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
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A poorly controlled acute inflammatory response can lead to organ dysfunction and death. Severe systemic inflammation can be induced and perpetuated by diverse insults such as the administration of toxic bacterial products (e.g., endotoxin), traumatic injury, and hemorrhage. Here, we probe whether these varied shock states can be explained by a universal inflammatory system that is initiated through different means and, once initiated, follows a course specified by the cellular and molecular mechanisms of the immune and endocrine systems. ⋯ We found that a single model with different initiators including the autonomic system could describe the response to various insults. This model was able to predict a dose range of endotoxin at which mice would die despite having been calibrated only in nonlethal inflammatory paradigms. These results show that the complex biology of inflammation can be modeled and supports the hypothesis that shock states induced by a range of physiologic challenges could arise from a universal response that is differently initiated and modulated.
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In laboratory models of uncontrolled hemorrhage, immediate resuscitation from hemorrhage is associated with high mortality. However, in clinical practice, resuscitation is often delayed and the rate of fluid administration is limited. We hypothesized that a slow rate of infusion after delayed resuscitation, reflecting the clinical environment, might improve survival in the presence of uncontrolled hemorrhage. ⋯ Blood loss was significantly higher in the bolus group (926 +/- 77 mL) compared with the slow infusion (714 +/- 83 mL) and control groups (604 +/- 46 mL). Hypertonic saline/Dextran administered slowly significantly increased cardiac output and blood pressure. Taken together, these results are consistent with the hypothesis that resuscitation solutions can be effective for treatment of uncontrolled hemorrhage when administered at a slow infusion rate 30 min after the insult.
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Acute injury produces an immediate activation of neuroendocrine mechanisms aimed at restoring hemodynamic and metabolic counter-regulatory responses. These counter-regulatory responses are mediated by the systemic and tissue-localized release of neuroendocrine-signaling molecules known to affect immune function. This has led to the recognition of the importance of neuroendocrine-immune modulation during acute injury as well as throughout the recovery period. ⋯ In turn, cells of the immune system and their products have been shown to influence peripheral and central neurotransmission, leading to the conceptualization of a bidirectional neuroimmune communication system. The reflex activation of this bidirectional neuroimmune pathway in response to injury, integrated with the parasympathetic nervous system, and opioid and glucocorticoid pathways responsible for orchestrating the counterregulatory stress response, results in dynamic regulation of host defense mechanisms vital for immune competence and tissue repair. This review provides the biological framework for the integration of our understanding of the neuroendocrine mechanisms involved in mediating the stress response and their role in modulating immune function during and after traumatic injury.
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The hamster chamber window model was subjected to hemorrhagic shock by the withdrawal of 50% of blood volume (BV). BV was restored 1 h after hemorrhage with a single volume infusion (resuscitation) of 25% BV with polyethylene glycol (PEG)-conjugated bovine serum albumin (Alb) and hydroxyethyl starch (HES). Hemorrhage, shock, and resuscitation were monitored continuously in terms of mean arterial pressure (MAP), microvascular blood flow, capillary perfusion, and tissue pH. ⋯ However, oxygen-dependant parameters corrected for pH varied less than 10% from uncorrected data. Early differences found at the microvascular levels suggest that decisions to amend end-result of resuscitation may be short and on the order of minutes. Furthermore, PEG-Alb appears to provide early and long-term sustained systemic and microvascular recovery when used to restitute perfusion and metabolic conditions after resuscitation from hemorrhagic shock.
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Rho, a Ser-Thr kinase identified as a member of the RAS GTPase super family, is highly expressed in the heart, and has been implicated in the development of heart failure. GTPase Rho is located downstream of Gq, and Rho and the associated kinase (Rho kinase) regulate myofibril organization, apoptosis, and myofibrillar sensitivity to calcium. Myocardial injury and dysfunction occur after major burn injury, and this phenomenon has been linked to cardiac myocyte synthesis and the secretion of proinflammatory cytokines. ⋯ In vivo burn injury or in vitro burn serum challenge of isolated myocytes increased Rho-kinase expression and promoted cardiomyocyte secretion of tumor necrosis factor-alpha, interleukin 1beta, and interleukin 6, and increased cardiomyocyte calcium and sodium levels compared with values measured when myocytes were incubated in medium alone (P < 0.05). Pretreating cardiomyocytes with Rho-kinase inhibitor (HA1077 or Y27632) prevented burn serum-related upregulation of Rho-kinase and attenuated the associated inflammatory cytokine responses, and attenuated myocyte calcium and sodium loading. Our data suggest that the Rho-kinase pathway is one potential upstream regulator of cardiac inflammatory response to burn injury.