Broad adsorption of sepsis-related PAMP and DAMP molecules, mycotoxins, and cytokines from whole blood using CytoSorb® sorbent porous polymer beads

Maryann C Gruda, Karl-Gustav Ruggeberg, Pamela O'Sullivan, Tamaz Guliashvili, Andrew R Scheirer, Thomas D Golobish, Vincent J Capponi, Phillip P Chan, Maryann C Gruda, Karl-Gustav Ruggeberg, Pamela O'Sullivan, Tamaz Guliashvili, Andrew R Scheirer, Thomas D Golobish, Vincent J Capponi, Phillip P Chan

Abstract

Objective: Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. In sepsis and septic shock, pathogen-associated molecular pattern molecules (PAMPS), such as bacterial exotoxins, cause direct cellular damage and/or trigger an immune response in the host often leading to excessive cytokine production, a maladaptive systemic inflammatory response syndrome response (SIRS), and tissue damage that releases DAMPs, such as activated complement and HMGB-1, into the bloodstream causing further organ injury. Cytokine reduction using extracorporeal blood filtration has been correlated with improvement in survival and clinical outcomes in experimental studies and clinical reports, but the ability of this technology to reduce a broader range of inflammatory mediators has not been well-described. This study quantifies the size-selective adsorption of a wide range of sepsis-related inflammatory bacterial and fungal PAMPs, DAMPs and cytokines, in a single compartment, in vitro whole blood recirculation system.

Measurements and main results: Purified proteins were added to whole blood at clinically relevant concentrations and recirculated through a device filled with CytoSorb® hemoadsorbent polymer beads (CytoSorbents Corporation, USA) or control (no bead) device in vitro. Except for the TNF-α trimer, hemoadsorption through porous polymer bead devices reduced the levels of a broad spectrum of cytokines, DAMPS, PAMPS and mycotoxins by more than 50 percent.

Conclusions: This study demonstrates that CytoSorb® hemoadsorbent polymer beads efficiently remove a broad spectrum of toxic PAMPS and DAMPS from blood providing an additional means of reducing the uncontrolled inflammatory cascade that contributes to a maladaptive SIRS response, organ dysfunction and death in patients with a broad range of life-threatening inflammatory conditions such as sepsis, toxic shock syndrome, necrotizing fasciitis, and other severe inflammatory conditions.

Conflict of interest statement

Competing Interests: Authors Phillip P. Chan, MD, PhD and Vincent J. Capponi, MS, serve as the Chief Executive Officer and Chief Operating Officer of CytoSorbents Corporation, respectively. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Adsorption of cytokines from whole…
Fig 1. Adsorption of cytokines from whole blood with CS hemoadsorptive polymer beads or a control (no polymer) device.
Percent remaining from the mean ± SEM of 4 runs. * p

Fig 2. Adsorption of DAMPs from whole…

Fig 2. Adsorption of DAMPs from whole blood with CS hemoadsorptive polymer beads or a…

Fig 2. Adsorption of DAMPs from whole blood with CS hemoadsorptive polymer beads or a control (no polymer) device.
Percent remaining from the mean ± SEM of 4 runs per analyte. * p

Fig 3. Adsorption of bacterial PAMPs with…

Fig 3. Adsorption of bacterial PAMPs with CS hemoadsorptive polymer beads or a control (no…

Fig 3. Adsorption of bacterial PAMPs with CS hemoadsorptive polymer beads or a control (no polymer) device from whole blood spiked with S. pyogenic exotoxin B, Staph TSST-1 or serum with Staph aureus alpha-toxin.
Percent remaining from the mean ± SEM of 4 runs. * p

Fig 4. Adsorption of mycotoxins with CS…

Fig 4. Adsorption of mycotoxins with CS hemoadsorptive polymer beads or a control (no polymer)…

Fig 4. Adsorption of mycotoxins with CS hemoadsorptive polymer beads or a control (no polymer) device from whole blood spiked with A. flavus aflatoxin B1 (10 mg/L) or Fusarium T-2 toxin (10 mg/L).
Percent remaining from the mean ± SEM of 4 runs. * p
Similar articles
Cited by
References
    1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801–10. doi: 10.1001/jama.2016.0287 - DOI - PMC - PubMed
    1. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007;81(1):1–5. doi: 10.1189/jlb.0306164 - DOI - PubMed
    1. Wiersinga WJ, Leopold SJ, Cranendonk DR, van der Poll T. Host innate immune responses to sepsis. Virulence. 2014;5(1):36–44. doi: 10.4161/viru.25436 - DOI - PMC - PubMed
    1. Ito T. PAMPs and DAMPs as triggers for DIC. J Intensive Care. 2014;2(1):67 doi: 10.1186/s40560-014-0065-0 - DOI - PMC - PubMed
    1. Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR, et al. Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med. 2007;167(15):1655–63. doi: 10.1001/archinte.167.15.1655 - DOI - PMC - PubMed
Show all 53 references
Publication types
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Grant support
All authors are employed by CytoSorbents Corporation and receive salary and stock compensation. This study is based upon work supported by DARPA and SSC Pacific under Contract N66001-12-C-4199, work supported by the ACC-APG under Contract W911QY-16-P-0048 and work supported by CytoSorbents Corporation. The content of this publication does not constitute approval by the government of the findings or conclusions herein. Authors Phillip P. Chan, MD, PhD and Vincent J. Capponi, MS, serve as the Chief Executive Officer and Chief Operating Officer of CytoSorbents Corporation, respectively. Hence, as stated in the author contributions, CytoSorbents Corporation had a role in the study design, decision to publish and editing of the manuscript.
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Fig 2. Adsorption of DAMPs from whole…
Fig 2. Adsorption of DAMPs from whole blood with CS hemoadsorptive polymer beads or a control (no polymer) device.
Percent remaining from the mean ± SEM of 4 runs per analyte. * p

Fig 3. Adsorption of bacterial PAMPs with…

Fig 3. Adsorption of bacterial PAMPs with CS hemoadsorptive polymer beads or a control (no…

Fig 3. Adsorption of bacterial PAMPs with CS hemoadsorptive polymer beads or a control (no polymer) device from whole blood spiked with S. pyogenic exotoxin B, Staph TSST-1 or serum with Staph aureus alpha-toxin.
Percent remaining from the mean ± SEM of 4 runs. * p

Fig 4. Adsorption of mycotoxins with CS…

Fig 4. Adsorption of mycotoxins with CS hemoadsorptive polymer beads or a control (no polymer)…

Fig 4. Adsorption of mycotoxins with CS hemoadsorptive polymer beads or a control (no polymer) device from whole blood spiked with A. flavus aflatoxin B1 (10 mg/L) or Fusarium T-2 toxin (10 mg/L).
Percent remaining from the mean ± SEM of 4 runs. * p
Similar articles
Cited by
References
    1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801–10. doi: 10.1001/jama.2016.0287 - DOI - PMC - PubMed
    1. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007;81(1):1–5. doi: 10.1189/jlb.0306164 - DOI - PubMed
    1. Wiersinga WJ, Leopold SJ, Cranendonk DR, van der Poll T. Host innate immune responses to sepsis. Virulence. 2014;5(1):36–44. doi: 10.4161/viru.25436 - DOI - PMC - PubMed
    1. Ito T. PAMPs and DAMPs as triggers for DIC. J Intensive Care. 2014;2(1):67 doi: 10.1186/s40560-014-0065-0 - DOI - PMC - PubMed
    1. Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR, et al. Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med. 2007;167(15):1655–63. doi: 10.1001/archinte.167.15.1655 - DOI - PMC - PubMed
Show all 53 references
Publication types
Related information
Grant support
All authors are employed by CytoSorbents Corporation and receive salary and stock compensation. This study is based upon work supported by DARPA and SSC Pacific under Contract N66001-12-C-4199, work supported by the ACC-APG under Contract W911QY-16-P-0048 and work supported by CytoSorbents Corporation. The content of this publication does not constitute approval by the government of the findings or conclusions herein. Authors Phillip P. Chan, MD, PhD and Vincent J. Capponi, MS, serve as the Chief Executive Officer and Chief Operating Officer of CytoSorbents Corporation, respectively. Hence, as stated in the author contributions, CytoSorbents Corporation had a role in the study design, decision to publish and editing of the manuscript.
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM

NCBI Literature Resources

MeSH PMC Bookshelf Disclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

Follow NCBI
Fig 3. Adsorption of bacterial PAMPs with…
Fig 3. Adsorption of bacterial PAMPs with CS hemoadsorptive polymer beads or a control (no polymer) device from whole blood spiked with S. pyogenic exotoxin B, Staph TSST-1 or serum with Staph aureus alpha-toxin.
Percent remaining from the mean ± SEM of 4 runs. * p

Fig 4. Adsorption of mycotoxins with CS…

Fig 4. Adsorption of mycotoxins with CS hemoadsorptive polymer beads or a control (no polymer)…

Fig 4. Adsorption of mycotoxins with CS hemoadsorptive polymer beads or a control (no polymer) device from whole blood spiked with A. flavus aflatoxin B1 (10 mg/L) or Fusarium T-2 toxin (10 mg/L).
Percent remaining from the mean ± SEM of 4 runs. * p
Similar articles
Cited by
References
    1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801–10. doi: 10.1001/jama.2016.0287 - DOI - PMC - PubMed
    1. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007;81(1):1–5. doi: 10.1189/jlb.0306164 - DOI - PubMed
    1. Wiersinga WJ, Leopold SJ, Cranendonk DR, van der Poll T. Host innate immune responses to sepsis. Virulence. 2014;5(1):36–44. doi: 10.4161/viru.25436 - DOI - PMC - PubMed
    1. Ito T. PAMPs and DAMPs as triggers for DIC. J Intensive Care. 2014;2(1):67 doi: 10.1186/s40560-014-0065-0 - DOI - PMC - PubMed
    1. Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR, et al. Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med. 2007;167(15):1655–63. doi: 10.1001/archinte.167.15.1655 - DOI - PMC - PubMed
Show all 53 references
Publication types
Related information
Grant support
All authors are employed by CytoSorbents Corporation and receive salary and stock compensation. This study is based upon work supported by DARPA and SSC Pacific under Contract N66001-12-C-4199, work supported by the ACC-APG under Contract W911QY-16-P-0048 and work supported by CytoSorbents Corporation. The content of this publication does not constitute approval by the government of the findings or conclusions herein. Authors Phillip P. Chan, MD, PhD and Vincent J. Capponi, MS, serve as the Chief Executive Officer and Chief Operating Officer of CytoSorbents Corporation, respectively. Hence, as stated in the author contributions, CytoSorbents Corporation had a role in the study design, decision to publish and editing of the manuscript.
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Fig 4. Adsorption of mycotoxins with CS…
Fig 4. Adsorption of mycotoxins with CS hemoadsorptive polymer beads or a control (no polymer) device from whole blood spiked with A. flavus aflatoxin B1 (10 mg/L) or Fusarium T-2 toxin (10 mg/L).
Percent remaining from the mean ± SEM of 4 runs. * p

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    1. Ito T. PAMPs and DAMPs as triggers for DIC. J Intensive Care. 2014;2(1):67 doi:
    1. Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR, et al. Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med. 2007;167(15):1655–63. doi:
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