Amorphous Silicon Thin-Film Solar Cells on Fabrics as Large-Scale Detectors for Textile Personal Protective Equipment in Active Laser Safety.

Laser safety is starting to play an increasingly important role, especially when the laser is used as a tool. Passive laser safety systems quickly reach their limits and, in some cases, provide inadequate protection. To counteract this, various active systems have been developed. Flexible and especially textile-protective materials pose a special challenge. The market still lacks personal protective equipment (PPE) for active laser safety. Covering these materials with solar cells as large-area optical detectors offers a promising possibility. In this work, an active laser protection fabric with amorphous silicon solar cells is presented as a large-scale sensor for continuous wave and pulsed lasers (down to ns). First, the fabric and the solar cells were examined separately for irradiation behavior and damage. Laser irradiation was performed at wavelengths of 245, 355, 532, and 808 nm. The solar cell sensors were then applied directly to the laser protection fabric. The damage and destruction behavior of the active laser protection system was investigated. The results show that the basic safety function of the solar cell is still preserved when the locally damaged or destroyed area is irradiated again. A simple automatic shutdown system was used to demonstrate active laser protection within 50 ms.

Early complementopathy after multiple injuries in humans.

After severe tissue injury, innate immunity mounts a robust systemic inflammatory response. However, little is known about the immediate impact of multiple trauma on early complement function in humans. In the present study, we hypothesized that multiple trauma results in immediate activation, consumption, and dysfunction of the complement cascade and that the resulting severe "complementopathy" may be associated with morbidity and mortality. Therefore, a prospective multicenter study with 25 healthy volunteers and 40 polytrauma patients (mean injury severity score = 30.3 ± 2.9) was performed. After polytrauma, serum was collected as early as possible at the scene, on admission to the emergency room (ER), and 4, 12, 24, 120, and 240 h post-trauma and analyzed for the complement profile. Complement hemolytic activity (CH-50) was massively reduced within the first 24 h after injury, recovered only 5 days after trauma, and discriminated between lethal and nonlethal 28-day outcome. Serum levels of the complement activation products C3a and C5a were significantly elevated throughout the entire observation period and correlated with the severity of traumatic brain injury and survival. The soluble terminal complement complex SC5b-9 and mannose-binding lectin showed a biphasic response after trauma. Key fluid-phase inhibitors of complement, such as C4b-binding protein and factor I, were significantly diminished early after trauma. The present data indicate an almost synchronical rapid activation and dysfunction of complement, suggesting a trauma-induced complementopathy early after injury. These events may participate in the impairment of the innate immune response observed after severe trauma.

Is the function of alveolar macrophages altered following blunt chest trauma?

PURPOSE: The purpose of this study was to characterize the local pulmonary inflammatory environment and to elucidate alterations of alveolar macrophage (AMØ) functions after blunt chest trauma. METHODS: Wistar rats were subjected to blunt chest trauma. AMØ were isolated, stimulated, and cultured. Bronchoalveolar lavage (BAL) was collected. Cytokines/chemokines were quantified in the BAL and in AMØ supernatants via ELISA. AMØ phagocytic and chemotactic activity and respiratory burst capacity were assessed. RESULTS: Following chest trauma, a significant increase of IL-1ß (at 6 and 24 h) and IL-6 (at 24 h) in BAL was observed, whereas IL-10 and TNF-α concentrations were not altered. MIP-2 and CINC were substantially increased as early as 6 h and PGE2 early at 10 min, whereas BAL MCP-1 was not elevated until 24 h after trauma. MIP-2 release by AMØ isolated form trauma animals was markedly increased as early as 10 min after injury. IL-1ß and IL-10 exhibited a late increase at 24 h. AMØ TNF-α release was increased at 6 h. At 6 or 24 h, AMØ from trauma animals incorporated significantly more opsonized latex beads than their sham controls, and their chemotactic activity was substantially enhanced at 24 h. AMØ oxidative burst capacity remained largely unchanged. CONCLUSIONS: Already very early after chest trauma, inflammatory mediators are present in the intraalveolar compartment. Additionally, AMØ are primed to release cytokines and chemokines. Blunt chest trauma also changes the phagocytic and chemotactic activity of AMØ. These functional changes of AMØ might enable them to better ward off potential pathogens in the course after trauma.

Inflammatory alterations in a novel combination model of blunt chest trauma and hemorrhagic shock.

