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The influence of the transport mode, i.e. Helicopter Emergency Medical Service (HEMS) versus ground-based Emergency Medical Service (EMS) on the mortality of multiple trauma patients is still controversially discussed in the literature. In this study a total of 333 multiple trauma patients treated over a 1-year period in a level I trauma center in Switzerland were analyzed. Using the newly established revised injury severity classification (RISC) score there was a tendency towards a better outcome for patients transported by HEMS (standardized mortality ratio 1.06 for HEMS versus 1.29 for EMS). Overall a short preclinical time and the presence of an emergency physician (EP) were associated with a better outcome.

Objective: To characterize the impact of abdominal aortic aneurysm repair (AAAR) on spontaneous as well as lipopolysaccharide (LPS)-induced gene expression of pro- and anti-inflammatory cytokines. Design: Prospective, controlled in vivo / ex vivo study. Setting: University hospital. Patients and interventions: Whole blood from 14 consecutive patients undergoing AAAR withdrawn prior to surgery (T1), at the end of ischemia (T2), 90 min after declamping (T3) and on the first postoperative day (T4) was cultured in the absence or presence of LPS. Five patients undergoing elective inguinal hernia repair served as controls. Measurements and results: While tumor necrosis factor (TNF), Interleukin (IL)-1 and IL-10 plasma concentrations did not increase significantly, IL-6 was elevated at each time point, as compared with T1. Despite the spontaneous release of trace amounts of IL-6, the ability of cultured whole blood to mount a cytokine response in vitro to LPS was impaired for all cytokines studied at T2 (TNF –62 %, IL-1 –51 %, IL-6 –20 %, IL-10 –51 %). The stimulated IL-6 response was restored early after declamping (T3: + 56 %) and enhanced 1 day after operation (T4: + 144 %). In contrast, stimulated TNF and IL-1 responses remained depressed at T3 (TNF –48 %, IL-1 –64 %) and T4 (TNF –40 %, IL-1 –24 %). A biphasic pattern was observed for IL-10 with initial depression at T3 (-51 %) and restoration at T4 ( + 40 %). Among the different cytokines monitored, only impaired TNF responsiveness at early reperfusion (T3) correlated with the postoperative course, as reflected by APACHE II. Cytokine response to LPS was maintained or even increased during and after surgery in the whole blood from patients undergoing hernia repair. Conclusions: Despite consistent development of clinical signs of systemic inflammatory response syndrome (SIRS) and spontaneous release of IL-6 abdominal aortic aneurysm repair produces a state of impaired pro-inflammatory cytokine response upon a subsequent in vitro Gram-negative stimulus. This early impairment of TNF responsiveness seems to correlate with an unfavorable postoperative course.

