Symposium 7, Sunday Sept. 23rd 4 pm–5.30 pm; Room: Lecture Hall 3
Alcohol: An immunological Jack-of-all-trades: Chairpersons: Spies C (Germany), Kovacs EJ (USA)
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Abstract |
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Presentation S7-1
Influence of alcohol on sex and immune response after injury
Kovacs EJ, Morgan MO, Ramirez L, Bird MD, Karavitis J (USA)
Aims. Abundant evidence reveals a naturally occurring sexual/dimorphism in the immune response, which plays a role in post-burn survival. Higher inflammatory responses in females lead to greater immunosuppression, which lead to increased mortality after injury. With alcohol on board at the time of injury, these parameters were exacerbated. Herein, we compared responses after ethanol and burn injury in male, intact female, and ovariectomized (OVX) female mice.
Methods. Mice were given ethanol (1.2 g/kg) and 30 minutes later, were subjected to a 15% total body surface area scald (burn) or sham injury.
Results. Mortality in females given the combined insult was over 50%, whereas it was less than 20% in males and OVX females (p < 0.05). Delayed type hypersensitivity and splenocyte proliferative responses were suppressed in both males and females at 24 hours. In contrast, at 7 days, immune parameters in intact females were still attenuated, but were restored in males and OVX females. IL-6 production by macrophages paralleled immune responses, with high levels of production by macrophages obtained from intact females given burn and ethanol when compared to male and OVX female. The aberrant pro-inflammatory response and immunosuppression seen 24 hours after male mice were given ethanol and burn could be abrogated by low, proestrus levels of 17β-estradiol. The restoration in immunity in estrogen-treated male mice correlated with reduced NF-kB activation. Interestingly, giving estrogen to females failed to improve these parameters, probably because of elevated endogenous levels of estrogen in injured females.
Conclusions. Taken together, these observations show that the effects of the combined insult is more prolonged in females than in males and suggest that gender-specific treatments should be considered for all burn patients.
(Supported by NIH R01AA12034, T32AA13527, the Ralph and Marian C. Falk Foundation, and an Illinois Excellence in Academic Medicine Grant.)
Presentation S7-2
Alcohol intoxication and traumatic injury; Hemodynamic, metabolic and immune dysregulation
Molina P (USA)
Acute alcohol intoxication is a frequent underlying condition associated with traumatic injury. Center for Disease Control-derived data indicates that 15% of Americans that consume alcohol (51% of the population) are ‘binge drinkers’ who have consumed five or more drinks on the same occasion at least once in the past month. The pathophysiology of traumatic-hemorrhagic injury involves hypovolemia- and hypoperfusion-mediated signaling to central cardiovascular centers involved in activation of descending autonomic neuro-endocrine pathways aimed at restoring hemodynamic stability. Overall, the focus of several research studies on the behavioral aspects of alcoholism has left a large body of knowledge on the biological consequences of alcohol abuse unexplored. Alcohol affects several aspects of neuroendocrine activation, particularly the hormonal and hypothalamic response to a stressor such as traumatic injury. These alcohol-induced alterations are critical in preventing adequate counteregulatory responses, and as we hypothesize may also be playing an important role in modulating host defense mechanisms during recovery from traumatic injury. Because of the importance of timely restoration of adequate tissue perfusion pressure, any disruption of the mechanisms responsible as is the case for alcohol intoxication is likely to further contribute to development of localized inflammation and tissue injury. This presentation will discuss preclinical findings of the impact of binge-alcohol abuse on the counteregulatory mechanisms activated during acute injury involving hemorrhagic shock. The consequences on the integrity of host defense mechanisms and its impact on the course of recovery will also be addressed.
Presentation S7-3
Alcohol, surgery and the immune response—A bedside to bench approach
Lanzke N, Kerschischnik S, Kleinwaechter R, Muehlbauer S, Lehmann A, Pipolo C, von Mettenheim M, Sargsyan L, Schlichting U, Spies C (Germany)
Aims. The prevalence of patients with alcohol use disorder is about 20% in hospitals. They develop postoperative complications 3–5 times more often; nosocomial pneumonia is a major event. We developed a clinically relevant surgical animal model to explore alcohol induced immunosuppression.
Methods. First experiment: Balb/c mice received Klebsiella pneumoniae intranasally after one week of i.p. alcohol-(EtOH) (3 mg/g BW) or saline-treatment (NaCl). 24 h later, mice were sacrificed; lungs were harvested for histopathology, spleens for determination of CD4+ and CD8+ cells producing IFN-
and TNF-
. Second experiment: After one week of EtOH- or NaCl-treatment, mice underwent laparotomy. 48 hr later mice received K. pneumoniae. 24 h later mice were sacrificed; lungs were removed for histopathology and detection of IL-6 and IL-10 levels, spleens for determination of CD4+ and CD8+ cells. Clinical scores (CS) were assessed throughout the experiment.