BACKGROUND: Chest trauma frequently occurs in severely injured patients and is often associated with hemorrhagic shock. Immune dysfunction contributes to the adverse outcome of multiple injuries. The aims of this study were to establish a combined model of lung contusion and hemorrhage and to evaluate the cardiopulmonary and immunologic response. METHODS: Male mice were subjected to sham procedure, chest trauma, hemorrhage (35 mm Hg±5 mm Hg, 60 minutes), or the combination. Respiratory rate, heart rate, and blood pressure were monitored. Plasma, Kupffer cells, blood monocytes, splenocytes, and splenic macrophages were isolated after 20 hours. Tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, 10, 12, 18, and macrophage inflammatory protein-2 levels in plasma and culture supernatants were determined. RESULTS: Heart rate and blood pressure dropped in all groups, and after chest trauma and the double hit, these values remained reduced until the end of observation. Blood pressure was lower after the double hit than after the single hits. Plasma and Kupffer cell TNF-α concentrations were increased after lung contusion but not further enhanced by subsequent hemorrhage. Peripheral blood mononuclear cell (PBMC) TNF-α and IL-6 release were suppressed after the combined insult. IL-18 concentrations were increased in PBMC supernatants after chest trauma and in splenic macrophage supernatants of all groups. CONCLUSIONS: Although physiologic readouts were selectively altered in response to the single or double hits, the combination did not uniformly augment the changes in inflammation. Our results suggest that the leading insult regarding the immunologic response is lung contusion, supporting the concept that lung contusion represents an important prognostic factor in multiple injuries.

Molecular intercommunication between the complement and coagulation systems.

The complement system as well as the coagulation system has fundamental clinical implications in the context of life-threatening tissue injury and inflammation. Associations between both cascades have been proposed, but the precise molecular mechanisms remain unknown. The current study reports multiple links for various factors of the coagulation and fibrinolysis cascades with the central complement components C3 and C5 in vitro and ex vivo. Thrombin, human coagulation factors (F) XIa, Xa, and IXa, and plasmin were all found to effectively cleave C3 and C5. Mass spectrometric analyses identified the cleavage products as C3a and C5a, displaying identical molecular weights as the native anaphylatoxins C3a and C5a. Cleavage products also exhibited robust chemoattraction of human mast cells and neutrophils, respectively. Enzymatic activity for C3 cleavage by the investigated clotting and fibrinolysis factors is defined in the following order: FXa > plasmin > thrombin > FIXa > FXIa > control. Furthermore, FXa-induced cleavage of C3 was significantly suppressed in the presence of the selective FXa inhibitors fondaparinux and enoxaparin in a concentration-dependent manner. Addition of FXa to human serum or plasma activated complement ex vivo, represented by the generation of C3a, C5a, and the terminal complement complex, and decreased complement hemolytic serum activity that defines exact serum concentration that results in complement-mediated lysis of 50% of sensitized sheep erythrocytes. Furthermore, in plasma from patients with multiple injuries (n = 12), a very early appearance and correlation of coagulation (thrombin-antithrombin complexes) and the complement activation product C5a was found. The present data suggest that coagulation/fibrinolysis proteases may act as natural C3 and C5 convertases, generating biologically active anaphylatoxins, linking both cascades via multiple direct interactions in terms of a complex serine protease system.

Interaction between the coagulation and complement system.

The complement system as a main column of innate immunity and the coagulation system as a main column in hemostasis undergo massive activation early after injury. Interactions between the two cascades have often been proposed but the precise molecular pathways of this interplay are still in the dark. To elucidate the mechanisms involved, the effects of various coagulation factors on complement activation and generation of anaphylatoxins were investigated and summarized in the light of the latest literature. Own in vitro findings suggest, that the coagulation factors FXa, FXIa and plasmin may cleave both C5 and C3, and robustly generate C5a and C3a (as detected by immunoblotting and ELISA). The produced anaphylatoxins were found to be biologically active as shown by a dose-dependent chemotactic response of neutrophils and HMC-1 cells, respectively. Thrombin did not only cleave C5 (Huber-Lang et al. 2006) but also in vitro-generated C3a when incubated with native C3. The plasmin-induced cleavage activity could be dose-dependently blocked by the serine protease inhibitor aprotinin and leupeptine. These findings suggest that various serine proteases belonging to the coagulation system are able to activate the complement cascade independently of the established pathways. Moreover, functional C5a and C3a are generated, both of which are known to be crucially involved in the inflammatory response.