Fragestellung: Die Untersuchung des Einflusses von Gamma-Hydroxy-Buttersaure (GHB) auf die spontane und durch Lipopolysaccharid (LPS) induzierte Freisetzung der Zytokine Tumor-Nekrose-Faktor alpha (TNF), Interleukin-1β (IL-1β), Interleukin-6 (IL-6) und Interleukin-10 (IL-10) bei aortokoronaren Bypassoperationen (ACB) unter Anwendung der extrakorporalen Zirkulation (EKZ) sowie die Charakterisierung des pharmakologischen Effekts von GHB in 2 Praparationen (GHB-Na und GHB-Ethanolamid) auf die Lipopolysaccharid (LPS)-induzierte Zytokinfreisetzung in vitro. Methodik: In einer prospektiven, randomisierten Doppelblindstudie wurden insgesamt 12 Patienten untersucht, die sich einer elektiven ACB unterzogen. Je 6 Patienten erhielten intraoperativ entweder NaCl 0,9% (Kontrollgruppe) oder GHB-Na (25 mg/kg/h nach einem initialen Bolus von 25 mg/kg). Zu insgesamt 3 Meszeitpunkten (A=praoperativ, B=20 min nach EKZ, C=24 h postoperativ) erfolgte die Blutentnahme zur Zytokindiagnostik. Die Plasmakonzentrationen (spontane Freisetzung) und die unter LPS-Stimulation beobachtete Freisetzung der verschiedenen Zytokine zu den einzelnen Meszeitpunkten wurden in einem Vollblutansatz ex vivo gemessen und mit der m-RNA-Expression in peripheren mononuklearen Zellen (PBMC) korreliert. Weiterhin erfolgte in einem in vitro-Ansatz die Analyse des pharmakologischen Einflusses von GHB selbst (GHB-Na und GHB-Ethanolamid) auf die LPS-induzierte Zytokinfreisetzung. Ergebnisse: Die Plasmakonzentrationen von IL-6 und IL-10 waren nach Ende der EKZ in beiden Gruppen (Kontrolle und GHB) im Vergleich zum praoperativen Ausgangswert signifikant erhoht, wahrend TNF und IL-1β nur vereinzelt nachweisbar waren. Am Ende der EKZ war zu diesem Meszeitpunkt die durch LPS stimulierbare Freisetzung aller untersuchten Zytokine ex vivo signifikant gegenuber dem praoperativen Ausgangswert vermindert. Trotz besser erhaltener Stimulierbarkeit der Zytokin-m-RNA war auch bei den mit GHB behandelten Patienten die Ausschuttung der Zytokine ex vivo signifikant gehemmt. Am ersten postoperativen Tag war die stimulierbare Zytokinantwort im statistischen Mittel wieder hergestellt, wobei deutliche interindividuelle Unterschiede auftraten. In vitro (pharmakologischer Dosierungen) bewirkte GHB-Na (2 mg/ml) eine signifikante, selektive Verminderung der Freisetzung von IL-1β, wahrend GHB-Ethanolamid keinerlei Veranderungen der Zytokinantwort bewirkte. Zusatzlich hemmte der kompetitive GHB-Rezeptorantagonist NCS-382 die monozytare IL-1β-Antwort fast vollstandig auf 2,5% des Ausgangswerts ohne NCS. Schlusfolgerung: Die Ergebnisse der Freisetzung verschiedener pro- und antiinflammatorischer Zytokine bei ACB zeigen einen biphasichen Verlauf. Initial kommt es ex vivo zu einer relativen Suppression mit partieller Toleranz gegenuber LPS-Stimulation, die am ersten postoperativen Tag weitgehend uberwunden ist. Ob die pharmakologischen Effekte von GHB-Na und NCS-382 auf die IL-1β-Freisetzung monozytarer Zellen uber spezifische GHB-Rezeptoren vermittelt sind, mus aufgrund der diskrepanten Ergebnisse offen bleiben. GHB-Na bewirkt in klinisch ublichen Dosierungen im Vergleich zur Kontrollgruppe keine statistisch nachweisbare Modulation der Zytokinfreisetzung.

Heme oxygenase (HO) catalyzes the oxidative cleavage of the alpha-mesocarbon of Fe-protoporphyrin-IX yielding equimolar amounts of biliverdin-IXa, iron, and carbon monoxide. The HO-system consists of two isoenzymes, namely HO-2 and the inducible isoform HO-1, also referred to as heat shock protein (hsp) 32. Although both parenchymal and non-parenchymal liver cells participate in heme metabolism, the expression pattern of the isoenzymes in normal and stress exposed liver is unknown. To study this, rats underwent either endotoxin (lipopolysaccharide [LPS]) challenge, hemorrhagic hypotension, glutathione (GSH) depletion, or cobalt chloride injection, all known to provoke oxidative stress. HO-2 messenger RNA (mRNA) and protein were constitutively expressed in hepatocytes, Kupffer/endothelial-, and stellate (Ito-) cell enriched fractions. Although both non-parenchymal cell fractions expressed HO-1 transcripts, HO-1 immunoreactive protein was restricted to Kupffer cells in the normal liver. In contrast to HO-2, a significant increase in HO-1 on the whole organ level was noted by hemorrhagic hypotension, GSH depletion, and cobalt chloride injection. However, the distinct stress models led to a strikingly different cell-type specific and sublobular expression pattern of HO-1 gene expression. HO-1 was inducible in sinusoidal lining cells (hemorrhagic hypotension, LPS challenge), in periportal (cobalt chloride), or pericentral (GSH depletion, hemorrhagic hypotension) hepatocytes. The blockade of protein translation before hemorrhage by cycloheximide reduced upregulation of HO-1/hsp32 mRNA significantly (65.4% reduction, P < .05), whereas the inducibility of hsp70 transcript was maintained. In addition to transcriptional regulation, HO-1 seems to be subject to posttranscriptional control in particular in non-parenchymal cells.

