ISSN:1073-2322    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

PGE2is known to suppress T cell proliferation and IL-2 production in many inflammatory conditions. Previous studies from our laboratory have shown that such suppression of T cell proliferation in burn and sepsis could result from alteration in T cell activation signaling molecule p59fyn. In this study, we examined the role of downstream signaling molecules NFAT and AP-1 in PGE2-mediated suppression of T cell in burn injury. These studies were carried out utilizing splenic T cells from sham and burn rats 3 days after injury. The data presented in this manuscript suggest a significant suppression of IL-2 production by T cells from burn injured rats compared with the T cells from sham rats. The suppression in T cell IL-2 production was accompanied by a decrease in the activation of NFAT and AP-1 as well as a decrease in T cell p59fynkinase activity. The treatments of burn-injured animals with PGE2synthesis blocker indomethacin prevented both the decrease in NFAT and AP-1 binding to IL-2 sequences.In vitroincubation of control rat T cells with PGE2suppressed the activation of NFAT and AP-1. These results suggested that the suppression of T cell IL-2 production could result from PGE2-mediated alterations in the T cell signaling molecule p59fynand NFAT/AP-1.

ISSN:1073-2322    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Monocyte adhesion contributes to perfusion abnormalities, tissue damage, and activation of the coagulation system seen during trauma, shock, or overwhelming inflammation. This study was performed to determine whether an intravenous fish oil emulsion used for parenteral nutrition attenuates monocyte-endothelial interactions under flow and reduces procoagulant activity, measured as tissue factor (TF) expression on adherent monocytesin vitro.Endothelial cell monolayers were incubated with either an intravenous fish oil emulsion or a conventional ω-6 lipid emulsion at 0.05 to 1 mg/ml for 24 h. Six hours following activation with TNF&agr; (25 ng/ml), expression of endothelial cell adhesion molecules was measured by flow cytometry. Adhesion of isolated monocytes to pretreated endothelium was examined in a parallel plate flow chamber at a shear stress of 1.5 dynes/cm2. Following perfusion, the cells were cocultured for an additional 4 h and TF expression on monocytes was determined by flow cytometry. In contrast to ω-6 lipids, fish oil down-regulated E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in a dose-dependent manner. P-selectin, however, remained unchanged. In addition, firm adhesion was reduced to 54%, whereas rolling interactions remained unchanged. Fish oil exhibited no effect on the TF expression on cocultured monocytes. We conclude that intravenous fish oil emulsions reduce both endothelial cell adhesion molecule expression and monocyte adhesion. However, under postcapillary flow conditions, rolling interactions via P-selectin remain unaltered. The functional importance of this effect is illustrated by the corresponding upregulation of TF in response to residual monocyte-endothelial interactions.

ISSN:1073-2322    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Burn injury often leads to distant organ injury such as acute respiratory distress syndrome. We hypothesize that the pathophysiologic changes in distant organs result from orchestrated regulation of multiple genes in response to burn injury. Differential display was performed to identify genes regulated in distant organs in response to burn injury. Initial characterization of differentially amplified products demonstrated that HAX-1s mRNA was regulated in several distant organs after 18% total body surface area (TBSA) full-thickness flame burn injury in mice. Further characterization of HAX-1s mRNA revealed a novel transcript variant, which is rapidly and transiently induced in multiple tissues of mice within 6 h after burn injury. This novel HAX-1s transcript variant, called HAX-1xs, has an internal deletion of 252 nucleotides and single point mutation, resulting in reading frame intact. Western blot and immunohistochemical analyses of multiple tissues of mice using rabbit antibody raised against a 15-mer synthetic peptide clearly revealed the presence of HAX-1xs protein in the duodenum, and suggested that expression of HAX-1xs and/or HAX-1s was tissue- and cell type-specific. The expression of HAX-1xs and/or HAX-1s was distinctively regulated in Paneth cells of the duodenum and macrophages of the thymus after burn injury. These findings suggest that HAX-1xs has a different biological activity from HAX-1s and participates in a cascade of immediate-early cellular events in response to burn injury.

