Productive capacity of alveolar macrophages and pulmonary organ damage after femoral fracture and hemorrhage in IL-6 knockout mice
Introduction
After severe trauma and surgical interventions, the balance or imbalance of the pro- and anti-inflammatory immune response in part influences the clinical course after trauma. Whereas predominance of the pro-inflammatory response leads to the “Systemic Inflammatory Response Syndrome (SIRS)”, the anti-inflammatory reaction might result in immune suppression with an enhanced risk of infectious complications. SIRS as well as immune suppression play a decisive role in the development of sepsis and the “Multiple Organ Dysfunction Syndrome (MODS)” [1]. The lung is consistently the most susceptible organ in rodent models to sepsis and trauma as well as in clinical studies dealing with septic and trauma patients [2]. Therefore, pulmonary failure (Adult Respiratory Distress Syndrome, ARDS) remains one of the most common causes of trauma-related death [1], [2].
Alveolar macrophages are considered to be primary scavengers of particulate matter that reaches the alveoli. Alveolar macrophages have also been implicated in the pathogenesis of acute pulmonary injury [3]. In sepsis-induced lung injury, the pulmonary damage has been reported to be dependent on the presence of functional alveolar macrophages [4], [5]. Furthermore, experimental studies suggest a possible mechanistic role of mediators released by alveolar macrophages in the induction of alveolar type II cell apoptosis, thereby initiating or maintaining pulmonary injury [6], [7].
Alveolar macrophages have also been identified as the major source of pulmonary Interleukin (IL)-6 [8]. IL-6 affects a variety of biological functions, including immunoglobulin production, the acute phase response and inflammation. IL-6 is assumed to be a proximal mediator of pulmonary injury promoting lung neutrophil (polymorhonuclear leucocytes, PMN) infiltration. As reported by Solomkin locally instilled IL-6 resulted in a significant increase of PMN infiltration and lung injury [9]. This might support the hypothesis that locally generated IL-6 exerts pro-inflammatory effects that are central in pulmonary damage. However, the role of IL-6 in the pathophysiology of remote lung injury is still discussed controversially. After intraperitoneal administration of LPS a more severe pulmonary hemorrhage in IL-6−/− mice than in WT animals has been observed, suggesting that IL-6 is protective against hemorrhagic organ damage related to LPS [2]. Thus, it appears that the role of IL-6 in acute inflammation depends on the stimulus and/or the model of inflammation used [10].
Therefore, further studies on the influence of trauma and hemorrhage on the immune function of alveolar macrophages are needed to clarify the importance of these cells in the development of complications after multiple trauma. Furthermore, the role of IL-6 within these pathophysiological changes has to be observed. In the present study we investigated the effects of femoral fracture with or without an additional hemorrhage on the immune function of alveolar macrophages and the remote pulmonary organ damage, and evaluated the role if pulmonary IL-6 under these conditions.
Section snippets
Animal care
Prior to initiation, the study was approved by the Animal Welfare Committee of the State of Lower Saxony. The experiments were performed in 18 male Bl6;12952-IL6tmlKopf IL-6 knockout (IL-6−/−) mice aged 10–12 weeks and weighing 22.0 ± 3.0 g. As a control 18 male C57Bl/6 wild type (WT) mice of similar weight were used. Genetically, C57Bl/6 mice are the background strain for the IL-6 knockout (IL-6−/−) mice. Animals were bred and raised under specific pathogen free conditions in the central animal
Survival rates
All animals survived the induction of the femoral fracture as well as the combination with hemorrhagic shock until the end of the observation period. Therefore no differences between the WT and IL-6−/− groups were observed.
Tumor-necrosis-factor-α (TNF-α)
An isolated femoral fracture resulted in a significantly increased TNF-α productive capacity of alveolar macrophages in WT (WT-Fx: 381.4 ± 175.1 pg/ml) and IL-6−/− mice (IL-6−/−-Fx: 217.5 ± 144.6 pg/ml) compared to sham animals (WT-S: 12.4 ± 4.3 pg/ml, IL-6−/−-S: 5.5 ± 3.1 pg/ml, p <
Discussion
Macrophages play an important role in regulating the immune response after trauma and hemorrhagic shock [12], [13]. Stimulation of macrophages is recognized as a physiological reaction of the organism to restore homeostasis. However, excessive and prolonged activation of macrophages in combination with other leukocytes and endothelial cells also significantly contributes to the development of the systemic inflammatory response syndrome and posttraumatic immunosuppression, which ultimately may
Conclusions
The results of the present study support the pivotal role of IL-6 in the pulmonary inflammatory response after trauma as the absence of IL-6 resulted in a significantly decreased release of pro-inflammatory cytokines and chemokine MCP-1, which was associated with reduced remote pulmonary damage. Therefore, IL-6 may represent a potential therapeutic target for posttraumatic immune modulation. Furthermore, adequate strategies for the treatment of femoral fractures have to be developed, as already
References (41)
- et al.
Effects of hypothermia and re-warming on the inflammatory response in a murine multiple hit model of trauma
Cytokine
(2005) - et al.
Androstenediol ameliorates alterations in immune cells cytokine production capacity in a two-hit model of trauma-hemorrhage and sepsis
Cytokine
(2006) - et al.
Kupffer cells and their mediators: the culprits in producing distant organ damage after trauma-hemorrhage
Am J Pathol
(2006) - et al.
Acute alcohol intoxication and gadolinium chloride attenuate endotoxin-induced release of CC chemokines in the rat
Alcohol
(2000) - et al.
Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment
Immunity
(1997) - et al.
Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent
Hepatology
(1997) - et al.
Comparison of the effects of aging and IL-6 on the hepatic inflammatory response in two models of systemic injury: scald injury versus i.p. LPS administration
Shock
(2009) - et al.
Role of interleukin-6 in fibrinolytic changes induced by lipopolysaccharide in mice
Blood Coagul Fibrinolysis
(2006) - et al.
Lung contusion: inflammatory mechanisms and interaction with other injuries
Shock
(2009) - et al.
Effects of macrophage inducible nitric oxide synthase in murine septic lung injury
Am J Physiol Lung Cell Mol Physiol
(2006)
Cardiopulmonary, histological, and inflammatory alterations after lung contusion in a novel mouse model of blunt chest trauma
Shock
Induction of apoptosis following blunt chest trauma
Shock
Pulmonary contusion induces alveolar type 2 epithelial cell apoptosis: role of alveolar macrophages and neutrophils
Shock
Cytokine expression by neutrophils and macrophages in vivo: endotoxin induces tumor necrosis factor-alpha, macrophage inflammatory protein-2, interleukin-1 beta, and interleukin-6 but not RANTES or transforming growth factor-beta 1 mRNA expression in acute lung inflammation
Am J Respir Cell Mol Biol
Focus on “Essential role for IL-6 in postresuscitation inflammation in hemorrhagic shock”
Am J Physiol Cell Physiol
IL-6 knock-out mice exhibit resistance to splanchnic artery occlusion shock
J Leukoc Biol
Potential role of hepatic macrophages in neutrophil-mediated liver injury in rats with sepsis
Hepatology
Hemorrhage induces enhanced Kupffer cell cytotoxicity while decreasing peritoneal or splenic macrophage capacity. Involvement of cell-associated tumor necrosis factor and reactive nitrogen
J Immunol
Injury, sepsis, and the regulation of toll-like receptor responses
J Leukoc Biol
Effect of gender and sex hormones on immune responses following shock
Shock
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