摘要:

Abdominal compartment syndrome (ACS) has emerged to be a significant problem in patients who develop postinjury multiple organ failure (MOF). Current laboratory research suggests that ACS could be a second hit for the development of MOF. Recent studies demonstrate that ACS is an independent predictor of MOF and that the prevention of ACS decreases the incidence of MOF. The Trauma Research Centers at the University of Colorado and the University of Texas-Houston Medical School are focused on defining the role of the gut in postinjury MOF. Because ACS is a plausible modifiable risk factor, our interest has been to 1) describe the epidemiology of ACS, 2) build prediction models, 3) provide strategies for prevention and treatment of ACS, and 4) develop relevant laboratory models. This review summarizes our findings.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

A potential role of Fas/FasL in sepsis is suggested by recent clinical studies showing that Fas and FasL could serve as markers for severity of sepsis. We sought to determine the effect of endotoxin infusion on expression of Fas and FasL. Healthy volunteers (n = 30) received 2 ng/kg endotoxin i.v. Endotoxin infusion decreased Fas expression on neutrophils and monocytes by 15–20% at 2–4 hin vivoand alsoin vitro.A rebound increase in Fas (30%) was seen on neutrophils at 24 h, and soluble FasL levels increased by 100% at 24 h. Fas mRNA levels increased 6-fold 4–6 h after endotoxin infusion as measured by real-time polymerase chain reaction. In contrast, FasL-mRNA levels in circulating leukocytes decreased by >80% 2h after lipopolysaccharide infusion. In summary, low-grade endotoxemia induces early down-modulation of Fas on leukocytes, followed by a several-fold increase in Fas-mRNA expression leading to later Fas surface upregulation on neutrophils. The upregulation of Fas expression, Fas mRNA, and later in FasL and sFas levels in endotoxemia replicates the increased fas levels found in septic patients.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The initial transfusion therapy after trauma has been identified as an independent risk factor for the incidence of multiple organ failure (MOF). Late occurrence of MOF in severely injured patients may be a clinical consequence of disturbed mediator homeostasis. For this reason, levels of interleukin (IL)-6, IL-10, and soluble tumor necrosis factor receptors (sTNFR) p55 and p75 were analyzed in the plasma of patients with comparable injury severity but with a different supply of packed red blood cells (PRBC). Thirty-eight multiple trauma patients with an injury severity score range of 25–54 points were separated into two groups according to their PRBC supply within the first 24 h after trauma. Patients who received at least 15 units of PRBC were analyzed in group 2 (n = 11); the remaining patients (n = 27) were assigned to group 1. The incidence of MOF was higher (P< 0.05) in group 2 patients. Correspondingly, levels of all assayed mediators were found significantly elevated at several time points in this patient group. We conclude that increases in mediator concentrations may be causally related to the extent of blood transfusion therapy itself or to the conditions for which it was needed.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Device-associated infections after implants or endoprostheses inflict local inflammation and ultimately osteolysis, a clinical entity referred to as posttraumatic osteomyelitis. The underlying molecular mechanisms are not yet known; formation of bacterial biofilms on the implant is presumed, conferring resistance to antibiotics and to host defense mechanisms as well. To gain insight into the pathogenesis of post-traumatic osteomyelitis, the infected site was analyzed for the presence of immunocompetent cells. In 18 patients, the infected site was rinsed intraoperatively. This so-called lavage contained 1–2 × 107leukocytes, predominantly highly activated polymorphonuclear neutrophils (PMNs), as characterized by low expression of CD62L (selectin), and high expression of the adhesion protein CD18, of the high-affinity immunoglobulin (IgG) receptor CD64, and of the LPS-receptor CD14. CD16, the low-affinity IgG receptor, was affected in some patients only. Because the majority of infections were caused by staphylococci species, the effect of bacteria-derived lipoteichoic acid on PMN of healthy donors was testedin vitro.A similar activation pattern was found: rapid down-regulation of CD62L, a slower loss of CD16, and upregulation of CD18, CD64, and CD14. Lipoteichoic acid signaling required p38 mitogen-activated protein kinase and resulted in induction of CD14-specific mRNA andde novoprotein synthesis. We conclude that PMNs infiltrate the infected site, but despite local activation they are unable to clear the bacteria, presumably because of biofilm formation. Our data are consistent with the hypothesis that during the ineffective “frustrated” attempt to phagocytose, PMNs release cytotoxic and proteolytic entities that in turn contribute to the progression of tissue injury and ultimately to osteolysis.