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Traffic of leukocytes and cytokine up-regulation in the central nervous system in sepsis

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Abstract

Purpose

To evaluate the effects of sepsis on brain microvasculature leukocyte rolling and adherence, myeloperoxidase (MPO) activity, cytokine and chemokine concentrations, and behavioral screening 6, 12, and 24 h after sepsis induction.

Methods

C57BL/6 mice or Wistar rats underwent cecal ligation and perforation (CLP) or sham operation. At 6, 12, and 24 h after sepsis induction, intravital microscopy was performed in the mice brain microvasculature to evaluate leukocyte rolling and adherence. Animals were killed and had the brain removed to determine MPO activity and the levels of cytokines and chemokines. A behavioral screening was also performed in a separate cohort of animals. Blood–brain barrier (BBB) permeability and cytokines and chemokines were determined in different brain regions in Wistar rats.

Results

There was a decrease in circulating leukocyte levels at 6, 12, and 24 h, an increase in rolling and adhesion of leukocytes in the brain microvasculature, followed by an increase in brain MPO activity. In addition, there was an increase in both brain cytokines and chemokines at different times. There was a decrease in the neuropsychiatric state muscle tone and strength only at 6 h, and a decrease in the autonomous function at 6 and 12 h. The pattern of brain cytokines and chemokines, and BBB permeability between the analyzed regions seemed to be similar with minor differences.

Conclusions

During sepsis the brain’s production of cytokines and chemokines is an early event and it seemed to participate both in central nervous system (CNS) dysfunction and BBB permeability alterations, reinforcing the role of brain inflammatory response in the acute CNS dysfunction associated with sepsis.

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Acknowledgments

This research was supported by grants from CNPq (JQ and FD-P), FAPESC (JQ and FD-P), UNESC (JQ and FD-P) and Rede Instituto Brasileiro de Neurociência (ALT). ALT, JQ, and FD-P are CNPq Research Fellows. CMC, MCV, and FP are holders of CNPq Studentships, LSC is holder of a FAPESC studentship, and DHR and NLQ are holders of CAPES studentships.

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Authors and Affiliations

  1. Laboratório de Neurociências, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, 88806-000, Brazil

    Clarissa M. Comim & João Quevedo

  2. Laboratório de Fisiopatologia Experimental, Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, 88806-000, Brazil

    Larissa S. Constantino, Fabrícia Petronilho, Franciele Vuolo, João Luiz da Rocha & Felipe Dal-Pizzol

  3. Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil

    Márcia C. Vilela, Norinne Lacerda-Queiroz, David H. Rodrigues & Antônio L. Teixeira

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  1. Clarissa M. Comim
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  2. Márcia C. Vilela
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  3. Larissa S. Constantino
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  4. Fabrícia Petronilho
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  5. Franciele Vuolo
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  6. Norinne Lacerda-Queiroz
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  7. David H. Rodrigues
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  8. João Luiz da Rocha
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  9. Antônio L. Teixeira
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  10. João Quevedo
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  11. Felipe Dal-Pizzol
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Corresponding author

Correspondence to Felipe Dal-Pizzol.

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134_2011_2151_MOESM1_ESM.tif

Figure 1. Plasma cytokines and chemokines levels after CLP in the mice. Sepsis was induced and after 6, 12, and 24 h cytokine (IL-10, TNF-α) and chemokine (CXCL1/Kc, CCL5/RANTES) levels were measured in the plasma from CLP and sham groups using ELISA kits. Data indicate mean ± SEM, 8 mice per group. One-way ANOVA with Newman–Keuls correction, *p < 0.05, **p < 0.01, and ***p < 0.001. (TIFF 445 kb)

134_2011_2151_MOESM2_ESM.doc

Figure 2. Myeloperoxidase activity in the brain after CLP. Sepsis was induced and after 6, 12, and 24 h brain myeloperoxidase activity was measured spectrophotometrically in brain extracts from CLP and sham groups in both mice (A) and rat (B). Data indicate mean ± SEM, 8 animals per group. One-way ANOVA with Newman–Keuls correction, *p < 0.05, **p < 0.01, and ***p < 0.001. (DOC 101 kb)

134_2011_2151_MOESM3_ESM.doc

Figure 3. Cytokine and chemokine levels in different brain regions after CLP in the rat. Sepsis was induced and after 6, 12, and 24 h cytokine (IL-1β, IL-10, TNF-α) and chemokine (CXCL1, CCL2/MCP-1) levels were measured in the hippocampus, cerebellum, cortex, and pre-frontal cortex using ELISA kits. Data indicate mean ± SEM, 8 rats per group. One-way ANOVA with Newman–Keuls correction, *p < 0.05, **p < 0.01, and ***p < 0.001. (DOC 164 kb)

134_2011_2151_MOESM4_ESM.doc

Figure 4. Brain histopathological alterations in an animal model of sepsis. Sepsis was induced and after A 6, B 12, C 24 h brain histopathological alterations were determined by a blinded pathologist. Representative illustrations from the cortex (n = 12). Hematoxylin and eosin; original magnification, ×400. (DOC 23451 kb)

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Comim, C.M., Vilela, M.C., Constantino, L.S. et al. Traffic of leukocytes and cytokine up-regulation in the central nervous system in sepsis. Intensive Care Med 37, 711–718 (2011). https://doi.org/10.1007/s00134-011-2151-2

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  • DOI: https://doi.org/10.1007/s00134-011-2151-2

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