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Lymphocyte Modulation with FTY720 Improves Hemorrhagic Shock Survival in Swine  [PDF]
Jason S. Hawksworth, J. Christopher Graybill, Trevor S. Brown, Shannon M. Wallace, Thomas A. Davis, Doug K. Tadaki, Eric A. Elster
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034224
Abstract: The inflammatory response to severe traumatic injury results in significant morbidity and mortality. Lymphocytes have recently been identified as critical mediators of the early innate immune response to ischemia-reperfusion injury. Experimental manipulation of lymphocytes following hemorrhagic shock may prevent secondary immunologic injury in surgical and trauma patients. The objective of this study is to evaluate the lymphocyte sequestration agent FTY720 as an immunomodulator following experimental hemorrhagic shock in a swine liver injury model. Yorkshire swine were anesthetized and underwent a grade III liver injury with uncontrolled hemorrhage to induce hemorrhagic shock. Experimental groups were treated with a lymphocyte sequestration agent, FTY720, (n = 9) and compared to a vehicle control group (n = 9). Animals were observed over a 3 day survival period after hemorrhage. Circulating total leukocyte and neutrophil counts were measured. Central lymphocytes were evaluated with mesenteric lymph node and spleen immunohistochemistry (IHC) staining for CD3. Lung tissue infiltrating neutrophils were analyzed with myeloperoxidase (MPO) IHC staining. Relevant immune-related gene expression from liver tissue was quantified using RT-PCR. The overall survival was 22.2% in the vehicle control and 66.7% in the FTY720 groups (p = 0.081), and reperfusion survival (period after hemorrhage) was 25% in the vehicle control and 75% in the FTY720 groups (p = 0.047). CD3+ lymphocytes were significantly increased in mesenteric lymph nodes and spleen in the FTY720 group compared to vehicle control, indicating central lymphocyte sequestration. Lymphocyte disruption significantly decreased circulating and lung tissue infiltrating neutrophils, and decreased expression of liver immune-related gene expression in the FTY720 treated group. There were no observed infectious or wound healing complications. Lymphocyte sequestration with FTY720 improves survival in experimental hemorrhagic shock using a porcine liver injury model. These results support a novel and clinically relevant lymphocyte immunomodulation strategy to ameliorate secondary immune injury in hemorrhagic shock.
Recruitment of neutrophils across the blood-brain barrier: the role of posttraumatic hepatic ischemia
Mantovani, Mario;Fontelles, Mauro José;Hirano, Elcio Shiyoiti;Morandin, Rosana Celestina;Schenka, André Almeida;
Acta Cirurgica Brasileira , 2003, DOI: 10.1590/S0102-86502003000500004
Abstract: purpose: to study the effects of total hepatic ischemia, and reperfusion on the accumulation of neutrophils in the brain of rats submitted to normovolemic conditions as well as to controlled hemorrhagic shock state. methods: thirty two adult male wistar rats, were divided into four groups: the control group, was submitted to the standard procedures for a period of 60 min of observation; shock group, was submitted to controlled hemorrhagic shock (mean arterial blood pressure=40mmhg, 20min) followed by volemic resuscitation (lactated ringer's solution + blood, 3:1) and reperfusion for 60min; pringle group, was submitted to total hepatic ischemia for 15min and reperfusion for 60min. the total group was submitted to controlled hemorrhagic shock for 20min followed by volemic resuscitation (lactated ringer's solution + blood, 3:1), total hepatic ischemia for 15min and reperfusion for 60min. measurements of serum lactate and base excess were used to characterize the hemorrhagic shock state with low tissue perfusion. the counting of neutrophils on the brain was performed after the euthanasia of animals. results: the values for the counting of neutrophils on the brain indicate that did not occur difference among studied groups (p=0.196) (control 0.12± 0.11, shock 0.12± 0.13, pringle 0.02± 0.04, total 0.14± 0.16). conclusion: hemorrhagic shock associated to total hepatic ischemia for 15 minutes, followed by 60 minutes of reperfusion, did not causes significant neutrophils accumulation in the brain of rats.