Erythropoietin during porcine aortic balloon occlusion-induced ischemia/reperfusion injury.

BACKGROUND: Aortic occlusion causes ischemia/reperfusion injury, kidney and spinal cord being the most vulnerable organs. Erythropoietin improved ischemia/reperfusion injury in rodents, which, however, better tolerate ischemia/reperfusion than larger species. Therefore, we investigated whether erythropoietin attenuates porcine aortic occlusion ischemia/reperfusion injury. MATERIALS AND METHODS: Before occluding the aorta for 45 mins by inflating intravascular balloons, we randomly infused either erythropoietin (n = 8; 300 IU/kg each over 30 mins before and during the first 4 hrs of reperfusion) or vehicle (n = 6). During aortic occlusion, mean arterial pressure was maintained at 80% to 120% of baseline by esmolol, nitroglycerine, and adenosine 5'-triphosphate. During reperfusion, noradrenaline was titrated to keep mean arterial pressure >80% of baseline. Kidney perfusion and function were assessed by fractional Na-excretion, p-aminohippuric acid and creatinine clearance, spinal cord function by lower extremity reflexes and motor evoked potentials. Blood isoprostane levels as well as blood and tissue catalase and superoxide dismutase activities allowed evaluation of oxidative stress. After 8 hrs of reperfusion, kidney and spinal cord specimens were taken for histology (hematoxylin-eosin, Nissl staining) and immunohistochemistry (TUNEL assay for apoptosis). RESULTS: Parameters of oxidative stress and antioxidative activity were comparable. Erythropoietin reduced the noradrenaline requirements to achieve the hemodynamic targets and may improve kidney function despite similar organ blood flow, histology, and TUNEL staining. Neuronal damage and apoptosis was attenuated in the thoracic spinal cord segments without improvement of its function. CONCLUSION: During porcine aortic occlusion-induced ischemia/reperfusion erythropoietin improved kidney function and spinal cord integrity. The lacking effect on spinal cord function was most likely the result of the pronounced neuronal damage associated with the longlasting ischemia.

Effects of intrarenal administration of the calcium antagonist nimodipine during porcine aortic occlusion-induced ischemia/reperfusion injury.

Ca++ antagonists have been tested to improve I/R injury in the kidney, but their clinical use is limited due to their hypotensive properties. Therefore, we tested the hypothesis on whether infusing the Ca++ blocker nimodipine directly into the renal artery would reduce kidney cell apoptosis and thus improve organ function in a porcine model of suprarenal abdominal aortic cross-clamping. In a prospective, randomized, controlled, blinded study, anesthetized, mechanically ventilated, and instrumented pigs underwent 45 min of suprarenal aortic cross-clamping animals receiving either 0.25 microg kg(-1) min(-1) nimodipine (n = 8) or vehicle (n = 8). Systemic and right kidney hemodynamics, oxygen exchange, and metabolism were assessed before clamping, as well as before and at 75 and 195 min of reperfusion (i.e., at 120 and 240 min after aortic occlusion). At the end of the experiments, the right kidney was harvested for conventional hematoxylineosin staining and immunohistochemistry for the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) gene expression and apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin end labeling test). Neither systemic nor renal hemodynamics and oxygen exchange, plasma and urine protein concentrations, urine osmolarity, and lactate-pyruvate ratios showed any intergroup difference. Nimodipine infusion resulted in a significantly higher creatinine clearance after 195 min of reperfusion (26 [17 - 42] vs. 17 [9 - 22] mL x min(-1)) and attenuated renal tubular damage, as indicated by lower urinary small protein (25 kd) concentrations. Improved renal function was concomitant with significantly less pronounced positive nuclear terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin end labeling staining. In a porcine model of suprarenal aortic cross-clamping, intrarenal nimodipine infusion improved postischemia kidney function, most likely as a result of attenuated glomerular apoptosis.

Effects of a cantaloupe melon extract/wheat gliadin biopolymer during aortic cross-clamping.

