RESUMO
The aim of this study was to explore the relationship between adiponectin (ADPN) and hemorrhagic shock (HS) and the recovery after HS. This is significant for further understanding of the pathophysiological processes of HS and the development of better treatments. In total, 72 male C57BL/6 mice were assigned randomly to three groups: control, HS, and recovery (N = 24). The HS mouse model was constructed by hemorrhage of the carotid artery and recovery was achieved by tail vein injection of Ringer's solution. The level of ADPN in the peripheral blood of mice before and after recovery was detected by enzyme-linked immunosorbent assay. Compared to control, HS mice showed significantly decreased ADPN levels with the extension of HS time while the level of ADPN in recovery mice increased significantly and remained high. The variation of ADPN levels was closely associated with the occurrence of HS in mice and their recovery, suggesting that ADPN might act as a biomarker of inflammation and have potential for the treatment of HS.
Assuntos
Adiponectina/sangue , Modelos Animais de Doenças , Inflamação , Recuperação de Função Fisiológica , Choque Hemorrágico/sangue , Adiponectina/imunologia , Animais , Biomarcadores , Artérias Carótidas/metabolismo , Artérias Carótidas/fisiopatologia , Masculino , Camundongos , Choque Hemorrágico/imunologia , Choque Hemorrágico/metabolismo , Choque Hemorrágico/fisiopatologiaRESUMO
Trauma is one of the world's leading causes of death within the first 40 years of life and thus a significant health problem. Trauma accounts for nearly a third of the lost years of productive life before 65 years of age and is associated with infection, hemorrhagic shock, reperfusion syndrome, and inflammation. The control of hemorrhage, coagulopathy, optimal use of blood products, balancing hypo and hyperperfusion, and hemostatic resuscitation improve survival in cases of trauma with massive hemorrhage. This review discusses inflammation in the context of trauma-associated hemorrhagic shock. When one considers the known immunomodulatory effects of traumatic injury, allogeneic blood transfusion, and the overlap between patient populations, it is surprising that so few studies have assessed their combined effects on immune function. We also discuss the relative benefits of curbing inflammation rather than attempting to prevent it.
Assuntos
Inflamação/etiologia , Inflamação/terapia , Choque Hemorrágico/complicações , Ferimentos e Lesões/complicações , Humanos , Guias de Prática Clínica como Assunto , Choque Hemorrágico/etiologia , Choque Hemorrágico/imunologia , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Ferimentos e Lesões/imunologiaRESUMO
Trauma is one of the world's leading causes of death within the first 40 years of life and thus a significant health problem. Trauma accounts for nearly a third of the lost years of productive life before 65 years of age and is associated with infection, hemorrhagic shock, reperfusion syndrome, and inflammation. The control of hemorrhage, coagulopathy, optimal use of blood products, balancing hypo and hyperperfusion, and hemostatic resuscitation improve survival in cases of trauma with massive hemorrhage. This review discusses inflammation in the context of trauma-associated hemorrhagic shock. When one considers the known immunomodulatory effects of traumatic injury, allogeneic blood transfusion, and the overlap between patient populations, it is surprising that so few studies have assessed their combined effects on immune function. We also discuss the relative benefits of curbing inflammation rather than attempting to prevent it.
O Trauma é uma das principais causas de morte até 40 anos de idade em todo o mundo e, portanto, um significativo problema de saúde. Esta doença é ainda responsável por quase um terço dos anos perdidos de vida produtiva até os 65 anos de idade e esta associada com infecção, choque hemorrágico, síndrome de reperfusão e inflamação. O controle da hemorragia, coagulopatia, utilização dos produtos derivados do sangue, equilibrando hipo e hiperperfusão, e reanimação hemostática melhoraram a sobrevida em casos de trauma com hemorragia volumosa. Esta revisão discute a inflamação no contexto de choque hemorrágico associado ao trauma. Quando consideradosos efeitos imunomoduladores conhecidos da lesão traumática e transfusão de sangue alogênico em relação aos doentes, é surpreendente que tão poucos estudos avaliaram os seus efeitos combinados sobre a função imunológica. Discutimos também os benefícios relativos de reduzir a inflamação ao invés de tentar impedi-la.