Recruitment of neutrophils across the blood-brain barrier: the role of posttraumatic hepatic ischemia
Mantovani Mario,Fontelles Mauro José,Hirano Elcio Shiyoiti,Morandin Rosana Celestina
Acta Cirurgica Brasileira , 2003,
Abstract: PURPOSE: To study the effects of total hepatic ischemia, and reperfusion on the accumulation of neutrophils in the brain of rats submitted to normovolemic conditions as well as to controlled hemorrhagic shock state. METHODS: Thirty two adult male Wistar rats, were divided into four groups: the Control group, was submitted to the standard procedures for a period of 60 min of observation; Shock group, was submitted to controlled hemorrhagic shock (mean arterial blood pressure=40mmHg, 20min) followed by volemic resuscitation (lactated Ringer's solution + blood, 3:1) and reperfusion for 60min; Pringle group, was submitted to total hepatic ischemia for 15min and reperfusion for 60min. The total group was submitted to controlled hemorrhagic shock for 20min followed by volemic resuscitation (lactated Ringer's solution + blood, 3:1), total hepatic ischemia for 15min and reperfusion for 60min. Measurements of serum lactate and base excess were used to characterize the hemorrhagic shock state with low tissue perfusion. The counting of neutrophils on the brain was performed after the euthanasia of animals. RESULTS: The values for the counting of neutrophils on the brain indicate that did not occur difference among studied groups (p=0.196) (Control 0.12± 0.11, Shock 0.12± 0.13, Pringle 0.02± 0.04, Total 0.14± 0.16). CONCLUSION: Hemorrhagic shock associated to total hepatic ischemia for 15 minutes, followed by 60 minutes of reperfusion, did not causes significant neutrophils accumulation in the brain of rats.
Effect of pentoxifylline on oxygen free radicals in liver as a result of ischemia-reperfusion in rats with severe hemorrhagic shock  [cached]
Zhi-long GENG,Hua-mei LU,Hong CAO,Li-li NIU
Medical Journal of Chinese People's Liberation Army , 2011,
Abstract: Objective To investigate the effects of pentoxifylline(PTX) on oxygen free radicals in liver as a result of ischemia-reperfusion in rats with severe hemorrhagic shock.Method Forty-eight SD rats were randomly divided into four groups(12 each): control group(C),no resuscitation group(NR),Ringer lactate solution(LR)-treatment group(LR),and LR combined PTX(25mg/kg) group(LRPTX).The rat model of severe hemorrhagic shock was established according to Wiggers method.Blood samples were collected at Ts(before shock) and Td(before sacrifice) for determination of AST and ALT.The rats were sacrificed and the livers were obtained for the determination of the activity of SOD,the contents of MDA and iNOS,and the expression of NF-κB immediately after shock in NR group and 4 hours after resuscitation in C,LR and LRPTX group.The pathological changes in the livers were observed with light microscope and electron microscope.Results Compared with C group,the AST and ALT levels in venous blood,the contents of MDA and iNOS,and the expression of NF-κB in liver were all significantly increased in NR,LR and LRPTX groups at Td time point,while the activity of SOD significantly decreased(P < 0.05).There also showed signs of severe injury to the liver.Compared with LR group,the AST and ALT levels in venous blood,the contents of MDA and iNOS,and the expression of NF-κB were significantly decreased in LRPTX group,while the activity of SOD significantly increased(P < 0.05).Pathologic changes of injury to the liver were significantly milder.Conclusion PTX can protect liver against ischemia-reperfusion injury by decreasing iNOS production and NF-κB activation,inhibiting the generation of oxygen free radical and enhancing the activity of SOD.
