TRAIL-treated mice are highly protected from abdominal sepsis. Because diagnosis and therapy are frequently delayed in human sepsis, it is remarkable that TRAIL is effective when given via a therapeutic approach. Therefore, this study suggests a therapeutic potential for TRAIL in human sepsis. This should be addressed in future trials.
Carotid bodies harboring sensor cells for oxygen have a strategic location at the bifurcation of the carotid artery, which supplies the brain. Upon arterial hypoxia they transmit signals to the respiratory center, which increases the frequency of breathing. Dopamine is considered as the predominant transmitter of the rat carotid body sensor cells. Here we show that the rat carotid body sensor cells are the first cell type known to have the complete apparatus to synthesize, store and release both dopamine and histamine. The tyrosine hydroxylase positive dopaminergic sensor cells of juvenile rats express the histamine biosynthesis enzyme, histidine decarboxylase. Moreover, the sensor cells have not only vesicular monoamine transporter 1 (VMAT1) transporting catecholamines but also VMAT2, which is highly specific for histamine. Additionally, we found that these cells possess components of the neuroendocrine exocytosis apparatus, synaptosome-associated protein of 25 kDa (SNAP 25) and syntaxin1. The amount of histamine determined in the rat carotid body (164 pmol/carotid body) is more than 10-fold higher compared with that of dopamine. As a main effect, hypoxia significantly increased histamine release from isolated rat carotid bodies as it has been shown for dopamine. Finally, RT-PCR experiments indicate the presence of histamine receptors H1, H2 and H3 in the carotid body. Our data suggest that histamine is synthesized, stored and released upon hypoxia by dopaminergic sensor cells of the rat carotid body.
Sepsis remains a persistent problem on intensive care units all over the world. Understanding the complex mechanisms of sepsis is the precondition for establishing new therapeutic approaches in this field. Therefore, animal models are required that are able to closely mimic the human disease and also sufficiently deal with scientific questions. The Colon Ascendens Stent Peritonitis (CASP) is a highly standardized model for polymicrobial abdominal sepsis in rodents. In this model, a small stent is surgically inserted into the ascending colon of mice or rats leading to a continuous leakage of intestinal bacteria into the peritoneal cavity. The procedure results in peritonitis, systemic bacteraemia, organ infection by gut bacteria, and systemic but also local release of several pro-and anti-inflammatory cytokines. The lethality of CASP can be controlled by the diameter of the inserted stent. A variant of this model, the so-called CASP with intervention (CASPI), raises opportunity to remove the septic focus by a second operation according to common procedures in clinical practice. CASP is an easily learnable and highly reproducible model that closely mimics the clinical course of abdominal sepsis. It leads way to study on questions in several scientific fields e.g. immunology, infectiology, or surgery. Video LinkThe video component of this article can be found at http://www.jove.com/video/2299/ Protocol 1. Preparation of the Mouse 1. Anesthetize the mouse by intraperitoneal injection of the narcotic fluid (see table of reagents) and place it in supine position. 2. The feet of the mouse need to be fixed with tape on the plate to ensure a stable position of the animal during the operation. Operation
Our results suggest that seasonal changes of the host's hypothalamus-pituitary-adrenal axis response influence the risk of infection and the susceptibility to stress, which interferes with the outcome after infection.
CC chemokine receptor 4 (CCR4) and its two ligands, CCL17 and CCL22, are critically involved in different immune processes. In models of lipopolysaccharide-induced shock, CCR4-deficient (CCR4 ؊/؊ ) mice showed improved survival rates associated with attenuated proinflammatory cytokine release. Using CCR4 ؊/؊ mice with a C57BL/6 background, this study describes for the first time the role of CCR4 in a murine model of polymicrobial abdominal sepsis, the colon ascendens stent peritonitis (CASP). CASP-induced sepsis led to a massive downregulation of CCR4 in lymphoid and nonlymphoid tissues, whereas the expression of CCL17 and CCL22 was independent of the presence of CCR4. After CASP, CCR4؊/؊ animals showed a strongly enhanced bacterial clearance in several organs but not in the peritoneal lavage fluid and the blood. In addition, significantly reduced levels of proinflammatory cytokines/chemokines were measured in organ supernatants as well as in the sera of CCR4 ؊/؊ mice. CCR4 deficiency consequently resulted in an attenuated severity of systemic sepsis and a strongly improved survival rate after CASP or CASP with intervention. Thus, our data provide clear evidence that CCR4 plays a strictly detrimental role in the course of polymicrobial sepsis.Chemokines and chemokine receptors are crucially involved in innate and adaptive immune responses (6). Chemokines attract leukocytes and therefore are important for lymphocyte migration and development but also for recruitment of immune cells to sites of inflammation or infection. Regarding functional aspects, chemokines were recently classified into three subfamilies: inflammatory, homeostatic, and dual-function chemokines (48). CCL17 (thymus-and activation-regulated chemokine) and CCL22 (macrophage-derived chemokine) are assigned to the dual-function subfamily, as they are involved in T-cell development as well as in effector cell recruitment to sites of inflammation. CCL17 and CCL22 are the functional ligands of CC chemokine receptor 4 (CCR4) (31,32). CCR4 is expressed on T cells with the Th2 phenotype, Tregs, dendritic cells, macrophages, NK cells, basophils, and platelets (11). As Th2 cells express CCR4, the receptor and its ligands have been extensively studied in the context of Th2-triggered immune responses, especially concerning chronic diseases of the respiratory tract such as allergic rhinitis, bronchial asthma, or allergic aspergillosis (27,36,42,43,51,67). It could be demonstrated that blocking CCL17 as well as CCL22 by specific antibodies results in prevention of airway hyperresponsiveness and attenuates OVA-induced airway eosinophilia (26, 37).However, there is emerging evidence that CCR4 is involved in several immune reactions other than allergy and chronic airway disease. In a murine model of cardiac transplantation, CCR4-deficient recipients showed a significantly prolonged allograft survival accompanied by a reduced number of graftinfiltrating CD4 ϩ cells (30). Recent reports on different types of lymphatic neoplasm but also on other kinds of cancer such ...
