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Inter-α-inhibitor Ameliorates Endothelial Inflammation in Sepsis

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Abstract

Purpose

Vascular endothelial cells demonstrate severe injury in sepsis, and a reduction in endothelial inflammation would be beneficial. Inter-α-Inhibitor (IαI) is a family of abundant plasma proteins with anti-inflammatory properties and has been investigated in human and animal sepsis with encouraging results. We hypothesized that IαI may protect endothelia from sepsis-related inflammation.

Methods

IαI-deficient or sufficient mice were treated with endotoxin or underwent complement-induced lung injury. VCAM-1 and ICAM-1 expression was measured in blood and lung as marker of endothelial activation. Human endothelia were exposed to activated complement C5a with or without IαI. Blood from human sepsis patients was examined for VCAM-1 and ICAM-1 and levels were correlated with blood levels of IαI.

Results

IαI-deficient mice showed increased endothelial activation in endotoxin/sepsis- and complement-induced lung injury models. In vitro, levels of endothelial pro-inflammatory cytokines and cell growth factors induced by activated complement C5a were significantly decreased in the presence of IαI. This effect was associated with decreased ERK and NFκB activation. IαI levels were inversely associated with VCAM-1 and ICAM-1 levels in a human sepsis cohort.

Conclusions

IαI ameliorates endothelial inflammation and may be beneficial as a treatment of sepsis.

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Acknowledgements

The authors thank Drs. Michael B. Fessler and John House for constructive criticism, and Ms. Ligon Perrow for excellent animal husbandry. This work was supported, in part, by the Division of Intramural Research, National Institute of Environmental Health Sciences, NIH. Yow-Pin Lim gratefully acknowledges support from NIAID grant 2R42AI062095.

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Authors and Affiliations

  1. National Institute of Environmental Health Sciences, 111 TW Alexander Dr, Research Triangle Park, NC, 27709, USA

    Vandy P. Stober & Stavros Garantziotis

  2. Brown University, East Providence, RI, USA

    Yow-Pin Lim & Steven Opal

  3. Research Complex for Medicine Frontiers, Aichi Medical University, Nagakute, Aichi, Japan

    Lisheng Zhuo & Koji Kimata

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  1. Vandy P. Stober
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  2. Yow-Pin Lim
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  3. Steven Opal
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  4. Lisheng Zhuo
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  6. Stavros Garantziotis
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Contributions

Conception and design: SG. Experiments, analysis, and interpretation: VPS, Y-PL, SO, KK, and LZ. Darfting of manuscript: VPS and SG. Review of manuscript: VPS, Y-PL, SO, KK, LZ, and SG.

Corresponding author

Correspondence to Stavros Garantziotis.

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Conflict of interest

Y-PL is the President and Chief Scientific Officer at ProThera Biologics, LLC, a company which explores the use of IαI in several systemic inflammatory diseases, including sepsis.

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Stober, V.P., Lim, YP., Opal, S. et al. Inter-α-inhibitor Ameliorates Endothelial Inflammation in Sepsis. Lung 197, 361–369 (2019). https://doi.org/10.1007/s00408-019-00228-1

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  • DOI: https://doi.org/10.1007/s00408-019-00228-1

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