RESUMO
Acute kidney injury (AKI), defined as an abrupt increase in serum creatinine, a reduced urinary output, or both, is experiencing considerable evolution in terms of our understanding of the pathophysiological mechanisms and its impact on other organs. Oxidative stress and reactive oxygen species (ROS) are main contributors to organ dysfunction in AKI, but they are not alone. The precise mechanisms behind multi-organ dysfunction are not yet fully accounted for. The building up of uremic toxins specific to AKI might be a plausible explanation for these disturbances. However, controversies have arisen around their effects in organs other than the kidney, because animal models usually depict AKI as a kidney-specific injury. Meanwhile, humans present AKI frequently in association with multi-organ failure (MOF). Until now, medium-molecular-weight molecules, such as inflammatory cytokines, have been proven to play a role in endothelial and epithelial injury, leading to increased permeability and capillary leakage, mainly in pulmonary and intestinal tissues.
Assuntos
Injúria Renal Aguda/metabolismo , Insuficiência de Múltiplos Órgãos/metabolismo , Toxinas Urêmicas/metabolismo , Animais , Humanos , Ligação ProteicaRESUMO
Sepsis syndrome is the leading cause of mortality in critically ill patients admitted to intensive care. However, current therapies for sepsis treatment are unsatisfactory, and the mortality rate is still high. The main pathological characteristics observed during sepsis syndrome and endotoxemia include hypotension, tachycardia, multiple organ dysfunction syndrome (MODS), tissue damage, and cytokine and oxidative bursts. These conditions severely decrease the survival rates of endotoxemic patients. As a consequence of endotoxemia, large amounts of endotoxin circulate in the bloodstream throughout the vascular system and interact directly with endothelial cells that cover the inner wall of blood vessels. Endothelial cells exposed to lipopolysaccharides exhibit conversion to activated fibroblasts. By means of endotoxin-induced endothelial fibrosis, endothelial cells downregulate the expression of endothelial proteins and express fibrotic and ECM markers throughout endothelial protein expression reprogramming. Although endotoxin-induced endothelial fibrosis should, in theory, be detrimental to endothelial vascular function, the role of endothelial fibrosis in sepsis syndrome or endotoxemia is not known. Therefore, we employed a rat model to investigate whether the inhibition of endotoxin-induced endothelial fibrosis protects against endotoxemia and whether this inhibition increases survival. Our results show that the inhibition of endotoxin-induced endothelial fibrosis reduced both hypotension and tachycardia. Endotoxemia-induced MODS was also decreased when endothelial fibrosis was inhibited; treated rats showed normal kidney and liver function, inhibition of muscle mass wasting and normal glycemia. Liver and kidney histology was preserved, and organ fibrosis and fibrotic protein expression were reduced. Furthermore, pro-inflammatory cytokine secretion and NOX-2-mediated oxidative stress bursts were decreased when endothelial fibrosis was inhibited. Remarkably, the risk of death associated with sepsis syndrome at early and late time points was decreased when endotoxemia-induced endothelial fibrosis was inhibited, and a significant increase in survival was observed. These results reveal a potential novel treatment strategy to protect against sepsis syndrome and endotoxemia.
Assuntos
Citocinas/metabolismo , Endotoxemia/metabolismo , Fibrose/metabolismo , Insuficiência de Múltiplos Órgãos/metabolismo , Estresse Oxidativo/fisiologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Endotoxemia/mortalidade , Hipotensão , Masculino , Ratos , Ratos Sprague-Dawley , TaquicardiaRESUMO
Sepsis-induced organ failure is characterized by a massive inflammatory response and oxidative stress. Acute kidney injury (AKI) occurs in approximately half of patients in septic shock, and the mortality associated with sepsis-induced AKI is unacceptably high. Klotho is a protein expressed by renal cells and has anti-senescence properties. Klotho has also been shown to protect the kidneys in ischemia-reperfusion injury and to have antioxidant properties. To analyze the role of Klotho in sepsis-related organ dysfunction and AKI, we used a cecal ligation and puncture (CLP) model of sepsis in heterozygous Klotho-haploinsufficient mice and their wild-type littermates (CLP- Kl/+ and CLP-WT mice, respectively). In comparison with the CLP-WT mice, CLP- Kl/+ mice showed lower survival, impaired renal function, impaired hepatic function, greater oxidative stress, upregulation of inflammatory pathways (at the systemic and kidney tissue levels), and increased NF-κB activation. It is noteworthy that CLP- Kl/+ mice also showed lower heart-rate variability, less sympathetic activity, impaired baroreflex sensitivity to sodium nitroprusside, and a blunted blood pressure response to phenylephrine. We also demonstrated that sepsis creates a state of acute Klotho deficiency. Given that low Klotho expression exacerbates sepsis and multiple organ dysfunction, Klotho might play a protective role in sepsis, especially in elderly individuals in whom Klotho expression is naturally reduced.