OBJECTIVE: We previously reported in healthy volunteers that a cantaloupe melon extract chemically combined with wheat gliadin (melon extract/gliadin) and containing SOD, catalase and residual glutathione peroxidase (GPx), protected against DNA strand-break damage induced by hyperbaric oxygen (HBO), a well-established model of DNA damage resulting from oxidative stress. Aortic cross-clamping is a typical example of ischemia/reperfusion injury-related oxidative stress, and therefore we investigated whether this melon extract/gliadin would also reduce DNA damage after aortic cross-clamping and reperfusion. DESIGN: Prospective, randomized, controlled experimental study. SETTING: Animal laboratory. PATIENTS AND PARTICIPANTS: 18 anesthetized, mechanically ventilated and instrumented pigs. INTERVENTIONS: After 14 days of oral administration of 1250 mg of the melon extract/gliadin (n=9) or vehicle (n=9), animals underwent 30 min of thoracic aortic cross-clamping and 4 h of reperfusion. MEASUREMENTS AND RESULTS: Before clamping, immediately before declamping, and at 2 and 4 h of reperfusion, we measured blood isoprostane (immunoassay) and malondialdehyde concentrations (fluorimetric thiobarbituric acid test), SOD, catalase and GPx activities (spectrophotometric kits), NO formation (nitrate+nitrite; chemoluminescence), DNA damage in whole blood samples and isolated lymphocytes exposed to hyperbaric oxygen (comet assay). Organ function was also evaluated. Kidney and spinal cord specimen were analysed for apoptosis (TUNEL assay). The melon extract/gliadin blunted the DNA damage, reduced spinal cord apoptosis and attenuated NO release, however, without any effect on lipid peroxidation and organ function. CONCLUSIONS: Pre-treatment with the oral melon extract/gliadin may be a therapeutic option to reduce oxidative cell injury affiliated with aortic cross-clamping.

The parp-1 inhibitor ino-1001 facilitates hemodynamic stabilization without affecting DNA repair in porcine thoracic aortic cross-clamping-induced ischemia/reperfusion.

Inhibition of poly (ADP-ribose) polymerase 1 (PARP-1) improved hemodynamics and organ function in various shock models induced by sepsis or ischemia/reperfusion. PARP-1, however, is also referred to play a pivotal role for the maintenance of genomic integrity. Therefore, we investigated the effect of the PARP-1 blocker INO-1001 on hemodynamics, kidney function, and DNA damage and repair during porcine thoracic aortic cross-clamping. The animals underwent 45 min of aortic cross-clamping after receiving vehicle (n=9) or i.v. INO-1001 (n=9; total dose, 4 mg.kg, administered both before clamping and during reperfusion), data were recorded before clamping, before declamping, and 2 and 4 h after declamping. During reperfusion, continuous i.v. norepinephrine was incrementally adjusted to maintain blood pressure greater than or equal to 80% of the pre-clamping level. The plasma INO-1001 levels analyzed with high-pressure liquid chromatography were 1 to 1.4 micromol/L and 0.4 to 0.6 micromol/L before and after clamping, respectively. Although INO-1001-treated animals required less norepinephrine support, kidney function was comparable in the 2 groups. There was no intergroup difference either in the time course of DNA damage and repair (comet assay) as assessed both in vivo in whole blood before surgery, before clamping, before declamping, 2 h after declamping, and ex vivo in isolated lymphocytes (Ficoll gradient) sampled immediately before clamping and analyzed before, immediately, and 1 and 2 h after exposure to 4 bar 100% O2 for 2 h. There was no difference either in the expression of the cyclin-dependent kinase inhibitor gene, p27, in the kidney (immunohistochemistry). The reduced norepinephrine requirements during reperfusion suggest a positive inotropic effect of INO-1001, as demonstrated by other authors. In our model, INO-1001 proved to be safe with respect to DNA repair.

Effects of 15-deoxy-Delta12,14-prostaglandin-J2 during hyperdynamic porcine endotoxemia.

