Productive capacity of alveolar macrophages and pulmonary organ damage after femoral fracture and hemorrhage in IL-6 knockout mice

Abstract

Alveolar macrophages (AM) play an important role in the pathogenesis of posttraumatic pulmonary failure, and have been identified as major source of pulmonary cytokines. The effects of locally generated IL-6 as well as femoral fracture on the pulmonary inflammatory response and organ damage have not been fully elucidated. In the present study we evaluated the influence of femoral fracture, isolated or in combination with hemorrhage, on the immune function of AM and remote lung injury, and investigated the role of pulmonary IL-6 within this setting. 18 wild type (WT) and 18 IL-6 knockout mice (IL-6(-/-)) underwent standardized femoral fracture, isolated or in combination with volume-controlled hemorrhage, followed by fluid resuscitation and splint fixation of the fracture. Animals were sacrificed 4h after induction of fracture and hemorrhage. Animals were randomly assigned to three study groups (each consisting of six animals). Besides sham groups, experimental groups included animals with isolated femoral fracture or in combination with hemorrhagic shock. Cytokine release of AM was determined by flow cytometry. Pulmonary damage in terms of interstitial thickening and lung neutrophil infiltration was assessed by histology and immunohistology. The productive capacity of AM for pro-inflammatory cytokines was increased after isolated femoral fracture in WT and IL-6(-/-) mice. An additional hemorrhagic insult resulted in a further enhancement of pro-inflammatory cytokine release and an increased MCP-1 secretion in WT and IL-6(-/-) animals. MCP-1 and pro-inflammatory cytokine production of AM was attenuated in IL-6(-/-) mice compared to the respective WT groups. Interstitial thickening and lung neutrophil infiltration was only observed after femoral fracture combined with hemorrhagic shock with an attenuation of the pulmonary organ damage in IL-6(-/-) compared to WT animals. These results support the role of IL-6 as a therapeutic target for posttraumatic immune modulation. With an increased pro-inflammatory mediator release, already an isolated femoral fracture seems to influence the immune response of AM.