Assuntos
Glucuronidase/metabolismo , Rim/metabolismo , Fígado/metabolismo , Insuficiência de Múltiplos Órgãos/metabolismo , Sepse/metabolismo , Animais , Barorreflexo/fisiologia , Ceco/lesões , Modelos Animais de Doenças , Glucuronidase/genética , Haploinsuficiência , Frequência Cardíaca/fisiologia , Inflamação/metabolismo , Inflamação/fisiopatologia , Rim/fisiopatologia , Proteínas Klotho , Fígado/fisiopatologia , Camundongos , Camundongos Knockout , Insuficiência de Múltiplos Órgãos/genética , Insuficiência de Múltiplos Órgãos/fisiopatologia , NF-kappa B/metabolismo , Estresse Oxidativo/fisiologia , Sepse/genética , Sepse/fisiopatologia , Regulação para CimaRESUMO
Sepsis is a systemic inflammatory response as a result of uncontrolled infections. Neutrophils are the first cells to reach the primary sites of infection, and chemokines play a key role in recruiting neutrophils. However, in sepsis chemokines could also contribute to neutrophil infiltration to vital organs leading to multiple organ failure. ACKR2 is an atypical chemokine receptor, which can remove and degrade inflammatory CC chemokines. The role of ACK2 in sepsis is unknown. Using a model of cecal ligation and puncture (CLP), we demonstrate here that ACKR2 deficient () mice exhibited a significant reduction in the survival rate compared with similarly treated wild-type (WT) mice. However, neutrophil migration to the peritoneal cavity and bacterial load were similar between WT and ACKR2 mice during CLP. In contrast, ACKR2 mice showed increased neutrophil infiltration and elevated CC chemokine levels in the lung, kidney, and heart compared with the WT mice. In addition, ACKR2 mice also showed more severe lesions in the lung and kidney than those in the WT mice. Consistent with these results, WT mice under nonsevere sepsis (90% survival) had higher expression of ACKR2 in these organs than mice under severe sepsis (no survival). Finally, the lungs from septic patients showed increased number of ACKR2 cells compared with those of nonseptic patients. Our data indicate that ACKR2 may have a protective role during sepsis, and the absence of ACKR2 leads to exacerbated chemokine accumulation, neutrophil infiltration, and damage to vital organs.
Assuntos
Insuficiência de Múltiplos Órgãos/metabolismo , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Receptores de Quimiocinas/metabolismo , Sepse/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Insuficiência de Múltiplos Órgãos/patologia , Neutrófilos/patologia , Sepse/patologiaRESUMO
Severe hemorrhage can lead to global ischemia and hemorrhagic shock (HS), resulting in multiple organ failure (MOF) and death. Restoration of blood flow and re-oxygenation is associated with an exacerbation of tissue injury and inflammatory response. The neuronal nitric oxide synthase (nNOS) has been implicated in vascular collapse and systemic inflammation of septic shock; however, the role of nNOS in HS is poorly understood. The aim of this study was to evaluate the role of nNOS in the MOF associated with HS.Rats were subjected to HS under anesthesia. Mean arterial pressure was reduced to 30â mmHg for 90 âmin, followed by resuscitation with shed blood. Rats were randomly treated with two chemically distinct nNOS inhibitors [ARL 17477 (1âmg/kg) and 7-nitroindazol (5âmg/kg)] or vehicle upon resuscitation. Four hours later, parameters of organ injury and dysfunction were assessed.HS was associated with MOF development. Inhibition of nNOS activity at resuscitation protected rats against the MOF and vascular dysfunction. In addition, treatment of HS rats with nNOS inhibitors attenuated neutrophil infiltration into target organs and decreased the activation of NF-κB, iNOS expression, NO production, and nitrosylation of proteins. Furthermore, nNOS inhibition also reduced the levels of pro-inflammatory cytokines TNF-α and IL-6 in HS rats.In conclusion, two distinct inhibitors of nNOS activity reduced the MOF, vascular dysfunction, and the systemic inflammation associated with HS. Thus, nNOS inhibitors may be useful as an adjunct therapy before fluids and blood administration in HS patients to avoid the MOF associated with reperfusion injury during resuscitation.