ISSN:1073-2322    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Reactive oxygen species (ROS) contribute to the multiple organ failure (MOF) in hemorrhagic shock. Here we investigate the effects of two superoxide dismutase (SOD) mimetics with catalase activity (EUK-8 and EUK-134) on the circulatory failure and the organ injury and dysfunction associated with hemorrhagic shock in the anesthetised rat. Hemorrhage (sufficient to lower mean arterial blood pressure to 45 mmHg for 90 min) and subsequent resuscitation with shed blood resulted (within 4 h after resuscitation) in a delayed fall in blood pressure, liver injury and renal dysfunction as well as pancreatic injury. Treatment of rats on resuscitation with EUK-8 (3 mg/kg i.v. bolus followed by 3 mg/kg/h i.v. infusion) significantly attenuated liver injury, renal dysfunction and pancreatic injury caused by hemorrhage and resuscitation. Administration of EUK-134 (3 mg/kg i.v. bolus followed by 3 mg/kg/h) reduced the liver injury and renal dysfunction (but not the pancreatic injury) caused by hemorrhagic shock. However, neither EUK-8 nor EUK-134 reduced the delayed circulatory failure associated with hemorrhagic shock. Thus, we propose that an enhanced formation of ROS contributes to the MOF in hemorrhagic shock, and that membrane-permeable SOD-mimetics with catalase activity, such as EUK-8 or EUK-134, may represent a novel therapeutic approach for the therapy of hemorrhagic shock.

ISSN:1073-2322    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Pseudomonaspneumonia is a common complication of smoke inhalation injury. Airway casts formed from clotted mucous occur frequently in this condition. A recent report shows that intravenous heparin improves oxygenation and reduces lung damage in a sheep model of smoke inhalation. We hypothesized that nebulized heparin could be an effective means of reducing cast formation. Female sheep (n = 19) were surgically prepared for a study of acute lung injury (ALI). After a tracheotomy, 48 breaths of cotton smoke (<40°C) were inflated into the airway. Afterwards, livePseudomonas aeruginosa(5 × 1011CFU) was instilled into the lung. All sheep were mechanically ventilated with 100% O2and were divided into four groups: a heparin-nebulized group (n = 5; animals received aerosolized heparin [10,000 I.U.] 1 h after the bacterial instillation and subsequently every 4 h thereafter), an intravenous heparin group (n = 5,300U/kg/23 h, infusion was started 1 h after the injury), a saline-nebulization group (n = 5; animals received inhaled nebulized saline), and a sham injury group (n = 4, treated in the same fashion, but no injury). The animals were sacrificed after 24 h of mechanical ventilation, and lung samples were harvested. Sheep exposed to lung injury presented with typical hyperdynamic cardiovascular changes and a corresponding drop in PaO2. These changes were significantly attenuated in the heparin groups. Histological changes consisting of cellular infiltrates, lung edema, congestion, and cast formation were reduced by heparin. These data suggest that nebulized inhaled heparin is a beneficial therapy for sepsis-induced ALI.

ISSN:1073-2322    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Because end-organ injury can occur with reperfusion following hemorrhage or ischemia, we hypothesized that aggressive intravenous fluid resuscitation would aggravate tissue injury in a fixed-volume model of hemorrhagic shock. Unanesthetized chronically prepared male rats were hemorrhaged 33–36 mL/kg for 2.5 h. Then Lactated Ringer's Solution (3x hemorrhage volume) was infused over 5 min (FAST), 20 min (MEDIUM), 180 min (SLOW), or not at all (NO RESUS). Plasma ornithine carbamoyltransferase (OCT), lactate, and creatinine were measured as indices of hepatocellular injury, anaerobic metabolism, and renal function, respectively. At 1 h post-resuscitation (PR), MAP was greater after SLOW and MEDIUM treatment (tx) than after other txs (P< 0.05). OCT increased earliest after FAST tx to values greater than those after other txs from 30 min to 24 h PR (P< 0.01). Plasma lactate was elevated immediately before resuscitation in all groups (P< 0.01) and returned to baseline at 3 h PR after SLOW tx compared to 5 h PR after FAST tx (P< 0.05). Creatinine at 5 h PR was less in the groups treated with intravenous fluid compared to the NO RESUS group,P< 0.05. Survival at 72 h was reduced in the FAST (57%) and NO RESUS (58%) groups compared to the SLOW (87%) and MEDIUM (85%) groups (P< 0.05). Thus, overly aggressive fluid tx accelerates hepatocellular injury, is no better than lesser rates of resuscitation at correcting plasma lactate and preserving renal function, and provides no overall survival benefit.