Assuntos
Humanos , Choque Hemorrágico/complicações , Ferimentos e Lesões/complicações , Inflamação/etiologia , Inflamação/terapia , Choque Hemorrágico/etiologia , Choque Hemorrágico/imunologia , Ferimentos e Lesões/imunologia , Guias de Prática Clínica como Assunto , Síndrome de Resposta Inflamatória Sistêmica/etiologiaRESUMO
METHODS: Male rats were 'pretreated' with phosphate-buffered saline (PBS; i.p.) or LPS (1 mg/kg; i.p.) 24 h prior to HS. Mean arterial pressure (MAP) was maintained at 30 ± 2 mmHg for 90 min or until 25% of the shed blood had to be re-injected to sustain MAP. This was followed by resuscitation with the remaining shed blood. Four hours after resuscitation, parameters of organ dysfunction and systemic inflammation were assessed. RESULTS: HS resulted in renal dysfunction, and liver and muscular injury. At a first glance, LPS preconditioning attenuated organ dysfunction. However, we discovered that HS-rats that had been preconditioned with LPS (a) were not able to sustain a MAP at 30 mmHg for more than 50 min and (b) the volume of blood withdrawn in these animals was significantly less than in the PBS-control group. This effect was associated with an enhanced formation of the nitric oxide (NO) derived from inducible NO synthase (iNOS). Thus, a further control group in which all animals were resuscitated after 50 min of hemorrhage was performed. Then, LPS preconditioning aggravated both circulatory failure and organ dysfunction. Most notably, HS-rats pretreated with LPS exhibited a dramatic increase in NF-κB activation and pro-inflammatory cytokines. CONCLUSION: In conclusion, LPS preconditioning predisposed animals to an earlier vascular decompensation, which may be mediated by an excess of NO production secondary to induction of iNOS and activation of NF-κB. Moreover, LPS preconditioning increased the formation of pro-inflammatory cytokines, which is likely to have contributed to the observed aggravation of organ injury/dysfunction caused by HS.
Assuntos
Lipopolissacarídeos/farmacologia , Choque Hemorrágico/imunologia , Animais , Citocinas/sangue , Rim/metabolismo , Rim/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos Wistar , Choque Hemorrágico/sangue , Choque Hemorrágico/patologiaRESUMO
BACKGROUND: This study investigated the effects of pentoxifylline (PTX) combined with resuscitation fluids on microcirculatory dysfunctions in a two-hit model of shock and sepsis. MATERIALS AND METHODS: Male Wistar rats (250 g) were submitted to hemorrhagic shock and reperfusion followed by sepsis induced by cecal ligation and puncture. For the initial treatment of shock, rats were randomly divided into: sham, no injury, no treatment; hypertonic saline solution (HS) (7.5%, 4 mL/kg); lactated Ringer's solution (LR, 3 × shed blood volume); HS + PTX (4 mL/Kg + 25 mg/kg PTX); and LR + PTX (3 × shed blood volume + 25 mg/kg PTX). After 48 h of being exposed to the double injury, leukocyte-endothelial interactions were assessed by intravital microscopy of the mesentery. Endothelial expression of P-selectin and intercellular adhesion molecule-1 (ICAM-1) was evaluated by immunohistochemistry, as well as lung neutrophil infiltration by histology. RESULTS: Lactated Ringer's solution induced marked increases (P < 0.001) in the number of rolling leukocytes per 10 min (two-fold), adherent leukocytes per 100 µm venule length (six-fold), migrated leukocytes per 5000 µm(2) (eight-fold), P-selectin and ICAM-1 expression (four-fold), and lung neutrophil infiltration (three-fold) compared with sham. In contrast, PTX attenuated leukocyte-endothelial interactions, P-selectin and ICAM-1 expression at the mesentery when associated with either LR (P < 0.001) or HS (P < 0.05). Neutrophil migration into the lungs was similarly reduced by PTX (P < 0.05). CONCLUSIONS: Data presented showed that pentoxifylline attenuates microcirculatory disturbances at the mesenteric bed with significant minimization of lung inflammation after a double-injury model of hemorrhagic shock and reperfusion followed by sepsis.