In recent years, Gadolinium chloride (GdCl3), a rare earth metal, has frequently been used to study the role and function of Kupffer cells under physiological and pathological conditions. This study was performed to elucidate the consequences of GdCl3-induced Kupffer cell blockade for hepatic microcirculation, hepatocellular function and integrity.Using intravital fluorescence microscopy, we studied the hepatic microcirculation of rats pretreated with either GdCl3 (n = 12; 10 mg/kg; 1 ml i.v. for 2 d) or saline (n = 9; 1 ml). The GdCl3-treated animals revealed a significantly lower phagocytic activity of Kupffer cells when compared to controls. Concomitantly, GdCl3-treatment resulted in a pronounced rise of serum cytokine activity (tumor necrosis factor-alpha; interleukin-6). The hepatic microvascular perfusion was characterized by a moderate increase in the number of non-perfused sinusoids accompanied by a reduction of bile flow. In addition, GdCl3-treatment caused a slight increase in liver enzyme activity (200 U/l) (aspartate aminotransferase and alanine aminotransferase) with no substantial parenchymal tissue injury (light microscopy). The groups did not differ in concentrations of circulating endotoxin (GdCl3-treatment: 0.044 +/- 0.042 ng/ml; controls: 0.052 +/- 0.014 ng/ml).We conclude that hepatic alterations following Kupffer cell blockade with GdCl3 may possibly be the consequence of cytokine release as a response to the phagocytic challenge of GdCl3-aggregates. If used for Kupffer cell blockade, the hepatic alterations following GdCl3-treatment described in the present study should be taken into consideration.

Spinal metastases are a common concomitant phenomenon of advanced tumor disease. Beside the lung and liver, the spine is the third most common localization of manifestation. Apart from chronic and increasing pain, spinal metastases lead to neurological deficits due to destruction of the vertebral body and subsequent epidural growth expansion. The aim of a surgical treatment is the reduction of pain and the maintenance of neurological function as well as spine stability. The indication for surgery should be determined individually in an interdisciplinary consultation. The purpose of this article was to provide a brief overview regarding diagnostics and therapy of metastatic spine tumors.

The management of tibial plateau fractures can be challenging because of the scarcity of soft tissue associated with a high rate of wound healing disorders. Classic open reduction and internal plate fixation require extensive soft tissue dissection and periosteal stripping, and elevation of depressed fragments and maintenance of the reduction is difficult. In the current report the authors describe a novel operative approach to percutaneously reduce depressed tibial plateau fractures using an inflatable balloon in combination with minimally invasive plate fixation. The results of the first 5 cases treated with this technique are reported.

Osteoporotic fractures most frequently first occur in the axial skeleton, especially in the vertebral bodies of the thoracolumbar transition. Beside pain, these fractures cause increasing kyphosis leading to changes in statics and a shift of the bodies' center of gravity. This results in physiological, functional as well as neurological consequences that cannot be managed by means of a conservative therapy. The purpose of this article is to provide a brief overview on diagnostics and therapy of such fractures. Furthermore, fractures of the pubic rami need to be mentioned. They pose another frequent location for osteoporotic fractures and are also associated with a high rate of morbidity and mortality.