Sex differences in inflammatory cytokine production in hepatic ischemia-reperfusion
Elahé T Crockett, William Spielman, Shadi Dowlatshahi, Jun He
Journal of Inflammation , 2006, DOI: 10.1186/1476-9255-3-16
Abstract: Adult C57BL/6 mice underwent 90 min of hepatic ischemia followed by various reperfusion periods (0, 1.5, 3, 6 hr). Plasma cytokine TNF-α, IL-6, MIP-2, and KC were measured. Liver injury was assessed by plasma alanine transaminase (ALT) levels and liver histopathology.A reperfusion time-dependent increase in hepatocellular injury was observed in both males and females, as indicated by increasing levels of plasma ALT and liver histopathology. The plasma cytokines were significantly increased in both female and male I/R groups compared to their respective sham counterparts. However, there was a significant difference in cytokine kinetics between the female and male I/R groups. Female mice initially had a higher level of IL-6, KC, and MIP-2 in response to I/R, which began to decline after 3 hr of reperfusion and were significantly lower than the male I/R counterparts by 6 hr of reperfusion. In contrast, the hepatocellular injury and TNF production were only moderately lower in female IR than male IR.The study underscores role of the gender in differential inflammatory cytokine expression in response to hepatic I/R, which may reflect the host response outcome.Hepatic ischemia/reperfusion (I/R) injury occurs when there is a disruption of the blood flow to the liver followed by restoration of blood flow. This injury usually manifests itself during hepatic surgery, transplantation, trauma and hemorrhagic shock, and can lead to liver injury. Hepatic I/R injury is exemplified by a biphasic pattern – the early phase is characterized by Kupffer cell activation, release of pro-inflammatory cytokines, and the generation of reactive oxygen species (ROS), while the late phase is characterized by a massive neutrophil infiltration and further production of the inflammatory mediators [1].Although it is known that cytokines, neutrophils and ROS play a role in mediating the inflammatory response during I/R injury, the exact mechanism has yet to be elucidated. It is believed that Kupffer
Lymphocyte Depletion in Experimental Hemorrhagic Shock in Swine
Hawksworth Jason S,Graybill Christopher,Brown Trevor S,Gillern Suzanne M
Journal of Inflammation , 2012, DOI: 10.1186/1476-9255-9-34
Abstract: Background Hemorrhagic shock results in systemic activation of the immune system and leads to ischemia-reperfusion injury. Lymphocytes have been identified as critical mediators of the early innate immune response to ischemia-reperfusion injury, and immunomodulation of lymphocytes may prevent secondary immunologic injury in surgical and trauma patients. Methods Yorkshire swine were anesthetized and underwent a grade III liver injury with uncontrolled hemorrhage to induce hemorrhagic shock. Experimental groups were treated with a lymphocyte depletional agent, porcine polyclonal anti-thymocyte globulin (PATG) (n = 8) and compared to a vehicle control group (n = 9). Animals were observed over a 3 day survival period. Circulating lymphocytes were examined with FACS analysis for CD3/CD4/CD8, and central lymphocytes with mesenteric lymph node and spleen staining for CD3. Circulating and lung tissue16 infiltrating neutrophils were measured. Circulating CD3 lymphocytes in the blood and in central lymphoid organs (spleen/lymph node) were stained and evaluated using FACS analysis. Immune-related gene expression from liver tissue was quantified using RT-PCR. Results The overall survival was 22% (2/9) in the control and 75% (6/8) in the PATG groups, p = 0.09; during the reperfusion period (following hemorrhage) survival was 25% (2/8) in the control and 100% (6/6) in the PATG groups, p = 0.008. Mean blood loss and hemodynamic profiles were not significantly different between the experimental and control groups. Circulating CD3+CD4+ lymphocytes were significantly depleted in the PATG group compared to control. Lymphocyte depletion in the setting of hemorrhagic shock also significantly decreased circulating and lung tissue infiltrating neutrophils, and decreased expression of liver ischemia gene expression. Conclusions Lymphocyte manipulation with a depletional (PATG) strategy improves reperfusion survival in experimental hemorrhagic shock using a porcine liver injury model. This proof of principle study paves the way for further development of immunomodulation approaches to ameliorate secondary immune injury following hemorrhagic shock.