OBJECTIVE: To investigate the hemodynamic and metabolic effects of the peroxisome proliferator-activated receptor (PPAR)-gamma ligand and nuclear-factor (NF)-kappa B inhibitor 15-deoxy-Delta12,14-prostaglandin-J2 (15d-PGJ2) during long-term, hyperdynamic porcine endotoxemia. DESIGN: Prospective, randomized, controlled experimental study with repeated measures. SETTING: Investigational animal laboratory. SUBJECTS: 19 anesthetized, mechanically ventilated and instrumented pigs. INTERVENTIONS: At 12 h of continuous intravenous endotoxin and hydroxyethylstarch to keep mean arterial pressure (MAP)>60 mmHg, swine randomly received vehicle (control group, n=10) or 15-deoxy-Delta12,14-prostaglandin-J2 (15d-PGJ2 group, n=9; 1 microg kg(-1) min(-1) loading dose during 1 h; thereafter,0.25 microg kg(-1) min(-1) for 11 h). MEASUREMENTS AND RESULTS: Hemodynamic, metabolic and organ function parameters were assessed together with parameters of nitric oxide production and oxidative stress. 15d-PGJ2 prevented the endotoxin-induced progressive hypotension, due to a positive inotropic effect, which resulted in a significantly higher blood pressure during the treatment phase and prevented the rise in hepatic vein alanine-aminotransferase activity. It did not affect, however, any other parameter of organ function nor of nitric oxide production, proinflammatory cytokine release or lipid peroxidation (8-isoprostane). CONCLUSIONS: 15d-PGJ2 stabilized systemic hemodynamics, due to improved myocardial performance, and resulted in an only transient effect on alanine-aminotransferase activity, without further beneficial effect on endotoxin-induced metabolic and organ function derangements. Low tissue 15d-PGJ2 concentrations and/or the delayed drug administration may explain these findings.

The pulmonary and hepatic immune microenvironment and its contribution to the early systemic inflammation following blunt chest trauma.

OBJECTIVE: Blunt chest trauma is accompanied by an early increase in plasma cytokine concentrations. However, the local sources of these mediators are poorly defined. We investigated the impact of blunt chest trauma on the inflammatory mediator milieu in different compartments (lung tissue, bronchoalveolar lavage, liver tissue, Kupffer cells, plasma) along with the time course of trauma-induced pulmonary endothelial barrier dysfunction to elucidate potential relationships. In addition, the correlation between intratracheally instilled interleukin-6 and its systemic release were studied. DESIGN: Prospective, randomized, controlled animal study. SETTING: Basic science laboratory of a university affiliated level 1 trauma center. SUBJECTS: Male C3H/HeN mice, 8-9 wks old, n = 141. INTERVENTIONS: Blunt chest trauma induced by a focused blast wave, intravenous injection of Evans blue, and intratracheal instillation of recombinant human interleukin-6. MEASUREMENTS AND MAIN RESULTS: Two hours after blunt chest trauma, plasma interleukin-6 was markedly increased. Simultaneously, interleukin-6, tumor necrosis factor-alpha, macrophage inflammatory protein-2, monocyte chemotactic polypeptide-1 and neutrophil/monocyte accumulation in bronchoalveolar lavage and interleukin-6, monocyte chemotactic polypeptide-1, and myeloperoxidase activity in lung tissue were significantly increased. This was accompanied by a coinciding elevation in the Evans blue lung-plasma ratio. Recombinant human interleukin-6, instilled intratracheally before blunt chest trauma, was detected in a dose-dependent manner in the plasma of the mice. Additionally, Kupffer cell interleukin-6, tumor necrosis factor-alpha, and interleukin-10 production was significantly augmented as early as 30 mins after the insult. CONCLUSIONS: These results indicate that early increased cytokine concentrations in the lung, particularly interleukin-6, are important mediator sources as their local peak coincides with the systemic inflammatory response and is accompanied by a simultaneous impaired function of the pulmonary endothelial barrier. A direct relationship between their local and systemic concentrations can be established. Furthermore, this is the first study to show that Kupffer cells are activated early after blunt chest trauma.

MAPkinase gene expression, as determined by microarray analysis, distinguishes uncomplicated from complicated reconstitution after major surgical trauma.

Microarray expression analysis was performed in patients with major surgical trauma to identify signaling pathways which may be indicative for complicated versus uneventful reconstitution post trauma. In addition to a generalized upregulation of nonspecific stress response genes in all patients, a remarkable number of differences in gene expression patterns were found in individual patients. Some of the differing genes were associated with uncomplicated convalescence such as upregulation of both the ERK5 pathway (MAPK7 [mitogen-activated protein kinase-7]) and transcription factors which stimulate hematopoiesis and tissue reconstitution (MEF2, BMP-2, TNFRSF11A [RANK], and RUNX-1). Chemokine genes active in stem cell recruitment from the bone marrow as well as dendritic cell and natural killer (NK) cell maturation (SCYA14 [HCC-1]), and activators of the lymphoid compartment (TNFRSF7 [CD27], CD3zeta and perforin [PRF1]) were increased. In contrast, all these transcripts were downregulated in complicated reconstitution and later development of septic shock. Moreover, p38 kinase (MAPK14), S100 molecules, and members of the lipoxygenase pathway were associated with a more eventful outcome. Microarray expression studies are a promising tool for screening and then selecting differentially regulated genes in favorable as compared to complicated reconstitution post trauma.