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The cause for the high morbidity of blunt chest trauma is not fully understood. It is still unclear if and to what extent a second insult, e.g., apoptotic tissue damage initiated by the primary insult itself, may contribute to the development of serious complications. This study was done to elucidate whether a pulmonary contusion may induce programmed cell death. Sixty-four Wistar rats were evenly randomized to eight experimental groups: four sets were subjected to a standardized blast wave injury and sacrificed 6, 24, 48, and 72 h after the trauma; four groups served as controls for the same time points. Lung and liver samples were stained (H&E; TUNEL), and PMN infiltration was determined by myeloperoxidase (MPO) activity. Caspase 8 was analyzed by Western blot, and TNF-&agr; plasma levels by ELISA. Postmortem examination revealed bilateral pulmonary contusion in trauma animals with higher (P< 0.05) numbers of apoptotic cells in lung but not in liver tissue as early as 6 h after the injury. This amount gradually increased and reached a maximum after 48 h: 6.8 ± 1.1 apoptotic cells/hpf vs. 0.6 ± 0.06 in controls. Chest trauma caused an increased expression of active caspase 8 in lung but not in liver tissue at 48 and 72 h. TNF-&agr; plasma levels were not different. MPO activity in lung tissue of trauma animals increased (P< 0.05) after 6 h and peaked at 72 h. This study has provided the first evidence that apoptotic cell death in lung tissue is initiated following (experimental) pulmonary contusion. The exact mechanism remains, however, unclear and has to be elucidated further.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Cutaneous burn injury-induced T lymphocyte suppression is a well-known phenomenon. In this study, we evaluated the effect of treatment of burn rats with pentoxifylline (PTX) on the burn-induced suppression of T lymphocytes. Anesthetized rats were subjected to 30% total body surface area burn by exposing skin to 95°C water for 10 s. T lymphocytes were isolated from sham and burn rats with or without PTX treatment (120 mg/kg, ip). T cell proliferation and interleukin (IL)-2 production in response to T cell mitogen concanavalin A was measured using 3 H-thymidine uptake and enzyme-linked immunosorbent assay, respectively. P59 fyn autophosphorylation and its kinase activity was determined using in vitro kinase assay. In addition, T lymphocyte Ca2+signaling was assessed using Ca2+imaging technique. Two days after injury, there was a significant decrease in mesenteric lymph node T cell proliferation and IL-2 production in burn injured rats compared with those obtained from sham-injured rats. This decrease in T cell proliferation and IL-2 production in burn-injured rats was accompanied by a significant suppression in both P59 autophophorylation and kinase activity as well as Ca2+signaling. Treatment of burn-injured rats with PTX produced a near complete recovery of T cell proliferation and IL-2 production. Furthermore, PTX treatment also prevented the burn-mediated suppression in P59fyn and kinase activity as well as restored Ca2+signaling similar to those observed in sham injured rats. These findings altogether suggested that PTX treatment attenuate T cell suppression in burn-injured rats and that the effects of PTX are mediated via modulating P59 fyn and Ca2+signaling.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Ethyl pyruvate (EP) has been shown to be an effective anti-inflammatory agent. Herein, we sought to test the following hypotheses: 1) the pharmacological effects of EP persist after cells have been exposed to the compoundin vitro, even if the cultures are washed to minimize the amount of EP that is retained in the media; 2) the pharmacological effects of EP persistin vivo, even after waiting a prolonged period (i.e., 6 h) after the last dose of the compound; and 3) thein vivopharmacological effects of EP are distinct from those of the closely related compound, sodium pyruvate. Incubation of Caco-2 human enterocyte-like monolayers with cytomix, a mixture of interleukin-1&bgr;, interferon-&ggr;, and tumor necrosis factor, increased permeability to the fluorescent macromolecule, FITC-labeled Dextran (mol wt 4,000 Da). Co-incubation of the cells with 5 mM EP ameliorated cytomix-induced hyperpermeability and induction of iNOS mRNA expression. EP was associated with similar pharmacological effects when cells were pre-incubated with the compound for 24 h prior and then washed extensively prior to adding the cytokine cocktail. Injecting C57Bl/6 mice with lipopolysaccharide (LPS) resulted in gut barrier dysfunction and hepatocellular injury. Although equivalent doses of both EP and sodium pyruvate ameliorated these phenomena, EP was more efficacious than pyruvate. Pretreatment with EP ameliorated the deleterious effects of LPS, even when the duration between the last dose of EP and the endotoxic challenge was 6 h. We conclude that EP provides durable protection against some of the deleterious effects of LPS or pro-inflammatory cytokines.