Modulation of chemokine gradients by apheresis redirects leukocyte trafficking to different compartments during sepsis, studies in a rat model
Zhi-Yong Peng, Jeffery V Bishop, Xiao-Yan Wen, Michele M Elder, Feihu Zhou, Anan Chuasuwan, Melinda J Carter, Jason E Devlin, A Murat Kaynar, Kai Singbartl, Francis Pike, Robert S Parker, Gilles Clermont, William J Federspiel and John A Kellum
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Critical Care 2014, 18:R141 doi:10.1186/cc13969
Published: 3 July 2014
Abstract (provisional)
Introduction
Prior work suggests that leukocyte trafficking is determined by local chemokine gradients between the nidus of infection and the plasma. We have recently demonstrated that therapeutic apheresis can alter immune mediator concentrations in the plasma, protect against organ injury, and improve survival. Here we aimed to determine if the removal of chemokines from the plasma by apheresis in experimental peritonitis changes chemokine gradients and subsequently enhances leukocyte localization into the infected compartment, and away from healthy tissues.
Methods
A total of 76 male adult Sprague-Dawley rats weighing 400 g to 600 g were included in this study. Eighteen hours after inducing sepsis by cecal ligation and puncture, we randomized these rats to apheresis or sham treatment for four hours. Cytokines, chemokines and leukocyte counts from blood, peritoneal cavity and lung were measured. In a separate experiment, we labeled neutrophils from septic donor animals and injected them into either apheresis or sham-treated animals. All numeric data with normal distribution were compared with one-way analysis of variance, and numeric data not normally distributed were compared with Mann-Whitney U test.
Results
Apheresis significantly removed plasma cytokines and chemokines, increased peritoneal fluid to blood chemokine (C-X-C motif ligand 1, ligand 2, and C-C motif ligand 2) ratios, and decreased bronchoalveolar lavage fluid to blood chemokine ratios resulting in enhanced leukocyte recruitment into the peritoneal cavity and improved bacterial clearance, but decreased recruitment into the lung. Apheresis also reduced myeloperoxidase activity and histological injury in the lung, liver and kidney. These Labeled donor neutrophils exhibited decreased localization in the lung when infused into apheresis treated animals.
Conclusions
Our results support the concept of chemokine gradient control of leukocyte trafficking and demonstrate efficacy of apheresis to target this mechanism and reduce leukocyte infiltration into the lung.
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