Effects of intrarenal administration of the cox-2 inhibitor parecoxib during porcine suprarenal aortic cross-clamping.

The aim of this study was to investigate the effects of intrarenal administration of the cyclooxygenase-2 inhibitor parecoxib during suprarenal aortic cross-clamping. In a prospective, controlled, blinded, randomized manner, 16 anesthetized and mechanically ventilated pigs were instrumented to measure systemic and right kidney hemodynamics, oxygen exchange, and metabolism. During 45 min of suprarenal aortic cross-clamping, animals received 40 mg of parecoxib (n = 8) or vehicle (n = 8) infused continuously into the right renal artery. Hemodynamic and metabolic data, right kidney venous blood, as well as urine samples were obtained before clamping, as well as before and 75 and 195 min after declamping. Clamping transiently increased mean arterial pressure in both groups. Systemic and renal blood flow did not differ between the pre- and postclamping measurements or between groups. Parecoxib attenuated the otherwise significant fall in right kidney creatinine clearance (controls: from 45 [7;111] to 17 [9;22] mL/min; parecoxib: from 39 [3;59] to 27 [11;45] mL/min, P = 0.039 and P = 0.297, respectively versus before clamping, P = 0.021 versus controls at 195 min) and prevented the impairment of renal lactate balance observed in the control group (controls: from 0.5 [-0.8;3.5] to 0.2 [-0.2;0.6] mumol/kg/min; parecoxib: from 0.6 [-1.0;2.0] to 0.4 [-1.2;0.6] mumol/kg/min, P = 0.038 and P = 0.285, respectively, versus before clamping). In conclusion, intrarenal parecoxib infusion beneficially influenced kidney function in this clinically relevant model of suprarenal aortic cross-clamping.

Ethyl pyruvate improves systemic and hepatosplanchnic hemodynamics and prevents lipid peroxidation in a porcine model of resuscitated hyperdynamic endotoxemia.

OBJECTIVE: To investigate the systemic, pulmonary, and hepatosplanchnic hemodynamic and metabolic effects of delayed treatment with ethyl pyruvate in a long-term porcine model of hyperdynamic endotoxemia. DESIGN: Prospective, randomized, controlled experimental study with repeated measures. SETTING: Investigational animal laboratory. SUBJECTS: Anesthetized, mechanically ventilated, and instrumented pigs. INTERVENTIONS: After 12 hrs of continuous infusion of lipopolysaccharide and hydroxyethyl starch to keep mean arterial pressure >60 mm Hg, swine randomly received placebo (Ringer's solution; control group, n = 11) or ethyl pyruvate in lactated Ringer's solution (n = 8; 0.03 g.kg(-1) loading dose over 10 mins, thereafter 0.03 g.kg(-1)hr(-1) for 12 hrs). MEASUREMENTS AND MAIN RESULTS: Whereas mean arterial pressure significantly decreased in control animals, mean arterial pressure was maintained at the baseline level in pigs treated with ethyl pyruvate. Global oxygen uptake was comparable, so that the trend toward a higher oxygen transport and the significantly higher mixed venous hemoglobin oxygen saturation resulted in a significantly lower oxygen extraction in the ethyl pyruvate group. Ethyl pyruvate reduced intrapulmonary venous admixture and resulted in significantly greater Pa(O2)/F(IO2) ratios. Despite comparable urine production in the two groups during the first 18 hrs of endotoxemia, ethyl pyruvate significantly increased diuresis during the last 6 hrs of the study. Lipopolysaccharide-induced systemic and regional venous metabolic acidosis was significantly ameliorated by ethyl pyruvate. Endotoxemia increased both blood nitrate + nitrite and isoprostane concentrations, and ethyl pyruvate attenuated the response of these markers of nitric oxide production and lipid peroxidation. CONCLUSIONS: Ethyl pyruvate infusion resulted in improved hemodynamic stability and ameliorated acid-base derangements induced by chronic endotoxemia in pigs. Reduced oxidative stress and an decreased nitric oxide release probably contributed to these effects.