Portal sinusoids' neutrophil plugging after experimental ischemia reperfusion liver injury
Annals of Gastroenterology , 2007,
Abstract: ABSTRACT The aim of the present study was the demonstration of a relationship between reduced liver microcirculation - after different periods of ischemia-reperfusion - and the number of neutrophils plugged to the microvasculature at reperfusion. Ninety male Wistar rats were included in the study. These were subdivided into control group, 30min ischemia and 60min ischemia groups as well as 30min ischemia - 60min reperfusion and 60min ischemia - 60min reperfusion groups. Samples of liver tissue were obtained for the assessment of the number of neutrophils entrapped within portal sinusoids, after histochemical staining and morphometry. Hepatic microcirculation was estimated by laser-Doppler flowmetry. Additionally, ALT serum levels were evaluated, as an established marker of liver ischemiareperfusion injury. A course of 60min ischemia - 60min reperfusion resulted to a statistically significant increase of neutrophils plugged within liver sinusoids in relation to the 30min ischemia - 60min reperfusion [p=0.001]. Similarly, hepatic tissue microcirculation exhibited a flux recovery of 70% in 30min ischemia - 60min reperfusion group and only 57% in the 60min ischemia - 60min reperfusion group [p=0,001]. Serum ALT activities were found significantly increased during reperfusion, in both groups. It is thus concluded that capillary perfusion failure occurring during liver reperfusion depends on ischemia time and is associated with a significant increase of neutrophils accumulation into liver sinusoids. Key words: liver, ischemia/reperfusion injury, neutrophils, microcirculation
Severe reperfusion lung injury after double lung transplantation
Giorgio Della Rocca, Federico Pierconti, Maria Gabriella Costa, Cecilia Coccia, Livia Pompei, Monica Rocco, Federico Venuta, Paolo Pietropaoli
Critical Care , 2002, DOI: 10.1186/cc1496
Abstract: A 24-year-old female with cystic fibrosis underwent double lung transplantation. During implantation of the second lung a marked increase in pulmonary artery pressure associated with systemic hypotension, hypoxemia and low cardiac output were observed. Notwithstanding the patient received support from cardiovascular drugs and pulmonary vasodilators cardiopulmonary by-pass was necessary. In the intensive care unit the patient received the same drug support, inhaled nitric oxide and two bronchoscopic applications of bovine surfactant.A rapid improvement in PaO2/FiO2 within 2–3 hours of administration of surfactant was seen. The patient is well at follow-up 1 year post-transplant.There is a potential role for a combined therapy with inhaled nitric oxide and surfactant replacement in reperfusion injury after lung transplantation.Reperfusion injury is one of the major causes of early morbidity and mortality after lung transplantation [1]. In animal experiments the role of surfactant in the reduction of early reperfusion injury during lung transplantation has been widely investigated, but only recently have data become available for humans [2]. Ischemia reperfusion injury is characterized by pulmonary edema caused by endothelial dysfunction, platelet aggregation, and neutrophil activation and sequestration. Particularly at the time of reperfusion, free radicals are produced in the endothelial cell membranes and in neutrophils causing an increase in cell membrane permeability [1]. Lipid peroxidation can also occur during ischemia reperfusion injury [3]. In addition, sludging of red blood cells, together with the obstruction by white blood cells, vasospasm and the narrowing of the vessel lumen as a result of the edema of the vascular endothelium, can cause blood flow from the arterioles into the capillaries to be markedly diminished (i.e. the no-reflow phenomenon). Moreover, inadequate surfactant function was found in all patients after lung transplantation [4].During respi
Pathophysiology of mesenteric ischemia/reperfusion: a review
Cerqueira, Nereide Freire;Hussni, Carlos Alberto;Yoshida, Winston Bonetti;
Acta Cirurgica Brasileira , 2005, DOI: 10.1590/S0102-86502005000400013
Abstract: during ischemia, the cell structures are progressively damaged, but restoration of the blood flow, paradoxically, intensifies the lesions caused by the ischemia. the mechanisms of ischemia injury and reperfusion (i/r) have not been completely defined and many studies have been realized in an attempt to find an ideal therapy for mesenteric i/r. the occlusion and reperfusion of the splanchnic arteries provokes local and systemic alterations principally derived from the release of cytotoxic substances and the interaction between neutrophils and endothelial cells. substances involved in the process are discussed in the present review, like oxygen-derived free radicals, nitric oxide, transcription factors, complement system, serotonin and pancreatic proteases. the mechanisms of apoptosis, alterations in other organs, therapeutic and evaluation methods are also discussed.
Pathophysiology of mesenteric ischemia/reperfusion: a review  [cached]
Cerqueira Nereide Freire,Hussni Carlos Alberto,Yoshida Winston Bonetti
Acta Cirurgica Brasileira , 2005,
Abstract: During ischemia, the cell structures are progressively damaged, but restoration of the blood flow, paradoxically, intensifies the lesions caused by the ischemia. The mechanisms of ischemia injury and reperfusion (I/R) have not been completely defined and many studies have been realized in an attempt to find an ideal therapy for mesenteric I/R. The occlusion and reperfusion of the splanchnic arteries provokes local and systemic alterations principally derived from the release of cytotoxic substances and the interaction between neutrophils and endothelial cells. Substances involved in the process are discussed in the present review, like oxygen-derived free radicals, nitric oxide, transcription factors, complement system, serotonin and pancreatic proteases. The mechanisms of apoptosis, alterations in other organs, therapeutic and evaluation methods are also discussed.
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