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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Hyperoxia and tumor necrosis factor-alpha (TNFalpha) are two canonical signals centrally involved in the pathophysiology of acute lung injury. We have attempted to elucidate the effects of these two stimuli on the signal transduction pathways of lung parenchymal cells. In cultured human lung epithelial cells, exposure to hyperoxia alone (95% oxygen) did not affect NF-kappaB activation or degradation of the NF-kappaB inhibitory protein, IkappaB alpha. ⋯ Hyperoxia alone did not activate the intercellular adhesion molecule-1 (ICAM-1) promoter, but augmented TNFalpha-mediated activation of the ICAM-1 promoter. These data demonstrate that while hyperoxia alone does not affect activation of NF-kappaB, hyperoxia prolongs TNFalpha-mediated activation of NF-kappaB. The mechanism of this effect involves, in part, prolonged degradation of IkappaB alpha resulting from prolonged activation of IKK.
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Systemic inflammation triggered by insults like sepsis and acute pancreatitis may play a role in development of indirect acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Because little is known about the course of systemic inflammation on the days preceding diagnosis of ARDS, we prospectively monitored immune inflammatory status in 52 patients at risk and we assessed the presence of ALI and ARDS on day 7 after admission to the intensive care unit. On admission, serum interleukin (IL) 8, IL-6, and soluble IL-2 receptor concentrations were significantly higher in patients with subsequent ALI (n = 18) than in patients without ALI (n = 30). ⋯ Among 11 patients with acute pancreatitis, ALI patients had significantly higher IL-8, IL-6, and phagocyte CD11b expression levels than did non-ALI patients, whereas among 14 patients with massive transfusion, respective findings in ALI and non-ALI patients were comparable. Results give credence to the view that systemic inflammation plays a role in development of ALI triggered by pancreatitis, but not in that by massive transfusion. This finding, if confirmed in studies with sufficient statistical power, suggests that the patients with massive transfusion do not necessarily benefit from novel biotherapies aimed at altering the course of systemic inflammation.
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Sepsis is associated with a widespread production of proinflammatory cytokines and various oxidant species. Activation of the enzyme poly(ADP-ribose) polymerase (PARP) has been shown to contribute to cell necrosis and organ failure in various diseases associated with inflammation and reperfusion injury. The aim of the current study was to elucidate the role of PARP activation in the multiple organ dysfunction complicating sepsis in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). ⋯ PARP-/- mice had significantly lower plasma levels of TNF-alpha, IL-6, and IL-10, and they exhibited a reduced degree of organ inflammation, indicated by decreased MPO activity in the gut and lung. These effects were associated with a significant improvement in the survival of CLP in PARP-/- mice. Thus, PARP activation has an important role in systemic inflammation and organ damage in the present model of polymicrobial septic shock.
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Comparative Study
Resuscitation from severe hemorrhagic shock after traumatic brain injury using saline, shed blood, or a blood substitute.
The original purpose of this study was to compare initial resuscitation of hemorrhagic hypotension after traumatic brain injury (TBI) with saline and shed blood. Based on those results, the protocol was modified and saline was compared to a blood substitute, diaspirin cross-linked hemoglobin (DCLHb). Two series of experiments were performed in anesthetized and mechanically ventilated (FiO2 = 0.4) pigs (35-45 kg). ⋯ Thus, whole blood was more effective than saline for resuscitation of TBI, whereas DCLHb was no more, and according to many variables, less effective than saline resuscitation. These experimental results are comparable to those in a recent multicenter trial using DCLHb for the treatment of severe traumatic shock. Further investigations in similar experimental models might provide some plausible explanations why DCLHb unexpectedly increased mortality in patients.
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Our recent evidence suggests that pancreatic digestive enzymes in the lumen of the intestine may play a major role in the production of cardiovascular stimulatory factors during splachnic artery occlusion and reperfusion. These stimulators are detected in plasma, but their origin and mechanism of production has remained uncertain. ⋯ These results support the hypothesis that pancreatic enzymes may escape across the brush border barrier during intestinal ischemia and thereby initiate the production of a powerful set of cytotoxic mediators. Blockade of pancreatic enzymes in the lumen of the intestine may be a tool to interfere with inflammation and early indicators of multiorgan failure.