Assuntos
Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Choque Hemorrágico/complicações , Choque Hemorrágico/metabolismo , Amidinas/farmacologia , Animais , Indazóis/farmacologia , Interleucina-6/metabolismo , Masculino , Insuficiência de Múltiplos Órgãos/enzimologia , NF-kappa B/metabolismo , Infiltração de Neutrófilos/efeitos dos fármacos , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismoRESUMO
We investigated protein expression in the medullary visceral zone (MVZ) of rats with multiple-organ dysfunction syndrome (MODS) caused by subarachnoid hemorrhage (SAH) to discuss the possible regulatory mechanism of the MVZ in the course of SAH-induced MODS. A SAH-induced MODS model was established in rats by injecting arterial blood into the Willis' circle. Protein expression in the MVZ was analyzed by immunohistochemistry assay. Protein expression in the MVZ peaked 24-36 h after SAH, and was significantly higher than in the control and sham operation groups. Organs at each time point exhibited inflammatory injuries to varying degrees after SAH, which reached a maximum at 24-36 h. Incidences of systemic inflammatory response syndrome and MODS were 100 and 71.67%, respectively, after SAH. There is a consistency between MVZ protein expression and inflammatory changes in each organ after SAH. This prompts the suggestion that the MVZ may be one of the direct regulative centers in SAH-induced MODS, and may be involved in the functional regulation of the surrounding organs after SAH.
Assuntos
Bulbo/metabolismo , Hemorragia Subaracnóidea/metabolismo , Animais , Lesões Encefálicas/metabolismo , Estudos de Casos e Controles , Círculo Arterial do Cérebro/metabolismo , Modelos Animais de Doenças , Imuno-Histoquímica , Masculino , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/metabolismo , Ratos , Ratos Wistar , Hemorragia Subaracnóidea/sangueRESUMO
Sepsis progresses to multiple organ dysfunction (MOD) due to the uncontrolled release of inflammatory mediators. Carotid chemo/baro-receptors could play a protective role during sepsis. In anesthetized male rats, we measured cardiorespiratory variables and plasma TNF-α, glucocorticoids, epinephrine, and MOD marker levels 90min after lipopolysaccharide (LPS) administration in control (SHAM surgery) and bilateral carotid chemo/baro-denervated (BCN) rats. BCN prior to LPS blunted the tachypneic response and enhanced tachycardia and hypotension. BCN-LPS rats also showed blunted plasma glucocorticoid responses, boosted epinephrine and TNF-α responses, and earlier MOD onset with a lower survival time compared with SHAM-LPS rats. Consequently, the complete absence of carotid chemo/baro-sensory function modified the neural, endocrine and inflammatory responses to sepsis. Thus, carotid chemo/baro-receptors play a protective role in sepsis.
Assuntos
Corpo Carotídeo/fisiologia , Lipopolissacarídeos/toxicidade , Insuficiência de Múltiplos Órgãos/etiologia , Pressorreceptores/fisiologia , Sepse/induzido quimicamente , Sepse/complicações , Animais , Corpo Carotídeo/efeitos dos fármacos , Denervação/métodos , Epinefrina/sangue , Glucocorticoides/sangue , Frequência Cardíaca/efeitos dos fármacos , Masculino , Insuficiência de Múltiplos Órgãos/metabolismo , Ratos , Ratos Sprague-Dawley , Respiração/efeitos dos fármacos , Estatísticas não Paramétricas , Análise de Sobrevida , Volume de Ventilação Pulmonar/efeitos dos fármacos , Volume de Ventilação Pulmonar/fisiologia , Fator de Necrose Tumoral alfa/sangueRESUMO
The aim of this study was to evaluate the expression of surface molecules in splenic dendritic cells (DC) in multiple-organ dysfunction syndrome (MODS) mice and their effects on the immunosuppression of sepsis and MODS. One hundred thirty C57BL/6 mice were divided into 7 groups: 6, 12, 24, 48 h, 5-7 days, 10-12 days, and the normal control group. The sepsis-MODS mouse model was established by zymson injection into the peritoneal cavity. Histopathological changes in the spleen were evaluated by hematoxylin and eosin (HE) staining. After enrichment with BDTM IMag, the expressions of PD-1, PD-L1, MHC-II (I-A(b)), and CD86 in splenic DCs were examined by flow cytometry, and their relationship with sepsis development and MODS was analyzed. The histological structures of the spleen were damaged in the 24-, 48-h, and 10-12-day groups. PD-L1 expression increased 6 h after zymosan injection, decreased to normal levels at 24 and 48 h, and increased at 5-7 days, peaking at 10-12 days. The change in PD-1 expression roughly paralleled that of PD-L1. MHC-II and CD86 increased at 6 and 12 h, and dropped to normal levels at 10-12 days. In the early stage of injury, splenic DCs were mainly activated, whereas in the later stage, the expressions of the negative co-stimulatory molecules, PD-L1 and PD- 1, were upregulated, similar to tolerogenic DCs. Splenic DCs might suppress the stimulation of T lymphocytes in MODS mice through the PD-L1/PD-1 pathway, which would induce immunosuppression and the pathogenesis of MODS.