Delayed splenic injuries are rare but nevertheless well known and very dangerous complications after blunt abdominal trauma. The highest incidence is reported between four and eight days after trauma; however some cases with a latent period of weeks have been published. We present a case of delayed splenic rupture 13 days after trauma where most computed tomography (CT) examinations were interpreted as normal and present a review of the pathophysiology of delayed rupture, diagnosis and therapy.

In hohen Dosierungen hemmt niedermolekulares Heparin die Osteoblastenproliferation sowie die Expression von Osteocalcin und Cbfa-1 in vitro. Der bislang ungeklarte Mechanismus der Heparininduzierten Osteoporose scheint somit eine gestorte Osteoblastendifferenzierung zu beinhalten. Fondaparinux zeigt in vitro keine Beeinflussung der Osteoblastenproliferation und Differenzierung. Eine mogliche Erklarung ist die in vivo gegenuber Heparin deutlich verminderte Proteinbindungsfahigkeit von Fondaparinux. Parallel zum verminderten Risiko einer Thrombozytopenie scheint Fondaparinux auch keine Wirkung auf das Knochen-Remodelling zu haben.

Background The prolonged administration of heparin for prevention and treatment of venous thromboembolism has been associated with a risk of heparin-induced osteoporosis. Fondaparinux is a new antithrombotic drug that specifically inhibits factor Xa. Because of the known interactions of other antithrombotic agents with bone remodelling, the effects of fondaparinux on human osteoblasts were analysed in vitro. Methods Primary human osteoblast cell cultures were incubated with either the low molecular weight heparin dalteparin at concentrations of 30, 300 and 900 µg/ml or with fondaparinux at concentrations of 25, 50, 100, 150, 200 and 250 µg/ml. Cellular proliferation rate and protein synthesis were measured. Expression of genes encoding osteocalcin, collagen type I and alkaline phosphatase was examined by reverse transcriptase–polymerase chain reaction. Results Incubation with dalteparin led to a significant, dose-dependent inhibition of osteoblast proliferation, inhibition of protein synthesis, and inhibited expression of phenotype markers (osteocalcin and alkaline phosphatase genes) after 3 and 7 days. No inhibitory effects were observed in the fondaparinux-treated cells. Conclusion Fondaparinux did not inhibit osteoblast proliferation in vitro and may reduce the risk of heparin-induced osteoporosis associated with long-term heparin administration.

In endotoxin-exposed rat livers, G-CSF caused a reduction of CINC gene transcripts in the nonparenchymal cell fraction, which might be the mechanism for attenuation of microvascular leukocyte adherence and leukocyte-dependent tissue injury, as observed upon G-CSF application in a model of endotoxin-induced hepatotoxicity.

The effect of rG-CSF on wound healing in neutropenic mice was studied in the wound healing model on the ear of hairless mice. Animals were treated with a daily dose of rG-CSF (i.p.; 3 micrograms). rG-CSF significantly improved wound healing probably by modulation of the cellulary immune response.

Interleukin-6 seems to have a predictive value for the multiple organ dysfunction syndrome (MODS) in the early period after trauma.

Wundheilungsstorungen stellen eine haufige Komplikation bei diabetischer Stoffwechsellage dar. Hierfur masgeblich verantwortlich sind neben der Beeintrachtigung der lokalen Infektabwehr die Verminderung der Migration und Proliferation von Endothelzellen und Fibroblasten sowie die damit einhergehende Veranderung des Wundmilieus. G-CSF zeigte in experimentellen [1] und klinischen [2] Studien eine stimulierende Wirkung auf die Proliferation, Migration und Funktion sowohl von Granulozyten, als auch von Endothelzellen und Fibroblasten [3]. Daher war es Ziel unserer Studie der Frage nachzugehen inwieweit G-CSF zu einer Verbesserung der Wundheilung bei diabetischer Stoffwechsellage fuhrt.