Pulmonary contusion causes impairment of macrophage and lymphocyte immune functions and increases mortality associated with a subsequent septic challenge.

OBJECTIVE AND DESIGN: Pulmonary contusion is frequently followed by acute respiratory distress syndrome, pneumonia, and sepsis. However, immunologic alterations of circulating and resident immune cell populations contributing to the posttraumatic immunosuppression are poorly understood. We therefore characterized the influence of pulmonary contusion on peripheral blood mononuclear cells, peritoneal macrophages, splenocytes, and splenic macrophages. To address the significance of the immunosuppression associated with lung contusion, we investigated how the consecutive addition of moderate or severe sepsis affected survival after blunt chest trauma. SUBJECTS: Male C3H/HeN mice (n = 10 per group) were anesthetized and subjected to chest trauma or sham procedure. MEASUREMENTS: The cytokine release of cultured peripheral blood mononuclear cells, peritoneal macrophages, splenocytes, and splenic macrophages and plasma levels of tumor necrosis factor-alpha and interleukin-6 from those animals were quantified. Sepsis was induced via cecal ligation and puncture 24 hrs after lung contusion. MAIN RESULTS: Two hours after blunt chest trauma, plasma tumor necrosis factor-alpha and interleukin-6 were markedly increased, as was peripheral blood mononuclear cell cytokine production, lung myeloperoxidase activity, and lung chemokine concentrations. At 24 hrs and, in part, already at 2 hrs, cytokine release from peritoneal macrophages, splenic macrophages, and splenocytes was significantly suppressed. Furthermore, pulmonary contusion when followed by moderate sepsis significantly diminished survival rate when compared with chest trauma or moderate sepsis alone. CONCLUSIONS: These results indicate that pulmonary contusion causes severe immunodysfunction of splenocytes, macrophages, and monocytes in different local compartments and systemically. Moreover, this immunosuppression is associated with an increased susceptibility to infectious complications, which results in a decreased survival rate if blunt chest trauma is followed by a septic insult.

Low-dose terlipressin during long-term hyperdynamic porcine endotoxemia: effects on hepatosplanchnic perfusion, oxygen exchange, and metabolism.

OBJECTIVE: To investigate whether the vasopressin analog terlipressin might induce hepatosplanchnic ischemia during long-term, hyperdynamic, volume-resuscitated porcine endotoxemia. DESIGN: Prospective, randomized, controlled experimental study with repeated measures. SETTING: Investigational animal laboratory. SUBJECTS: Eighteen pigs were divided into two groups receiving either endotoxin alone (control group, n = 10) or endotoxin and terlipressin (n = 8). INTERVENTIONS: Pigs were anesthetized, mechanically ventilated, and instrumented and received a continuous intravenous infusion of Escherichia coli endotoxin. Animals were resuscitated with hydroxyethyl starch targeted to maintain mean arterial pressure >60 mm Hg. Twelve hours after the start of the endotoxin infusion, terlipressin (5-15 microg.kg.hr titrated to maintain mean arterial pressure at preendotoxin levels) or its vehicle was administered for 12 hrs. MEASUREMENTS AND MAIN RESULTS: Terlipressin increased mean arterial pressure and systemic vascular resistances, which was affiliated with a decrease in cardiac output and global oxygen consumption. Terlipressin restored the hepatic artery buffer response, which led to an increase in hepatic artery flow, ultimately resulting in well-maintained liver oxygen delivery, oxygen uptake, and all other variables of regional metabolism and organ function. Terlipressin markedly attenuated the hepatosplanchnic venous acidosis but was associated with pronounced hyperlactatemia. CONCLUSIONS: During long-term hyperdynamic porcine endotoxemia, the well-known vasoconstrictor properties of terlipressin blunted the progressive decrease in mean arterial pressure without any detrimental effect on hepatosplanchnic perfusion, oxygen exchange, and metabolism. The marked terlipressin-induced hyperlactatemia did not originate from the hepatosplanchnic organs but from extrasplanchnic tissues, possibly muscle and skin.

Changes in the novel orphan, C5a receptor (C5L2), during experimental sepsis and sepsis in humans.