ISSN:1073-2322    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Lipopolysaccharide (LPS)-binding protein (LBP) greatly facilitates LPS activation of monocytic cells through the CD14 receptor, triggering activation of innate immune responses. An acute phase protein, LBP is produced predominantly by the liver; however, we and others have shown that LBP is produced extrahepatically in multiple locations, including the lung. The importance of LBP in the lung has remained unclear. LBP may make the host more acutely sensitive to LPS and development of septic complications; alternatively, it may be protective, aiding in detection, opsonization, and killing of bacteria. Our objective was to determine the role LBP plays in local pulmonary immune defenses to bacterial challenge. LBP knockout mice and age-matched C57BL/6 wild-type controls were challenged with direct intratracheal inoculation ofKlebsiella pneumoniae.We observed a significant increase in mortality, earlier onset of bacteremia, and greater pulmonary bacterial loads in LBP knockout mice compared with controls. Total lung myeloperoxidase (MPO) activity, neutrophil recruitment to the alveolar space, and levels of KC—a chemokine involved in neutrophil recruitment—in bronchoalveolar lavage (BAL) fluid and lung homogenates were found to be significantly diminished in knockout mice compared with controls. Together, our findings suggest that LBP is essential in local pulmonary innate immune responses against bacteria.

ISSN:1073-2322    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

We previously reported direct evidence of respiratory bursting by neutrophils in the pulmonary circulation of endotoxin-infused rats. To evaluate the effect of the protease inhibitor nafamostat mesilate (NM) on leukocyte-mediated radical formation in the pulmonary circulation of rats infused with endotoxin, we observed and measured the number of sticking leukocytes and quantified radical production in the pulmonary circulation of endotoxin-infused rats by means of a fluorescent imaging technique. Plasma C3a (desArg) was also measured using an enzyme-linked immunosorbent assay. Three groups (n = 5) of rats were infused with 4.5 mg/kg/h endotoxin (Et group), 50 &mgr;g/kg/h NM + endotoxin (NM group), or physiological saline (Ct group) for 2 h. The number of the leukocytes adhering within pulmonary capillaries, oxygen radical production in the rat pulmonary circulation, and plasma C3a (desArg) were all lower in the NM group than in the Et group. The leukocytes producing oxygen radicals were confirmed to be neutrophils by electron microscopic analysis of cerium deposition. We conclude that NM attenuates plasma C3a formation, neutrophil adherence to pulmonary capillaries, and their production of oxygen radical in rats infused with endotoxin.

ISSN:1073-2322    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

We have recently identified the &agr;-chemokinemob-1as a highly inducible gene in several rat models of microvascular lung injury, whose expression was suppressed by inhibition of tumor necrosis factor-&agr; (TNF-&agr;). This work provides further insight into the relationship betweenmob-1and TNF-&agr; in the development of lung injury assessed by pulmonary edema and leukosequestration. First, pulmonarymob-1and TNF-&agr; were upregulated in animals subjected to lung injury produced by the intratracheal administration of recombinant TNF-&agr; and recombinantmob-1, respectively. Second,mob-1inhibition by intratracheal anti-mob-1antibody attenuated lung injury induced by recombinant TNF-&agr;. Third, pretreatment with anti-TNF-&agr; monoclonal antibody administered intratracheally abrogated recombinantmob-1-induced microvascular lung injury.In vitro,mob-1and TNF-&agr; increased each other's production in RAW 264.7 cells andmob-1or TNF-&agr; inhibition prevented endotoxin-induced upregulation of TNF-&agr; ormob-1, respectively, from these cells. Together, these data suggest thatmob-1and TNF-&agr; interact to promote lung inflammation.

ISSN:1073-2322    

出版商:OVID    

年代:2002

数据来源: OVID