I. H. Chaudry

The Apoptotic Response of the Lymphoid Immune System to Trauma, Shock, and Sepsis

Despite the rapid development and many significant advances in preventive methods and clinical care, trauma remains the most common cause of mortality during the first thirty years of life. It has been reported that approximately 50% of the deaths occur due to exsanguination or central nervous system complications within one hour following trauma and another 30% of victims die during the following 1–2 hours due to major internal injury [1]. Of those patients who survive the initial insult, more than 50% die over the next few days to week(s) due to secondary infections (i.e., sepsis) and/or multiple organ dysfunction [2]. Studies have indicated that there are marked alterations in both innate and acquired immune functions in patients exposed to major trauma such as thermal injury, soft tissue trauma or prolonged surgical procedures. These alterations include suppressed neutrophil bacterial killing function, defective opsonization, altered macrophage function, decreased humoral immunity, suppression of T- and B-lymphocyte responsiveness and altered pro- and anti-inflammatory mediator/cytokine release [3]. A number of studies indicate that traumatic injury and/or shock result in profound immunosuppression which predisposes the patients to septic infection and/or multiple organ failure (MOF).

Therapie des hämorrhagischen Schocks

ZusammenfassungDie etablierte Therapie des hämorrhagischen Schocks besteht heute in einer raschen Blutungskontrolle, Erhalt der Sauerstoffversorgung des Gewebes durch Volumentherapie, der Gerinnungstherapie sowie dem Erhalt einer normalen Körpertemperatur. Dennoch existieren große Unterschiede in der Flüssigkeits- und Blutersatztherapie in den verschiedenen Institutionen. Wesentliche Ursachen hierfür sind das Fehlen von evidenzbasierten Daten, welches aufgrund der großen ethischen und rechtlichen Hürden die Initiierung von randomisierten, kontrollierten Studien erschwert. Dies ist einer der Hauptgründe, warum neue Therapieansätze, welche sich vor allem auf experimentelle Daten stützen, zu keinen wesentlichen Änderungen in der etablierten Therapie geführt haben.Dieser Übersichtsartikel erläutert neue diagnostische und therapeutische Strategien unter Einbeziehung eines immunologisches Monitoring, neuer Wirkstoffe zum Erhalt der Herz-Kreislauf-Funktion, künstlicher Sauerstoffträger als Blutersatz und neue Flüssigkeitssubstitutionsregime, die aufgrund vielversprechender experimenteller Ergebnisse Einzug in die Klinik gehalten haben oder halten werden. Zusätzlich wird auf die Bedeutung von Alter, Geschlecht und genetischen Faktoren hingewiesen.AbstractDespite numerous promising experimental results control of bleeding, maintenance of tissue oxygenation by means of fluid replacement, support of the coagulation system and sustainment of normothermia are mainstays in the therapy of patients in hemorrhagic shock. Regimens for volume and blood replacement, however, vary widely between trauma centers due to the lack of evidence-based publications referring to randomized controlled clinical trials. Ethical and legal requirements for the inclusion of patients with hemorrhagic shock in clinical trials have impeded the rapid introduction of experimental strategies in the clinical arena.This review article will point out new therapeutic strategies, i.e. immunomodulation, cardiovascular maintenance, use of artificial oxygen carrying substances and new formulae for volume substitution, which have been introduced into clinical therapy or are in the process of being transformed from bench to bedside. In addition, the impact of gender, age and genetics on cardiovascular and immune responses will be reflected.

ARE THE PROTECTIVE EFFECTS OF 17??-ESTRADIOL ON SPLENIC MACROPHAGES AND SPLENOCYTES AFTER TRAUMA-HEMORRHAGE MEDIATED VIA ESTROGENRECEPTOR (ER)-?? OR ER-???

