Intravascular heavy chain-modification of hyaluronan during endotoxic shock

Kevin Ni, Amar Gill, Danting Cao, Kengo Koike, Kelly S. Schweitzer, Stavros Garantziotis, Irina Petrache

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

During inflammation, the covalent linking of the ubiquitous extracellular polysaccharide hyaluronan (HA) with the heavy chains (HC) of the serum protein inter alpha inhibitor (IαI) is exclusively mediated by the enzyme tumor necrosis factor α (TNFα)-stimulated-gene-6 (TSG-6). While significant advances have been made regarding how HC-modified HA (HC-HA) is an important regulator of inflammation, it remains unclear why HC-HA plays a critical role in promoting survival in intraperitoneal lipopolysaccharide (LPS)-induced endotoxemia while exerting only a modest role in the outcomes following intratracheal exposure to LPS. To address this gap, the two models of intraperitoneal LPS-induced endotoxic shock and intratracheal LPS-induced acute lung injury were directly compared in TSG-6 knockout mice and littermate controls. HC-HA formation, endogenous TSG-6 activity, and inflammatory markers were assessed in plasma and lung tissue. TSG-6 knockout mice exhibited accelerated mortality during endotoxic shock. While both intraperitoneal and intratracheal LPS induced HC-HA formation in lung parenchyma, only systemically-induced endotoxemia increased plasma TSG-6 levels and intravascular HC-HA formation. Cultured human lung microvascular endothelial cells secreted TSG-6 in response to both TNFα and IL1β stimulation, indicating that, in addition to inflammatory cells, the endothelium may secrete TSG-6 into circulation during systemic inflammation. These data show for the first time that LPS-induced systemic inflammation is uniquely characterized by significant vascular induction of TSG-6 and HC-HA, which may contribute to improved outcomes of endotoxemia.

Original languageEnglish (US)
Pages (from-to)114-121
Number of pages8
JournalBiochemistry and Biophysics Reports
Volume17
DOIs
StatePublished - Mar 1 2019

Fingerprint

Hyaluronic Acid
Septic Shock
Genes
Lipopolysaccharides
Endotoxemia
Inflammation
Gene Knockout Techniques
Knockout Mice
Lung
Tumor Necrosis Factor-alpha
Plasmas
Acute Lung Injury
Endothelial cells
Endothelium
Polysaccharides
Blood Vessels
Blood Proteins
Endothelial Cells
Tissue
Survival

Keywords

  • Endotoxic shock
  • Hyaluronic acid
  • Inter-alpha-inhibitor
  • Serum-derived hyaluronan-associated protein
  • TNFα stimulated gene 6

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Intravascular heavy chain-modification of hyaluronan during endotoxic shock. / Ni, Kevin; Gill, Amar; Cao, Danting; Koike, Kengo; Schweitzer, Kelly S.; Garantziotis, Stavros; Petrache, Irina.

In: Biochemistry and Biophysics Reports, Vol. 17, 01.03.2019, p. 114-121.

Research output: Contribution to journalArticle

Ni, Kevin ; Gill, Amar ; Cao, Danting ; Koike, Kengo ; Schweitzer, Kelly S. ; Garantziotis, Stavros ; Petrache, Irina. / Intravascular heavy chain-modification of hyaluronan during endotoxic shock. In: Biochemistry and Biophysics Reports. 2019 ; Vol. 17. pp. 114-121.
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