Background: Resident tissue macrophages exert important functions during severe systemic infection and contribute to changes in local as well as systemic immune responses. Alveolar macrophages (AM) play a crucial role in airway diseases and in the defense against microorganisms invading the body via the bronchopulmonary tract. It has been postulated that AM are involved in the development of acute local disorders as a consequence of extrapulmonary stimuli like pancreatitis, peritonitis, or trauma. Objective: The aim of this study was to analyze the local and systemic role of AM during sepsis using selective AM depletion in the murine colon ascendens stent peritonitis (CASP) model of polymicrobial sepsis. Methods: 48 h prior to CASP surgery, AM of female C57BL/6 mice were selectively depleted by intratracheal application of clodronate liposomes (Lipo-clod). For control purposes, phosphate-buffered saline (PBS) liposomes (Lipo-PBS) were used. Results: CASP led to significantly elevated levels of local and systemic cytokines independent of the presence of AM. In contrast, levels of gut-derived bacteria in bronchoalveolar lavage and lung of septic mice were significantly higher in Lipo-clod-treated animals compared to Lipo-PBS-treated animals. After CASP-induced sepsis, local barrier dysfunction in the lung was detected; AM depletion resulted in severely enhanced development of acute lung injury. Consequently, Lipo-clod-treated animals showed strongly reduced survival rates after CASP. Conclusions: Contrarily to other macrophage populations, AM do not significantly contribute to local and systemic cytokine release during polymicrobial abdominal sepsis. AM have important protective functions for local clearance of gut-derived bacteria and attenuation of lung injury.
Abdominal surgery is regularly followed by immune dysfunction that can last for several days. In case of septic complications during this period, there is imminent danger of mortality due to reduced immune function. This fact leads to classification of sepsis in regard to its genesis: spontaneously acquired sepsis type A is distinguishable from sepsis type B, which is acquired postoperatively. The main difference between these types is the immunologic condition at the time point of sepsis development. Postoperative immune dysfunction can be described by several parameters, i.e. reduction of HLA-DR expression on monocytes and increased apoptosis of T lymphocytes. A direct correlation exists between magnitude of immune dysfunction and complexity of the previous surgical trauma. For the first time it is now possible to study this phenomenon of postoperative immune dysfunction by use of an adequate animal model. Intestinal manipulation in mice fulfils the necessary criteria to serve as a model of surgically induced immune dysfunction.
Background: Postoperatively acquired immune dysfunction is associated with a higher mortality rate in case of septic complications. As details of this severe clinical problem are still unknown, animal models are essential to characterise the mechanisms involved. Methods: Mice were laparotomised and the small intestine was pressed smoothly in antegrade direction. For extension of trauma, the intestine was manipulated three times consecutively. Following this, the ex vivo cytokine release of splenocytes was determined. The degree of surgical trauma was analysed by detection of HMGB1 and IL-6 in serum and by neutrophil staining in the muscularis mucosae. Results: We adapted the previously described animal model of intestinal manipulation to provide a model of surgically induced immune dysfunction. Following intestinal manipulation, the mice showed elevated serum levels of HMGB1 and IL-6 and increased infiltration of granulocytes into the muscularis mucosae. Ex vivo cytokine release by splenocytes was suppressed in the postoperative period. The degree of suppression correlated with the extent of surgical trauma. Conclusions: In this study, we describe a surgically induced immune dysfunction animal model, in which a significant surgical trauma is followed by an immune dysfunction. This model may be ideal for the characterisation of the postoperative immune dysfunction syndrome.
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