The depression in cell-mediated immune function following trauma-hemorrhage is shown to be restored by 17 -estradiol (E2) administration. However, it remains unknown which of the two estrogenreceptors, (ER)or ER, plays the predominant role in mediating the beneficial effects of E2. Female B57BL/J6 ER/ transgenic mice [knockout (KO)] and corresponding ovariectomized wild-type (WT) mice were subjected to laparotomy and hemorrhagic shock (35.0 5.0 mmHg for 90 min) and treated with E2 (50 g/25 g) or ERagonist propyl pyrazole triol (PPT; 50 g/25 g) following traumahemorrhage. Four hours after resuscitation, systemic cytokine concentrations and cytokine release by splenocytes and splenic macrophages were determined by cytometric bead array. Trauma-hemorrhage resulted in a significant increase in plasma tumor necrosis factor (TNF), interleukin (IL)-6, and IL-10. In contrast, the release of these cytokines by splenic macrophages was decreased significantly in WT and KO animals. Administration of E2 or PPT following trauma-hemorrhage produced a significant reduction in systemic TNFand IL-6 concentrations in WT and KO mice. Although the suppression in the productive capacity of these cytokines following trauma-hemorrhage by macrophages and splenocyte was also prevented in E2and PPT-treated WT mice, the release of cytokines by macrophages and splenocytes in E2and PPT-treated KO mice was not restored to the levels observed in sham animals. These findings collectively suggest that both receptors appear to play a significant role in mediating the immunoprotective effects of E2 in different tissue compartments following trauma-hemorrhage. J. Leukoc. Biol. 79: 000–000; 2006.

THE PI3K/AKT PATHWAY MEDIATES THE NONGENOMIC CARDIOPROTECTIVE EFFECTS OF ESTROGEN FOLLOWING TRAUMA-HEMORRHAGE

OBJECTIVE To determine whether the nongenomic actions of E2 have any beneficial effect on cardiac function following trauma-hemorrhage and whether those effects are mediated via the PI3K/Akt pathway. SUMMARY BACKGROUND DATA Since studies suggest that both genomic and nongenomic pathways are involved in mediating the salutary effects of 17beta-estradiol (estradiol) following trauma-hemorrhage, we examined if the nongenomic effects of estradiol on cardiac function after trauma-hemorrhage involve the PI3K/Akt pathway. METHODS Male Sprague-Dawley rats ( approximately 300 g) underwent trauma-hemorrhage (mean blood pressure, 40 mm Hg for 90 min, then resuscitation). Estradiol conjugated to bovine serum albumin (BSA) (estradiol-BSA; 1 mg/kg estradiol) with or without estrogen receptor antagonist (ICI 182,780), PI3K inhibitor (Wortmannin), or vehicle was injected intravenously during resuscitation. At 2 hours after trauma-hemorrhage or sham operation, cardiac output, stroke volume, heart rate, mean arterial pressure, and +/-dP/dt were measured. Cardiomyocyte PI3K, p-Akt, Akt protein expressions and apoptosis were also determined. One-way ANOVA and Tukeys test were used for statistical analysis. RESULTS Cardiac output, stroke volume, and +/-dP/dt decreased significantly after trauma-hemorrhage. Administration of estradiol or estradiol-BSA significantly improved these parameters of cardiac function. Although trauma-hemorrhage decreased cardiomyocyte PI3K protein expression and Akt phosphorylation (p-Akt), estradiol or estradiol-BSA treatment following trauma-hemorrhage prevented such decreases in cardiomyocyte PI3K protein expressions and p-Akt. The increase in cardiomyocyte apoptosis was also prevented in rats receiving estradiol-BSA. Co-administration of ICI 182,780 or Wortmannin abolished beneficial effects of estradiol-BSA on cardiac functions following trauma-hemorrhage. CONCLUSION The PI3K/Akt pathway plays a critical role in mediating the nongenomic salutary effects of estradiol on cardiac function following trauma-hemorrhage.

Welche Rolle spielt lnterleukin-10 in der Immunantwort nach Trauma kombiniert mit hämorrhagischem Schock?

