The Journal of surgical research
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In acute respiratory distress syndrome, pulmonary vascular permeability increases, causing intravascular fluid and protein to move into the lung's interstitium. The classic model describing the formation of pulmonary edema suggests that fluid crossing the capillary endothelium is drawn by negative interstitial pressure into the potential space surrounding extra-alveolar vessels and, as interstitial pressure builds, is forced into the alveolar air space. However, the validity of this model is challenged by animal models of acute lung injury in which extra-alveolar vessels are more permeable than capillaries under a variety of conditions. In the current study, we sought to determine whether extravascular fluid accumulation can be produced because of increased permeability of either the capillary or extra-alveolar endothelium, and whether different pathophysiology results from such site-specific increases in permeability. ⋯ Phenotypic differences between vascular segments resulted in site-specific increases in permeability, which have different pathophysiological outcomes. Our findings suggest that insults leading to acute respiratory distress syndrome may increase permeability in extra-alveolar or capillary vascular segments, resulting in different pathophysiological sequela.
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Hemorrhagic shock with conventional resuscitation (CR) primes circulating neutrophils and activates vascular endothelium for increased systemic inflammation, superoxide release, and end-organ damage. Adjunctive direct peritoneal resuscitation (DPR) with intraperitoneal instillation of a clinical peritoneal dialysis solution decreases systemic inflammation and edema formation by enhancing tissue perfusion. The aim of this study is to determine the effect of adjunctive DPR on neutrophil and fluid sequestration. ⋯ Hemorrhagic shock and resuscitation produces time-dependent organ-specific trends of neutrophil sequestration as measured with tissue levels of myeloperoxidase, a marker of neutrophil infiltration. Modulation of the splanchnic blood flow by direct peritoneal resuscitation did not alter the time-dependent neutrophil infiltration in end-organs, suggesting a subordinate role of blood rheology in the hemorrhage-induced neutrophil sequestration. Vulnerable window for neutrophil-mediated tissue damage exists during the first 4 h following resuscitation from hemorrhagic shock in rats. Direct peritoneal resuscitation prevents the early obligatory fluid sequestration and promotes early fluid mobilization.
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Gelsolin is a plasma protein that functions to depolymerize actin filaments preventing capillary plug formation following tissue injury. It also functions to mediate the inflammatory response by binding proinflammatory lipids such as lysophosphatidic acid, sphingosine-1-phosphate and phosphoinositides. Clinically, reduced gelsolin concentrations have been associated with increased mortality in critically ill, trauma, and burn patients. We have previously shown that following hemorrhagic shock with splanchnic hypoperfusion, mesenteric lymph contains lipid components that cause neutrophil and EC activation and that protein concentrations are severely diluted due to resuscitation. We hypothesized that lipid binding proteins such as gelsolin may be depleted after trauma/hemorrhagic shock leading to increased lipid bioactivity. ⋯ Gelsolin is found at high levels (comparable to plasma) in mesenteric lymph. Following hemorrhagic shock, gelsolin levels decrease significantly, possibly due to consumption by the actin scavenging system. The magnitude of this change in concentration could release lipid bioactivity and predispose the lung and other organs to capillary injury.
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Posthemorrhagic shock mesenteric lymph (PSML) has been shown to activate pulmonary endothelial cells and cause lung injury. Although multiple mediators may be involved, most of these effects are mediated by nuclear factor-kappa B (NF-kappaB) activation. Degradation of the inhibitor of kappa B (IkappaB) is a key regulatory step in the activation of NF-kappaB. We therefore hypothesized that PSML would cause IkappaB degradation with subsequent NF-kappaB phosphorylation and nuclear translocation. ⋯ Postshock mesenteric lymph bioactivity is mediated by pathways which involved IkappaB degradation. These pathways offer novel off targets for clinical intervention to prevent the distal organ injury caused by postinjury hemorrhagic shock.
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Evidence exists that resuscitation with Ringer's lactate (RL) contributes to postshock inflammation and lung injury. We hypothesized that the anti-inflammatory agent pentoxifylline (PTX) attenuates postresuscitative lung injury through modulation of transcription factors after hemorrhagic shock. ⋯ The addition of PTX to conventional RL infusion after shock significantly reduced histological lung injury and pulmonary neutrophil activity when compared to treatment with RL alone. The administration of PTX was also associated with diminished NF-kappaB and enhanced CREB activation. Therefore, the administration of PTX may serve as a novel therapeutic adjunct after hemorrhagic shock.