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Although LPS receptor (CD14) signaling is mediated in part by &bgr;2integrins, the role of &bgr;2integrins in macrophage LPS signaling postinjury remains unknown. To study this, splenic macrophages were isolated from mice 7 days postburn, and inflammatory mediator production was determined. Macrophages isolated from injured mice produced higher levels of PGE2, TNF-&agr;, IL-6, and IL-10 and lower levels of IL-12 in response to LPS stimulation than did cells from sham-treated mice. Blockade of &bgr;2integrin signaling by addition of antibodies against the CD11b (&agr;CD11b) to the cultures increased IL-10 production by macrophages from injured mice without affecting other mediators. In contrast, sham macrophage responses to LPS were unaffected by &agr;CD11b. Inhibition of p38 MAP kinase activity attenuated IL-10 production and abrogated the enhanced IL-10 response induced by &agr;CD11b, whereas ERK 1/2 inhibition had no effect. Burn injury was associated with increased levels of total and phosphorylated p38 MAP kinase. These findings indicate that LPS signaling via &bgr;2integrins acts to attenuate the exaggerated induction of IL-10 by macrophages postinjury. Moreover, this effect of &bgr;2integrin signaling postinjury appears to be downstream of the p38 MAP kinase pathway and is independent of other markers of macrophage hyperactivity.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Inflammation and catabolism in response to trauma, surgery, critical illness or bacteria lead to a compromise of essential organs, which can lead to prolonged clinical stay and even death. Mediators responsible for catabolism were thought to be proinflammatory cytokines, but recently the focus has shifted to signal transduction. The purpose of the present study was to determine differences between two pathophysiologic states, sepsis and thermal injury, in signal transduction and cytokine expression and thus define the importance of the signal transcription pathway. Rats were randomly divided to either receive lipopolysaccharide (3 mg/kg body weight or a 30% total body surface area burn) or they received no treatment and served as controls. Animals were sacrificed 1, 2, 5, and 7 days postinsult and serum and liver harvested for analysis. A thermal injury appeared to have a slow release and expression of signal transcription factors and cytokines and a sepsis showed a rapid increase of mediators and also a fast decrease. The changes in cytokine profiles after burn, particularly interleukin-1&bgr; and macrophage inhibitory factor, appear to be mediated by C/EBP-&bgr; and STAT-3, whereas after the induction of a sepsis, tumor necrosis factor and interleukin-6 are mainly mediated by STAT-5. Based on our findings we suggest that the pathophysiologic state of a thermal injury is not comparable with sepsis in association with signal transcription factors and the differences in intracellular and extracellular signaling therefore opens new ideas for therapeutic options.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The nuclear factor-&kgr;B (NF-&kgr;B) is a transcription factor that plays a pivotal role in the induction of genes involved in the response to injury and inflammation. Dithiocarbamates are antioxidants that are potent inhibitors of NF-&kgr;B. This study tested the hypothesis that pyrrolidine dithiocarbamate (PDTC) attenuates experimental acute pancreatitis. Intraperitoneal injection of cerulein in mice resulted in severe, acute pancreatitis characterized by edema, neutrophil infiltration, tissue hemorrhage and necrosis, and elevated serum levels of amylase and lipase. Infiltration of pancreatic and lung tissue with neutrophils (measured as increase in myeloperoxidase activity) was associated with enhanced lipid peroxidation (increased tissue levels of malondialdehyde). Immunohistochemical examination demonstrated a marked increase in immunoreactivity for nitrotyrosine and intracellular adhesion molecule-1 in the pancreas and lung of cerulein-treated mice. In contrast, the degree of 1) pancreas and lung injury, 2) upregulation/expression of intracellular adhesion molecule-1, 3) staining for nitrotyrosine, and 4) lipid peroxidation was markedly reduced by pretreatment with PDTC. This study demonstrates that prevention of the activation of NF-&kgr;B by PDTC ameliorates the tissue injury associated with experimental murine acute pancreatitis and provides an important insight into the molecular biology of acute pancreatitis.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID