Clinical hypothermia temperatures increase complement activation and cell destruction via the classical pathway

Journal of Translational Medicine

Kenji M Cunnion²  Neel K Krishna³  William Thomas Bass²  Michael P Stolz¹  Amandeep Sandhu³  Pamela S Hair¹  Clifford T Mauriello¹  Tushar A Shah² 

[1] Department of Pediatrics, Eastern Virginia Medical School, 855 West Brambleton Avenue, Norfolk, VA 23510, USA;Children’s Hospital of The King’s Daughters, 601 Children’s Lane, Norfolk, VA 23507, USA;Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, 700 West Olney Road, Norfolk, VA 23507-1696, USA

关键词: Inflammation;    Ischemia-reperfusion injury;    Complement inhibitor;    Classical pathway;    Complement;    Therapeutic hypothermia;   

Others  :  802500
DOI  :  10.1186/1479-5876-12-181

 received in 2013-12-11, accepted in 2014-06-16,  发布年份 2014

【 摘 要 】

Background

Therapeutic hypothermia is a treatment modality that is increasingly used to improve clinical neurological outcomes for ischemia-reperfusion injury-mediated diseases. Antibody-initiated classical complement pathway activation has been shown to contribute to ischemia-reperfusion injury in multiple disease processes. However, how therapeutic hypothermia affects complement activation is unknown. Our goal was to measure the independent effect of temperature on complement activation, and more specifically, examine the relationship between clinical hypothermia temperatures (31–33°C), and complement activation.

Methods

Antibody-sensitized erythrocytes were used to assay complement activation at temperatures ranging from 0-41°C. Individual complement pathway components were assayed by ELISA, Western blot, and quantitative dot blot. Peptide Inhibitor of complement C1 (PIC1) was used to specifically inhibit activation of C1.

Results

Antibody-initiated complement activation resulting in eukaryotic cell lysis was increased by 2-fold at 31°C compared with 37°C. Antibody-initiated complement activation in human serum increased as temperature decreased from 37°C until dramatically decreasing at 13°C. Quantitation of individual complement components showed significantly increased activation of C4, C3, and C5 at clinical hypothermia temperatures. In contrast, C1s activation by heat-aggregated IgG decreased at therapeutic hypothermia temperatures consistent with decreased enzymatic activity at lower temperatures. However, C1q binding to antibody-coated erythrocytes increased at lower temperatures, suggesting that increased classical complement pathway activation is mediated by increased C1 binding at therapeutic hypothermia temperatures. PIC1 inhibited hypothermia-enhanced complement-mediated cell lysis at 31°C by up to 60% (P = 0.001) in a dose dependent manner.

Conclusions

In summary, therapeutic hypothermia temperatures increased antibody-initiated complement activation and eukaryotic cell destruction suggesting that the benefits of therapeutic hypothermia may be mediated via other mechanisms. Antibody-initiated complement activation has been shown to contribute to ischemia-reperfusion injury in several animal models, suggesting that for diseases with this mechanism hypothermia-enhanced complement activation may partially attenuate the benefits of therapeutic hypothermia.

【 授权许可】

   
2014 Shah et al.; licensee BioMed Central Ltd.

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