Experimentelle und klinische Studien haben gezeigt, dass das anti-entzundliche Immunzytokin Interleukin-10 (IL-10) in der spaten Phase der Immunantwort nach Trauma und Schock ein wichtiger Mediator ist. Diese Phase ist gekennzeichnet durch eine unzureichende Immunfunktion, welche zu einer erhohten Anfalligkeit gegenuber Infektionen fuhrt. Wir untersuchten deshalb, in einem etablierten Tiermodell aus Weichteiltrauma kombiniert mit hamorrhagischem Schock, welche Rolle IL-10 in der posttraumatischen Immunantwort spielt. Methode: Bei 6-8 Wochen alten C3H/HeN Mausen wurde durch eine Mittellinienlaparotomie ein Weichteiltrauma induziert, gefolgt von einem 90-minutigen hamorrhagischen Schock mit konstantem arteriellen Mitteldruck von 30 mmHg mit folgender adaquater Volumenruckgabe in Form von Lactat-haltiger Ringer-Losung. In der Kontrollgruppe wurden beide Femoralarterien ligiert, ohne Laparotomie oder Blutungsschock. Blut wurde daraufhin zu bestimmten Zeitpunkten nach der Volumenruckgabe gewonnen und Plasmawerte fur IL-10, IL-6 und Tumornekrosefaktor-a (TNF-α) bestimmt. In einem zweiten Experiment applizierten wir den Tieren Gadolinium-(III)-chloride (GdCl3) intravenos 48 Stunden vor dem Experiment zur Blockade von Makrophagen. Plasmazytokin-werte wurden 2 Stunden nach dem Trauma gemessen. In einer dritten Gruppe wurde wahrend der Volumenruckgabe Antikorper gegen IL-10 (250 (ig/Tier) intraarteriell verabreicht. Die Blutgewinnung erfolgen ebenfalls 2 Stunden nach dem Trauma. Ergebnisse: Es zeigte sich 2 Stunden nach dem kombinierten Trauma der hochste Anstieg von IL-10 und IL-6 im Plasma. Die IL-10 Plasmawerte waren aber bereits 4 Stunden nach dem Trauma auf Hohe der Ausgangswerte, wahrend die IL-6 Werte langsam abfielen. TNF-α zeigte sich direkt nach dem Trauma erhoht mit anhaltend erhohten Werten bis 8 Stunden nach dem Trauma. Blockierung der Makrophagenfunktion durch Gabe von GdCl3 verhinderte den Anstieg aller gemessenen Zytokinwerte, wahrend N = 8/Gruppe, ANOVA, *p < 0,05 vs. Kontrolle. Neutralisation von IL-10 zu einem signifikanten Anstieg von TNF-α und IL-6 fuhrte. Schlusfolgerung: Die Ergebnisse zeigen, dass Interleukin-10 ein Mediator ist, der in der fruhen Phase nach Trauma und hamorrhagischem Schock von Makrophagen produziert wird und die fruhe proentzundliche Immunreaktion reguliert. Diese Beobachtung stimmt uberein mit klinischen Daten, die gezeigt haben, dass niedrige IL-10 Blutwerte und eine niedrige IL-10/IL-6 Ratio mit einer erhohten Mortalitat bei Intensivpatienten verbunden ist. Damit lasst sich auch die negative Auswirkung von fruher IL-10 Blockierung auf die Immunfunktion direkt nach traumatischer Verletzung und Sepsis erklaren.

DIFFERENTIAL ALTRATIONS IN SYSTEMIC AND REGIONAL OXYGEN DELIVERY AND CONSUMPTION DURING THE EARLY AND LATE STAGES OF SEPSIS

BACKGROUND Studies have indicated that regional changes in oxygen utilization during sepsis cannot be predicted from the changes in the whole body oxygen delivery (DO2) and consumption (VO2). The aim of this study, therefore, was to determine whether differential alterations in systemic and regional DO2 and VO2 occur during the early and late stages of sepsis. METHODS Adult male Sprague-Dawley rats were subjected to sepsis by cecal ligation and puncture (CLP). At 5 hours (i.e., the early, hyperdynamic phase of sepsis) or 20 hours (i.e., the late, hypodynamic phase) after CLP, cardiac output, and organ blood flow were measured by radioactive microspheres. Systemic and regional DO2 and VO2 were determined and plasma levels of lactate were measured. RESULTS Cardiac output and blood flow to the liver, small intestine, and kidneys increased at 5 hours and decreased at 20 hours after CLP. Although both systemic DO2 and VO2 increased at 5 hours after CLP, systemic DO2 but not VO2 decreased at 20 hours. At 5 hours after CLP, intestinal and renal DO2 increased. However, DO2 in all the tested organs decreased at 20 hours after CLP. VO2 increased in the liver, small intestine, and kidneys at 5 hours after CLP but decreased only in the liver and small intestine at 20 hours after the onset of sepsis. Moreover, plasma lactate levels increased at the late stage of sepsis. CONCLUSION Because hepatic and intestinal VO2 but not systemic and renal VO2 decreased at 20 hours after CLP, the liver and small intestine seem to be more vulnerable to the hypoxic insult during the hypodynamic stage of polymicrobial sepsis.