-D, and HS-K groups, whereas those of the HS-D+K group revealed mild lung injury. The effects of haemorrhagic shock on increasing cell number and protein concentration in bronchoalveolar lavage fluid as well as water content, leukocyte infiltration, and myeloperoxidase activity of lung tissues were significantly attenuated by dexmedetomidine–ketamine combination but not by dexmedetomidine or ketamine alone. Dexmedetomidine–ketamine combination, but not dexmedetomidine or ketamine alone, also significantly inhibited haemorrhagic shock-induced upregulation of pulmonary inflammatory molecules, including nitric oxide, prostaglandin E2, chemokine (e.g., macrophage inflammatory protein-2), and cytokines [e.g., interleukin (IL)-1β, and IL-6]. Conclusions: Dexmedetomidine–ketamine combination mitigates acute lung injury in haemorrhagic shock rats. [Copyright &y& Elsevier]

The article investigates the impact of the interaction between mechanical ventilation and hemorrhagic shock-resuscitation on the release of inflammatory cytokine in rat models. The researchers determined whether hemorrhagic shock and resuscitation (HSR) and high lung stress during mechanical ventilation interact to augment lung and systemic inflammatory responses. They asserted that mechanical ventilation is an indispensable treatment of respiratory failure.

Pentraxin 3 (PTX3) is an acute-phase protein, which can be produced by a variety of tissue cells at the site of infection or inflammation. It plays an important role in innate immunity in the lung and in mediating acute lung injury. The aim of this study was to determine the effect of mechanical ventilation on PTX3 expression in multiple lung injury models. Male Sprague-Dawley rats were challenged with intravenous injection of lipopoly-saccharide (LPS) or hemorrhage followed by resuscitation (HS). The animals were then subjected to either relatively higher (12 mI/kg) or lower (6 mI/kg, positive end-expiratory pressure of 5 cmH2O) volume ventilation for 4 h. High-volume ventilation significantly enhanced PTX3 expression in the lung, either alone or in combination with LPS or hemorrhage. A significant increase of PTX3 immunohistochemistry staining in the lung was seen in all injury groups. The PTX3 expression was highly correlated with the severity of lung injury determined by blood gas, lung elastance, and wet-to-dry ratio. To determine the effects of HS, LPS, or injurious ventilation (25 mI/kg) alone on PTX3 expression, another group of rats was studied. Injurious ventilation significantly damaged the lung and increased PTX3 expression. A local expression of PTX3 induced by high-volume ventilation, either alone or in combination with other pathological conditions, suggests that it may be an important mediator in ventilator-induced lung injury. [ABSTRACT FROM AUTHOR]