Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
-
In clinical practice, prolonged occlusion of main arteries causes accumulation of metabolic waste and lactate. Reperfusion of blood flow is usually accompanied by circulatory shock. This study investigates the molecular mechanisms responsible for acidosis-induced hypotension and proposes therapeutic strategies for improving hemodynamic stability following ischemia-reperfusion acidosis. ⋯ Recording of electrocardiogram showed progressive development of bradyarrhythmia with ST-segment elevation in animals pretreated with PNU37883A before reperfusion. We demonstrate that acidosis-induced vasodilation is, in part, mediated by the activation of KATP channels through reduction of intracellular Ca in VSMCs. However, systemic antagonism of KATP channel significantly increases the overall mortality secondary to the development of cardiac dysrhythmia in animals with profound experimental metabolic acidosis, suggesting that activation of KATP channel is a protective response during reperfusion acidosis.
-
Patients with crush injury often present systemic inflammatory response syndrome and fall into multiple organ failure. The mechanism by which the local tissue damage induces distant organ failure is still unclear. We focused on high-mobility group box 1 protein (HMGB1) as one of the damage-associated molecular pattern molecules that cause systemic inflammation in crush injury. ⋯ These results indicate that HMGB1 is released in response to damage immediately after crush injury and acts as a proinflammatory mediator. Administration of anti-HMGB1 antibody reduced inflammatory reactions and improved survival by blocking extracellular HMGB1. Thus, HMGB1 appears to be a therapeutic target, and anti-HMGB1 antibody may become a promising novel therapy against crush injury to prevent the progression to multiple organ failure.
-
The role and source of tumor necrosis factor-α in hemorrhage-induced priming for septic lung injury.
Tumor necrosis factor α (TNF-α) has been reported to be a key component of the functional priming, of both myeloid and nonmyeloid cells, that is thought to contribute to the lung's increased susceptibility to injury following shock. Not surprisingly, we found that mice deficient in TNF-α exhibited reduced acute lung injury (ALI) resultant from the combined insults of hemorrhagic shock and sepsis. However, we found that when we adoptively transferred neutrophils from mice expressing TNF-α to neutrophil-depleted mice that lacked TNF-α, they were not able to serve as priming stimulus for the development of ALI. ⋯ We hypothesized that alternately suppressing expression of TNF-α in lung endothelial (i.v.) or epithelial (i.t.) cells would produce a differential effect in shock-induced ALI. We found that when in vivo siRNA i.t. or i.v. against TNF-α was administered to C57/BL6 mice at 2 h after hemorrhage, 24 h before septic challenge, that systemic/i.v., but not i.t., delivery of TNF-α siRNA following hemorrhage priming significantly reduces expression of indices of ALI compared with controls. These findings suggest that an absence of local lung tissue TNF-α significantly reduces lung tissue injury following hemorrhage priming for ALI and that pulmonary endothelial and/or other possible vascular resident cells, not epithelial cells, play a greater role in mediating the TNF-α priming response in a mouse model of hemorrhage/sepsis-induced ALI.
-
The management of severe traumatic brain injury (TBI) focuses on prevention and treatment of intracranial hypertension (ICH) and cerebral hypoperfusion (CH). Predicting which patients will develop these secondary insults is currently not possible. This study investigates the systemic manifestation of neuroinflammation and its role in helping to predict clinical deterioration following severe TBI. ⋯ Interleukin 8 and TNF-α demonstrate promise as candidate serum markers of impending ICH and CH. This suggests that we may be able to "predict" imminent events following TBI before clinical manifestations. Given the morbidity of ICH and CH, minimizing the effects of these secondary insults may have a significant impact on outcome and help guide decisions about timing of interventions.
-
This study's objective was to investigate the daily dynamics of fibrinogen metabolism and coagulation function for 5 days after hemorrhagic shock in pigs. Sixteen pigs were randomized into the control (C) and the hemorrhage (H) groups. On day 1, hemorrhage was induced in H by bleeding 35% of the estimated total blood volume, followed by resuscitation with lactated Ringer's solution at three times the bled volume. ⋯ Compared with day 1 control value (1.3 ± 0.1 mg/kg per hour), fibrinogen synthesis in H was increased to 3.6 ± 0.1, 5.1 ± 0.5, 2.6 ± 0.4, 2.7 ± 0.5, and 2.3 ± 0.3 mg/kg per hour on days 1 through 5 (all P < 0.05); fibrinogen breakdown in H was elevated on days 1 and 2 but returned to control values afterward. Hemorrhage caused acute decreases in fibrinogen concentration and clot strength, followed by an increase in fibrinogen concentration and recovery of clot strength. The increase in fibrinogen appeared primarily due to a sustained increase in fibrinogen synthesis.