Results. First: In infected mice the percentages of CD4+ and CD8+ cells producing IFN- significantly decreased (both p < 0.01), the percentages of CD4+ and CD8+ cells producing TNF- significantly increased (p = 0.01/p < 0.01) in EtOH-mice compared to NaCl-mice. Second: EtOH in operated infected mice significantly decreased CD4+ and CD8+ cells producing TNF- (p < 0.01/p = 0.03) and CD4+ cells producing IFN- (p < 0.01). IL-6 and IL-10 significantly increased in lungs of EtOH-exposed infected mice versus NaCl-treated infected mice (p = 0.01/p = 0.02) and EtOH-treated non-infected mice (both p < 0.01). The CS correlated significantly with IL-6 (r = 0.71/p < 0.01) and IL-10 levels (r = 0.64/p < 0.01). In both experiments histopathology confirmed distinct lung injury due to infection. EtOH-treatment worsened the damage.
Conclusions. Immune impairment due to alcohol exposure already existed preoperatively. But alterations differed pre-and postoperatively and became only evident in the context of infection. Further investigations regarding the mechanism remain to be conducted.
Presentation S7-4
Influence of chronic alcohol abuse on the pulmonary immune function
Sander M (Germany)
Long term alcoholic (LTA) patients are reported to have an increased postoperative rate of complications. Moreover, the rates of morbidity and mortality during the postoperative period are also increased 2–5-fold in LTA patients as compared with nonalcoholic surgical patients. Because of this increased postoperative morbidity, treatment in the intensive care unit and overall hospital stay are increased. Among all complications, infections and especially infections of the lung are most relevant and are associated with a worse outcome. Chronic alcohol abuse is known to act immunosuppressive. LTA patients are shown to suffer from distinct immune alterations. In previous studies by our group and by others, decreased proinflammatory TNF and increased anti-inflammatory interleukin-10 production was seen in long-term alcoholic patients during surgery. This was also associated with an increased rate of postoperative pulmonal infection. Previous work has demonstrated that in LTA patients also the local pulmonal immune response to infections is compromised. In line with that the most common infection reported in previous investigations in LTA patients undergoing surgery is postoperative pneumonia. Several studies reported functional defects of alveolar macrophages. It was shown previously in experimental and clinical settings that the LPS induced TNF response was suppressed in the context of chronic alcohol exposure. Also defect of intrapulmonal immune signaling involving cytokines and chemokines as well as perturbances in cell-cell interaction within the lung was reported in this setting. Due to these reported immune defects and the clinically observed increased pneumonia rate the urgent need for interventional approaches providing modulation of the perioperative pulmonal immune response in these high-risk patients to counteract their postoperative immune suppression is apparent.
Presentation S7-5
Sympatholytic treatment of the immune system for prevention of pulmonary infection
Meisel C (Germany)
Infections are a leading cause of morbidity and mortality in patients suffering from acute central nervous system (CNS) injury such as stroke. Several risk factors have been attributed to the increased susceptibility to infections after CNS injury including the exposure of patients to invasive medical procedures and the loss of protective reflexes leading to dysphagia and aspiration. However, experimental and clinical studies have also demonstrated profound suppression of immune responsiveness after brain injury. In an experimental model of focal cerebral ischemia, we have recently described that mice develop spontaneous bacterial pneumonia 1–3 days after stroke, resulting from a neuroendocrine-mediated systemic down-regulation of cellular immune responses. In a new model of post-stroke pneumonia, we demonstrated that otherwise harmless minor bacterial aspiration of S. pneumoniae leads to severe pneumonia even 14 days after brain ischemia, suggesting that stroke induces a long-lasting suppression of pulmonary antibacterial responses. Prevention of spontaneous as well as aspiration-induced pulmonary infections by β-adrenoreceptor blockade suggests that immunodepression by sympathetic hyperactivity is an essential cause for the decreased antibacterial defense after acute stroke. Thus, CNS injury induces a disturbance of the normally well balanced interplay between the nervous and the immune system, resulting in secondary immunodeficiency (CNS injury-induced immunodepression, CIDS) and infection. A better understanding of the mechanisms of brain-immune interaction after acute CNS injury is required to develop better diagnostic tools to identify patients at high risk for the negative consequences of CIDS and to answer the question whether (and which) immunomodulatory therapy may improve patient outcome.