Liver ischemia and reperfusion (I/R) induce Kupffer cell (KC) activation with increased release of proinflammatory cytokines. Prostaglandins are potent counterregulatory mediators to control the production of cytokines by macrophages.To study the role of cyclooxygenase metabolites for the release of proinflammatory cytokines by KC in liver I/R, Sprague-Dawley rats were subjected to 20-minute global hepatic ischemia and 60 minutes of reperfusion. Sham-operated animals were used as controls. Kinetics of spontaneous and lipopolysaccharide (LPS)-induced release of proinflammatory cytokines and prostaglandin E2 (PGE2) by KC were assessed both in the presence and absence of the cyclooxygenase inhibitor ibuprofen.Early after liver I/R (4, 16 hours) the spontaneous secretion of TNF-alpha (+1,058%), IL-1alpha (+152%), and IL-6 (+161%) by KC was increased (P0.05), while PGE2 release in the I/R group was reduced by 51% (P0.05) in comparison with the sham-operated group. Increased release of PGE2 in the later period (32 hours) after I/R was associated with decreased TNF-alpha release by KC. Inhibition of PGE2 production by ibuprofen induced a prolonged and enhanced production of TNF-alpha, while the release of IL-1alpha and IL-6 was not affected.Liver I/R leads to a temporary suppression of PGE2 release by KC, while the release of TNF-alpha is increased. Thus, during early reperfusion, excessive secretion of TNF-alpha by KC may be the result of the absent negative feedback control of cyclooxygenase metabolites.

The influence of coronary artery bypass grafting (CABG) on spontaneous and lipopolysaccharide (LPS)-stimulated release of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-10 as well as its modulation by pentoxifylline (PTF) were studied in a prospective, randomized, double-blinded study. 12 patients undergoing elective CABG were randomly assigned to receive either saline or PTF (1 mg/kg as a loading dose followed by 1 mg/kg/h) intraoperatively. Blood samples were obtained (A) preoperatively, (B) 20 min after CABG, and (C) 24 h after CABG. Cytokine plasma levels as well as LPS-stimulated cytokine secretion were measured in a whole blood culture system ex vivo and correlated with mRNA expression in peripheral blood mononuclear cells. In addition, the dose-response characteristics of modulation of the cytokine response by PTF were studied in cultured whole blood in vitro. Plasma IL-6 and IL-10-levels were significantly elevated after CABG, whereas neither TNF-alpha nor IL-1beta were detectable. In contrast to the spontaneous release of IL-6 and IL-10, the expression of all cytokines studied was significantly reduced upon ex vivo LPS stimulation early after CABG. Proinflammatory cytokine response upon LPS stimulation was restored 24 h after CABG for the group mean, however, with substantial interindividual heterogeneity. Therapeutic doses of PTF in vitro attenuated LPS-induced TNF-alpha (-50.5%) and most notably IL-10 (-83.9%) release, whereas IL-1beta was even increased (+45.7%). However, application of PTF during CABG neither inhibited the spontaneous production of IL-10 nor modulated cytokine production ex vivo. These results suggest a biphasic response of stimulated peripheral blood mononuclear cell cytokine gene expression during CABG with an initial tolerance to LPS stimulation. The application of PTF during CABG in doses that are primarily based on its use in occlusive arterial disease do not seem to modulate the release of the cytokines studied.

Between October 1995 und December 1997, 57 patients with displaced 2-, 3-and 4-part fractures of the proximal humerus were treated by open reduction and internal fixation with two one-third tubular plates which were applied to the anterior and lateral aspect of the proximal humerus. For the follow-up evaluation shoulder function was assessed in 38 patients after an average of 16.8±4.2 months using the Constant-score: 32% of the patients showed excellent, 37% good, 21% satisfactory, and 10% unsatisfactory results. The high stability of this technique allows intensive physiotherapy in the early postoperative period and early reintegration in activities of daily living.

Neueste tierexperimentelle Untersuchungen zeigen, das die Vorbehandlung mit G-CSF uber eine Hemmung der Kupfferzell-Aktivitat mit konsekutiver Reduktion der mikrovaskularen Leukozyten-Endothelzell-Interaktion und verbesserter sinusoidaler Perfusion die Endotoxin-induzierte Leberfunktionsstorung verhindern kann [1]. Die exakten Mechanismen der G-CSF-vermittelten Gewebeprotektion sind bisher jedoch nicht bekannt.