Sepsis is associated with extensive complement activation, compromising innate immune defenses, especially in neutrophils (PMN). Recently, a second C5a receptor (C5L2) was detected on PMN without evidence of intracellular signaling. The current study was designed to determine changes in C5L2 in blood PMN during sepsis. In vitro exposure of PMN to C5a, but not to fMLP, led to reduced content of C5L2. Following cecal ligation and puncture-induced sepsis in rats, PMN demonstrated a time-dependent decrease in C5L2. In vivo blockade of C5a during experimental sepsis resulted in preservation of C5L2. Similarly, PMN from patients with progressive sepsis showed significantly reduced C5L2 expression (n = 26), which was virtually abolished in patients who developed multiorgan failure (n = 10). In contrast, sepsis survivors exhibited retention of C5L2 (n = 12/13). The data suggest that C5L2 on PMN diminishes during sepsis due to systemic generation of C5a, which is associated with a poor prognosis.

Blunt chest trauma induces delayed splenic immunosuppression.

Severe blunt chest trauma is frequently associated with multiple organ failure and sepsis. Posttraumatic immunosuppression seems to play a major role in their development. However, the immunologic alterations following pulmonary contusion are insufficiently elucidated. Specifically, it remains unknown whether immunocompetent cells located distant from the site of the impact are affected. We therefore aimed to characterize the influence of pulmonary contusion on lymphocytes and splenic macrophages. Male C3H/HeN mice (n = 8-10/group) were anesthetized and subjected to trauma or sham procedure. Blunt chest trauma was induced by a blast wave focused on the thorax. Two or 24 h later, splenocytes and splenic macrophages were isolated and stimulated for 48 h. The cytokine release (IFN-gamma, IL-2, IL-3, IL-10, IL-12, IL-18) from splenocytes as well as from splenic macrophages (TNF-alpha, IL-10, IL-12, IL-18) and plasma levels of TNF-alpha and IL-6 were quantified by ELISA. The results indicate that at 2 h after blunt chest trauma, plasma TNF-alpha and IL-6 were markedly increased. At the same time, no differences in splenocyte cytokine production were detectable. However, at 24 h a significantly depressed cytokine release was observed in trauma animals. Furthermore, splenic macrophages showed a significantly decreased production of TNF-alpha, IL-10, and IL-12 at 24 h and markedly increased release of IL-18 at 2 h after trauma. These results indicate that blunt chest trauma causes severe immunodysfunction of lymphocytes and splenic macrophages. Thus, lung contusion as a localized type of trauma causes dysfunction of immunocompetent cell populations, which are located distant from the site of injury.

HMR1402, a potassium ATP channel blocker during hyperdynamic porcine endotoxemia: effects on hepato-splanchnic oxygen exchange and metabolism.

OBJECTIVE: To assess the effects of the potassium ATP (KATP) channel blocker HMR1402 (HMR) on systemic and hepato-splanchnic hemodynamics, oxygen exchange and metabolism during hyperdynamic porcine endotoxemia. DESIGN: Prospective, randomized, controlled study with repeated measures. SETTING. Animal laboratory. SUBJECTS: Eighteen pigs allocated to receive endotoxin alone (control group, CON, n=10) or endotoxin and HMR (6 mg/kg h(-1), n=8). INTERVENTIONS: Anesthetized, mechanically ventilated, and instrumented pigs receiving continuous i.v. endotoxin were resuscitated with hetastarch to maintain mean arterial pressure (MAP) >60 mmHg. Twelve hours after starting the endotoxin infusion, they received HMR or its vehicle for another 12 h. RESULTS: HMR transiently increased MAP by about 15 mmHg, but this effect was only present during the first 1 h of infusion. The HMR decreased cardiac output due to a fall in heart rate, and thereby reduced liver blood flow. While liver O(2) delivery and uptake remained unchanged, HMR induced hyperlactatemia [from 1.5 (1.1; 2.0), 1.4 (1.2; 1.8), and 1.2 (0.8; 2.0) to 3.1 (1.4; 3.2), 3.2 (1.6; 6.5), and 3.0 (1.0; 5.5) mmol/l in the arterial, portal and hepatic venous samples, respectively] and further increased arterial [from 8 (3; 13) to 23 (11; 57); p<0.05], portal [from 9 (4; 14) to 23 (14; 39); p<0.05] and hepatic vein [from 7 (0; 15) to 30 (8; 174), p<0.05] lactate/pyruvate ratios indicating impaired cytosolic redox state. CONCLUSION: The short-term beneficial hemodynamic effects of KATP channel blockers have to be weighted with the detrimental effect on mitochondrial respiration.