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Modulation of chemokine gradients by apheresis redirects leukocyte trafficking


Crit Care. 2014 Jul 3;18(4):R141. doi: 10.1186/cc13969.

Modulation of chemokine gradients by apheresis redirects leukocyte trafficking to different compartments during sepsis, studies in a rat model.

Peng ZY, Bishop JV, Wen XY, Elder MM, Zhou F, Chuasuwan A, Carter MJ, Devlin JE, Kaynar AM, Singbartl K, Pike F, Parker RS, Clermont G, Federspiel WJ, Kellum JA.


Abstract


INTRODUCTION:

Prior work suggests that leukocyte trafficking is determined by local chemokine gradients between the nidus of infection and the plasma. We 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 whether 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:

In total, 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 4 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 distributions were compared with one-way analysis of variance, and numeric data not normally distributed were compared with the 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 histologic 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 the efficacy of apheresis to target this mechanism and reduce leukocyte infiltration into the lung.

http://www.ncbi.nlm.nih.gov/pubmed/24992991


Link to Cytosorbents:

Treatment with an immune modulating device restores cytokine
gradients between infected tissue and systemic circulation.
Leukocytes are redirected toward the infection and away from healthy tissue.

SEPsIS: Systems Engineering of a Pheresis Intervention for Sepsis
PI: John A. Kellum, MD

Co-Investigators: Vincent Capponi, MS; Phil Chan, MD; Steven Chang, MD; Gilles Clermont, MD; William Federspiel, PhD; Lan Kong, PhD; Robert Parker, PhD; Kai Singbartl, MD; Yoram Vodovotz, PhD; William Wagner, PhD; Lisa Weissfeld, PhD

Funding: NIH R01HL080926

www.sepsisbrp.org

Sepsis kills more than a quarter of a million patients per year in the US alone. Treatments are limited primarily to supportive care. Our project seeks to develop a device to treat sepsis by reprogramming the immune response and redirecting immune effector cells to the nidus of infection and away from healthy tissue.

http://www.ccm.pitt.edu/research/projects/sepsis-systems-engineering-pheresis-intervention-sepsis