Eine suffiziente Immunantwort ist eine Grundvoraussetzung fur eine komplikationslose Wundheilung. Somit birgt eine vorhandene Immunsuppresion stets ein erhohtes Risiko fur die Entwicklung einer Wundheilungsstorung. Sowohl in experimentellen [1] als auch in klinischen Untersuchungen [2] zeigte rG-CSF eine stimulierende Wirkung auf immunkompetente Zellen. Daher war es Ziel unserer Studie der Frage nachzugehen, inwieweit rG-CSF zu einer Verbesserung der Wundheilung bei Neutropenie fuhrt.

In contrast to the anticipation that in sepsis granulocyte colony-stimulating factor (G-CSF) would overactivate the nonspecific immune system by recruiting and priming leukocytes with consequent aggravation of inflammatory tissue lesions, recombinant (r) G-CSF pretreatment was protective in various experimental non-neutropenic models of inflammation. The mechanisms of protection, however, are not fully understood. Using intravital fluorescence microscopy, we show that rG-CSF enhances leukocyte endothelial cell interaction within the microvasculature of normal rat livers, whereas rG-CSF pretreatment of animals exposed to lipopolysaccharide (LPS) attenuates the LPS-induced leukocytic response, including stasis in sinusoids as well as rolling and adherence in postsinusoidal venules with subsequent tissue infiltration. Moreover, rG-CSF, which did not affect Kupffer cell activity in normal rat livers, reduced the immediate activation of Kupffer cells on LPS exposure, as indicated in vivo by the delayed adherence/phagocytosis of intra-arterially administered latex particles associated with attenuation of proinflammatory cytokine release (tumor necrosis factor α and interleukin-6). Finally, rG-CSF reduced LPS-induced nutritive perfusion failure and hepatocellular excretory dys function. This study provides evidence for a distinct, possibly tumor necrosis factor α-dependent modulation of LPS-induced cellular response within the liver by rG-CSF, thereby achieving protection against microcirculatory perfusion failure and hepatic dysfunction. J.

Neben der Wirkung von G-CSF (Granulozyten-koloniestimulierender Faktor) auf Vorlauferzellen im Knochenmark, beeinflust G-CSF auch verschiedene Funktionen ausgereifter Leukozyten in der Peripherie: G-CSF stimuliert die antikorperabhangige, zellvermittelte Zytotoxizitat von Leukozyten und aktiviert sowohl die Chemotaxis und die Adharenz an kunstliche Oberflachen als auch die Fahigkeit der Leukozyten zur Bildung und Freisetzung inflammatorischer Mediatoren, wie Arachidonsauremetabolite und toxische Sauerstoffradikale [1]. Aufgrund dieser Eigenschaften wurde G-CSF - neben seiner Bedeutung als hamatopoetischer Wachstumsfaktor - in jungster Zeit eine entscheidende Rolle in der Modulation der initialen Immunantwort bei Infektion und Sepsis zugeschrieben. Da Leukozyten bei einer Vielzahl pathologischinflammatorischer Prozesse, einschlieslich Endotoxinamie/Sepsis eine wesentliche Funktion in der Vermittlung des Organschadens besitzen [2], wurde angenommen, das G-CSF als potenter Stimulus der leukozytaren Funktion prinzipiell den zellabhangigen mikrovaskularen und parenchymatosen Schaden verstarkt. Neueste experimentelle Untersuchungen zur Endotoxin-assoziierten Toxizitat weisen jedoch auf eine Organprotektion, insbesondere der Leber, und/oder eine Reduktion der Endotoxin-assoziierten Letalitat bei Vorbehandlung bzw. Therapie mit G-CSF hin [3–5]. Die Wirkmechanismen von G-CSF sind bislang jedoch nicht bzw. nur unzureichend geklart.