Assuntos
Comunicação Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Pentoxifilina/farmacologia , Sepse/tratamento farmacológico , Choque Hemorrágico/tratamento farmacológico , Animais , Ceco/lesões , Modelos Animais de Doenças , Sequestradores de Radicais Livres/farmacologia , Molécula 1 de Adesão Intercelular/metabolismo , Soluções Isotônicas/farmacologia , Ligadura , Masculino , Microcirculação/efeitos dos fármacos , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/imunologia , Selectina-P/metabolismo , Ratos Wistar , Ressuscitação/métodos , Lactato de Ringer , Sepse/imunologia , Choque Hemorrágico/imunologia , Ferimentos PerfurantesRESUMO
Shock and resuscitation render patients more susceptible to acute lung injury due to an exacerbated immune response to subsequent inflammatory stimuli. To study the role of innate immunity in this situation, we investigated acute lung injury in an experimental model of ischemia-reperfusion (I-R) followed by an early challenge with live bacteria. Conscious rats (N = 8 in each group) were submitted to controlled hemorrhage and resuscitated with isotonic saline (SS, 0.9 percent NaCl) or hypertonic saline (HS, 7.5 percent NaCl) solution, followed by intratracheal or intraperitoneal inoculation of Escherichia coli. After infection, toll-like receptor (TLR) 2 and 4 mRNA expression was monitored by RT-PCR in infected tissues. Plasma levels of tumor necrosis factor α and interleukins 6 and 10 were determined by ELISA. All animals showed similar hemodynamic variables, with mean arterial pressure decreasing to nearly 40 mmHg after bleeding. HS or SS used as resuscitation fluid yielded equal hemodynamic results. Intratracheal E. coli inoculation per se induced a marked neutrophil infiltration in septa and inside the alveoli, while intraperitoneal inoculation-associated neutrophils and edema were restricted to the interseptal space. Previous I-R enhanced lung neutrophil infiltration upon bacterial challenge when SS was used as reperfusion fluid, whereas neutrophil influx was unchanged in HS-treated animals. No difference in TLR expression or cytokine secretion was detected between groups receiving HS or SS. We conclude that HS is effective in reducing the early inflammatory response to infection after I-R, and that this phenomenon is achieved by modulation of factors other than expression of innate immunity components.
Assuntos
Animais , Masculino , Ratos , Lesão Pulmonar Aguda/imunologia , Infecções por Escherichia coli/imunologia , Inflamação/imunologia , Traumatismo por Reperfusão/imunologia , Solução Salina Hipertônica/uso terapêutico , Choque Hemorrágico/tratamento farmacológico , Doença Aguda , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/microbiologia , Citocinas/sangue , Modelos Animais de Doenças , Imunidade Inata , Inflamação/sangue , Inflamação/tratamento farmacológico , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , RNA Mensageiro/sangue , Choque Hemorrágico/imunologia , /sangueRESUMO
Shock and resuscitation render patients more susceptible to acute lung injury due to an exacerbated immune response to subsequent inflammatory stimuli. To study the role of innate immunity in this situation, we investigated acute lung injury in an experimental model of ischemia-reperfusion (I-R) followed by an early challenge with live bacteria. Conscious rats (N = 8 in each group) were submitted to controlled hemorrhage and resuscitated with isotonic saline (SS, 0.9% NaCl) or hypertonic saline (HS, 7.5% NaCl) solution, followed by intratracheal or intraperitoneal inoculation of Escherichia coli. After infection, toll-like receptor (TLR) 2 and 4 mRNA expression was monitored by RT-PCR in infected tissues. Plasma levels of tumor necrosis factor alpha and interleukins 6 and 10 were determined by ELISA. All animals showed similar hemodynamic variables, with mean arterial pressure decreasing to nearly 40 mmHg after bleeding. HS or SS used as resuscitation fluid yielded equal hemodynamic results. Intratracheal E. coli inoculation per se induced a marked neutrophil infiltration in septa and inside the alveoli, while intraperitoneal inoculation-associated neutrophils and edema were restricted to the interseptal space. Previous I-R enhanced lung neutrophil infiltration upon bacterial challenge when SS was used as reperfusion fluid, whereas neutrophil influx was unchanged in HS-treated animals. No difference in TLR expression or cytokine secretion was detected between groups receiving HS or SS. We conclude that HS is effective in reducing the early inflammatory response to infection after I-R, and that this phenomenon is achieved by modulation of factors other than expression of innate immunity components.
Assuntos
Lesão Pulmonar Aguda/imunologia , Infecções por Escherichia coli/imunologia , Inflamação/imunologia , Traumatismo por Reperfusão/imunologia , Solução Salina Hipertônica/uso terapêutico , Choque Hemorrágico/tratamento farmacológico , Doença Aguda , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/microbiologia , Animais , Citocinas/sangue , Modelos Animais de Doenças , Imunidade Inata , Inflamação/sangue , Inflamação/tratamento farmacológico , Masculino , RNA Mensageiro/sangue , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Choque Hemorrágico/imunologia , Receptor 2 Toll-Like/sangueRESUMO
Several clinical and experimental studies have demonstrated gender dimorphism in immune and organ responsiveness and in the susceptibility to and morbidity from shock, trauma, and sepsis. In this respect, cell-mediated immune responses have been shown to be depressed in males following trauma-hemorrhage, whereas they were aintained/enhanced in proestrus females. Furthermore, sex hormones have been shown to be responsible for this gender-specific immune response following adverse circulatory conditions. More specifically, studies indicate that androgens produce immunodepression following trauma-hemorrhage in males. In contrast, female sex steroids appear to exhibit immunoprotective properties following trauma and severe blood loss. With regard to the underlying mechanisms, receptors for sex hormones have been identified on various immune cells suggesting direct effects of these hormones on the immune cells. Alternatively, indirect effects of sex hormones, ie, modulation of cardiovascular responses or androgen- and estrogen-synthesizing enzymes, might contribute to gender-specific immune responses. Recent studies indicate that sex hormones, eg, dehydroepiandrosterone (DHEA), also modulate the function of peripheral blood mononuclear cells in surgical patients. Thus, the immunomodulatory properties of sex hormones/receptor antagonists/sex steroid synthesizing enzymes following trauma-hemorrhage suggests novel therapeutic strategies for the treatment of immunodepression in surgical patients.