Assuntos
Antígeno B7-H1/metabolismo , Células Dendríticas/metabolismo , Insuficiência de Múltiplos Órgãos/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Baço/metabolismo , Animais , Células Dendríticas/imunologia , Citometria de Fluxo , Imunofenotipagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Insuficiência de Múltiplos Órgãos/imunologia , Baço/imunologia , Baço/patologiaRESUMO
Extracorporeal membrane oxygenation (ECMO) has gained renewed interest in the treatment of respiratory failure since the advent of the modern polymethylpentene membranes. Limited information exists, however, on the performance of these membranes in terms of gas transfers during multiple organ failure (MOF). We investigated determinants of oxygen and carbon dioxide transfer as well as biochemical alterations after the circulation of blood through the circuit in a pig model under ECMO support before and after induction of MOF. A predefined sequence of blood and sweep flows was tested before and after the induction of MOF with fecal peritonitis and saline lavage lung injury. In the multivariate analysis, oxygen transfer had a positive association with blood flow (slopeâ=â66, P<0.001) and a negative association with pre-membrane PaCO(2) (slopeâ=â-0.96, Pâ=â0.001) and SatO(2) (slopeâ=â-1.7, P<0.001). Carbon dioxide transfer had a positive association with blood flow (slopeâ=â17, P<0.001), gas flow (slopeâ=â33, P<0.001), pre-membrane PaCO(2) (slopeâ=â1.2, P<0.001) and a negative association with the hemoglobin (slopeâ=â-3.478, Pâ=â0.042). We found an increase in pH in the baseline from 7.50[7.46,7.54] to 7.60[7.55,7.65] (P<0.001), and during the MOF from 7.19[6.92,7.32] to 7.41[7.13,7.5] (P<0.001). Likewise, the PCO(2) fell in the baseline from 35 [32,39] to 25 [22,27] mmHg (P<0.001), and during the MOF from 59 [47,91] to 34 [28,45] mmHg (P<0.001). In conclusion, both oxygen and carbon dioxide transfers were significantly determined by blood flow. Oxygen transfer was modulated by the pre-membrane SatO(2) and CO(2), while carbon dioxide transfer was affected by the gas flow, pre-membrane CO(2) and hemoglobin.
Assuntos
Dióxido de Carbono/metabolismo , Oxigenação por Membrana Extracorpórea , Insuficiência de Múltiplos Órgãos/metabolismo , Insuficiência de Múltiplos Órgãos/terapia , Oxigênio/metabolismo , Animais , Modelos Animais de Doenças , Hemodinâmica , Insuficiência de Múltiplos Órgãos/fisiopatologia , Respiração , SuínosRESUMO
Metabolic activity can be down-regulated throughout the reduction of mitochondrial population. Lowering O2 demand in cardiogenic, hemorrhagic and septic shock is here examined through clinical observations and trials. A decrease in the availability of O will be followed by reductions in mitochondrial population and, therefore, in a decrease in O2 demand. This response may lessen or prevent the acquisition of an O2 debt; until now, cornerstone in the pathophysiology of shock. The cost of this adaptation is less energy production, and the resulting energy deficit has been linked to multiple organ failure (MOF), a complication of acute inflammatory processes and shock. MOF is better tolerated than anaerobic metabolism and is potentially reversible if the triggering causes are reversed and the energy level is re-established through mitochondrial biogenesis.Decoupling of mitochondrial oxidative phosphorylation occurs in both experimental models and in clinical septic shock. In critical patients this phenomenon may be detected by an inordinate increase in VO2 in response to a therapeutically increased DO. This hipermetabolic stage can be mistakenly interpreted as the repayment phase of an O2 debt.