Schwere traumatische Insulte und ausgedehnte Ischamie-/Reperfusionsereignisse pradisponieren zur Entwicklung einer Sepsis und eines MODS (multiple organ dysfunction syndrome). Der uberschiesenden Freisetzung proinflammatorischer Zytokine aus mononuklearen Zellen wird hierbei eine entscheidende pathophysiologische Rolle zugeschrieben [1, 2]. Andererseits ist eine adaquate endogene Zytokinantwort zur erfolgreichen Bekampfung eindringender Mikroorganismen von essentieller Bedeutung. Hiermit vereinbar hat die Blockade der proinflammatorischen Zytokinantwort bei Patienten mit dem Einschluskriterium „Sepsis“ keine befriedigenden klinischen Ergebnisse gezeigt [3, 4]. Dies ist u.a. auf den multiphasischen Verlauf der Zytokinantwort und das Fehlen eines adaquaten immunologischen Monitoring zuruckzufuhren. Zur Evaluierung einer geeigneten Screening-Methode wurde Blut von Patienten, die sich einer elektiven Bauchaortenaneurysma-(BAA) Ausschaltung unterzogen, mehrfach bezuglich der individuell stimulierbaren Zytokin-Genexpression analysiert.

Zyklische Nukleotide wie cAMP und cGMP sind zentrale „second messenger“ in der Regulation einer Vielzahl parenchymatoser und nicht-parenchymatoser Leberzellfunktionen, wie Akutphase-Antwort in Hepatozyten (HC), Regulation des sinusoidalen Tonus durch Ito-Zellen sowie Zytokin-Genexpression und Antigenprasentation durch Kupfferzellen (KC) [1–3]. Interessanterweise ist nach Schock und Volumentherapie der cGMP-Spiegel in KC und HC erhoht [4]. Im Gegensatz zu Endotoxinexposition fuhrt jedoch der hamorrhagische Schock nicht zur massiven Induktion der induzierbaren Stickstoffmonoxidsynthase (NOS-II) [5, 6]. Neueste Ergebnisse legen nahe, das alternativ zu NO auch endogenes Kohlenmonoxid (CO), welches ausschlieslich als Intermediarstoffwechselprodukt im Hamabbau entsteht, die Guanylatzyklase aktivieren kann und das Blockade dieses Stoffwechselweges zur drastischen Zunahme des Pfortaderwiderstandes nach therapiertem hamorrhagischen Schock fuhrt (7). Hamoxygenase (HO) katalysiert den Abbau von Ham zu Biliverdin und CO und liegt sowohl als konstitutives (HO-2), als auch als induzier-bares (HO-1/HSP-32) Isoenzym vor. Welche Zellpopulationen der Leber (Parenchym-/Nicht-Parenchymzellen) fur die HO-Synthese unter Normal-bzw. Stresbedingungen verantwortlich sind, ist bisher nicht geklart. Wir untersuchten daher das zelltypspezifische Expressionsmuster beider HO-Isoformen in normaler und stresexponierter Leber.

Heme oxygenase (HO)-derived carbon monoxide (CO) may contribute to vascular control through elevation of guanosine 3',5'-cyclic monophosphate. In the present study, we investigated the functional significance of expression of the isoenzyme HO-1 (heat-shock protein 32) in liver after hemorrhage/resuscitation (H/R) in rats anesthetized with pentobarbital sodium. An increase of mRNA levels for HO-1 was observed at 3 h after resuscitation, followed by induction of the protein at 6 h in pericentral hepatocytes and sinusoidal lining cells. Concomitantly, lower portal resistance was observed in H/R (0.33 +/- 0.060 mmHg.ml-1.min) compared with control rats (0.47 +/- 0.035 mmHg.ml-1.min). Blockade of the HO-CO pathway by tin protoporphyrin-IX (SnPP-IX) led to a transient increase in portal pressure with no effect on portal low in controls, whereas an increase in pressure and a decrease in flow contributed to the sustained increase in portal resistance after H/R. These results indicate that HO contributes to maintenance of hepatic perfusion in vivo under stressful conditions, suggesting a functional link between stress response and vascular control in portal circulation.