Assuntos
Hormônios Esteroides Gonadais/imunologia , Sepse/imunologia , Fatores Sexuais , Choque Hemorrágico/imunologia , Ferimentos e Lesões/imunologia , Adjuvantes Imunológicos/uso terapêutico , Antagonistas de Receptores de Andrógenos , Androgênios/imunologia , Circulação Sanguínea , Desidroepiandrosterona/imunologia , Desidroepiandrosterona/uso terapêutico , Suscetibilidade a Doenças , Estrogênios/imunologia , Feminino , Humanos , Imunocompetência , Masculino , Receptores Androgênicos/imunologia , Receptores Androgênicos/uso terapêutico , Receptores de Estrogênio/imunologia , Sepse/tratamento farmacológico , Sepse/fisiopatologia , Choque Hemorrágico/tratamento farmacológico , Choque Hemorrágico/fisiopatologia , Índices de Gravidade do Trauma , Ferimentos e Lesões/tratamento farmacológico , Ferimentos e Lesões/fisiopatologiaRESUMO
Several clinical and experimental studies have demonstrated gender dimorphism in immune and organ responsiveness and in the susceptibility to and morbidity from shock, trauma, and sepsis. In this respect, cell-mediated immune responses have been shown to be depressed in males following trauma-hemorrhage, whereas they were aintained/enhanced in proestrus females. Furthermore, sex hormones have been shown to be responsible for this gender-specific immune response following adverse circulatory conditions. More specifically, studies indicate that androgens produce immunodepression following trauma-hemorrhage in males. In contrast, female sex steroids appear to exhibit immunoprotective properties following trauma and severe blood loss. With regard to the underlying mechanisms, receptors for sex hormones have been identified on various immune cells suggesting direct effects of these hormones on the immune cells. Alternatively, indirect effects of sex hormones, ie, modulation of cardiovascular responses or androgen- and estrogen-synthesizing enzymes, might contribute to gender-specific immune responses. Recent studies indicate that sex hormones, eg, dehydroepiandrosterone (DHEA), also modulate the function of peripheral blood mononuclear cells in surgical patients. Thus, the immunomodulatory properties of sex hormones/receptor antagonists/sex steroid synthesizing enzymes following trauma-hemorrhage suggests novel therapeutic strategies for the treatment of immunodepression in surgical patients.
Uma série de estudos clínicos e experimentais demonstram a existência de dimorfismo sexual das respostas imunológicas e orgânicas, bem como da suscetibilidade e morbidade em relação ao choque, ao trauma e à sepse. Respostas imunes celularmente mediadas apresentam-se deprimidas em machos em resposta ao binômio trauma-hemorragia, mas conservados/enaltecidos em fêmeas em proestro. Adicionalmente demonstra-se que os hormônios sexuais são responsáveis por esta dicomotomia de resposta sexualmente específica, em condições cardiovasculares adversas. Estudos específicos indicam que os andrógenos produzem imunodepressão pós-trauma hemorragia em machos. Em contraste, esteróides sexuais femininos parecem exibir propriedades imunoprotetoras após episódios de trauma com ou sem perda importante de sangue. No terreno dos mecanismos subjacentes, foram identificados receptores para hormônios sexuais em várias células do sistema imunológico, sugerindo a existência de efeitos diretos destes hormônios sobre tais células. Alternativamente, observam efeitos indiretos de hormônios sexuais tais como modulação das respostas cardiovasculares das enzimas sintetizadores de andrógeno e estrógeno, que podem contribuir para as estas respostas sexualmente diferenciadas. Estudos recentes indicam que os hormônios sexuais, como por exemplo a dehidroepiandrosterona também modulam a função de células mononucleares da série branca em pacientes cirúrgicos. Assim, as propriedades imunomodulatórias de hormônios sexuais/antagonistas de receptores/enzimas sintetizadores de esteróides após a ocorrência de trauma ou de hemorragia sugerem o caminho para novas estratégias terapêuticas para o tratamento de imunodepressão em pacientes cirúrgicos.