Die Ischamie und Reperfusion der Leber fuhrt zu einer massiven Freisetzung von Tumornekrosefaktor α (TNF-α), Interleukin 1 α (IL-1 α) und Interleukin 6 (IL-6) aus Kupfferzellen (KC). Dies resultiert in einer Zytokinamie und systemischen inflammatorischen Reaktion (SIRS), mit Funktionseinschrankungen und signifikanten Gewebeschaden von Leber, Lunge, und Niere [1]. In vivo und in vitro Versuche [2–4] zeigten, das TNF-α den Trigger fur die Aktivierung der proinflammatorischen Zytokinkaskade darstellt. Ziel dieser Studie war, den Effekt der Neutralisation von TNF-α in vivo mittels monoklonaler Antikorper auf die Freisetzung proinflammatorischer Zytokine aus KC nach Ischamie/Reperfusion der Leber zu untersuchen.

Die Ischamie und Reperfusion der Leber, wie sie durch Abklemmen des Ligamentum hepatoduodenale wahrend ausgedehnter Leberresektion, Lebertransplantation oder nach schwerem Lebertrauma auftritt [1], fuhrt zu Leberfunktionsstorungen und Schaden in nachgeschalteten Organen [2]. Obwohl Makrophagen in vitro unter hypoxischen Bedingen [3, 4] vermehrt proinflammatorische Zytokine freisetzen, ist die Rolle der Leberischamie fur die Induktion einer lokalen und systemischen Inflammation durch Aktivierung von Kupfferzellen (KC) in vivo nicht bekannt. Es war das Ziel dieser Studie, die Freisetzung proinflammatorischer Zytokine aus KC nach Leberischamie/-reperfusion und Gewebeschadigung von Leber, Lunge, Niere und Dunndarm zu ermitteln.

Ausgedehnte chirurgische Eingriffe an der Leber, wie Leberteilresektionen, Lebertransplantation und die Versorgung von Leberverletzungen, erfordern haufig eine partielle oder globale Ischamie der Leber mit anschliesender Reperfusion. Die Ischamie-Reperfusion der Leber fuhrt uber die Aktivierung von Kupfferzellen (KC) zu einer erhohten Freisetzung von proinflammatorischen Zytokinen (TNF-α, IL-1, IL-6). Die hierdurch bedingte Zytokinamie korreliert mit histologischen Veranderungen in der Leber und in nachgeschalteten Organen [1]. In vitroUntersuchungen [2–4] zeigten, das Cyclooxygenasemetabolite die Synthese und Sekretion von pro- und anti-inflammatorischen Zytokinen beeinflussen und somit eine wichtige Rolle fur die Regulation und Synthese von pro- und anti-inflammatorischen Mediatoren spielen. Es war Ziel dieser Studie, in vitrodie Wirkung der Cyclooxygenaseinhibition auf die Freisetzung pro- und anti-inflammatorischer Zytokine nach Leberischamie-Reperfusion aus Kupfferzellen zu untersuchen.

Die Ischamie und Reperfusion der Leber konnen zu Einschrankungen der Organfunktion bis zum Leberversagen fuhren. Als Ursache fur die Beeintrachtigung der Hepatocyten- funktion wird neben Storungen der Mikrozirkulation eine Beteiligung inflammatorischer Mediatoren (TNF-α, IL-6, IL-1, Prostaglandine) diskutiert, die von Kupfferzellen unter diesen pathophysiologischen Bedingungen in erhohtem Mas freigesetzt werden. Es gibt Hinweise dafur [1, 2], das Hepatocytenfunktionen nach Ischamie/Reperfusion durch die veranderte Freisetzung von Mediatoren aus Kupfferzellen reguliert werden. Es war das Ziel dieser Studie, die veranderte Sekretion von TNF-α und IL-6 (hepatocyte-stimulating-factor) aus Kupfferzellen an einem Leberischamiemodell zu untersuchen.