Role of Covalent Modification of Hyaluronan with Inter-Alpha Inhibitor Heavy Chains During Acute Lung Injury

The extracellular matrix (ECM) provides a structural and signaling platform for cells that comprise various organs, playing a critical role in tissue maintenance, injury, and repair. Hyaluronan (also known as hyaluronic acid, HA) is a ubiquitous ECM polysaccharide consisting of a repeating disaccharide backbone that can be covalently modified by the heavy chains (HC) of the serum protein inter-alpha-inhibitor (IαI) during inflammation. Known as the only covalent modification of HA, the HC linking of HA is exclusively mediated by the inflammation-induced secreted enzyme TNFα-stimulated gene-6 (TSG-6). Mice deficient for HC-HA formation, due to the lack of either TSG-6 or IαI, display reduced survival during systemic lipopolysaccharide (LPS)-induced endotoxic shock and its associated acute lung injury. We therefore hypothesized that HC-HA should play an important protective role against acute lung injury induced by intratracheal LPS or Pseudomonas aeruginosa (PA) gram-negative bacteria. We also identified that lung instillation of LPS or PA caused rapid induction of lung parenchymal HC-HA that was largely cleared during resolution of injury, indicative of a high rate of HA turnover and remodeling during reversible lung injury. However, using TSG-6 knockout mice, we determined that HC-HA exerted minimal protective effects against intratracheal LPS or PA-induced acute lung injury. To better address the differential roles of HC-HA during systemic versus localized intratracheal exposure to LPS, we characterized and compared the induction of HC-HA in plasma and lung in these two models. While lung parenchymal HC-HA formed in both injury models, intravascular HC-HA and TSG-6 were exclusively induced during systemic LPS exposure and were associated with improved outcomes, including decreased number of circulating neutrophils and plasma TNFα levels. Our results suggest that LPS induces HC-HA formation in various tissues depending on the route of exposure and that the specific intravascular induction of HCHA during systemic LPS exposure may have a protective role during endotoxic shock.

Author dc:creator

• Ni, Kevin Chen

Advisors dc:contributor.advisor

• Petrache, Irina
• Evans-Molina, Carmella

• TSG-6 TNF stimulated gene 6
• Acute lung injury
• Endotoxic shock
• Hyaluronan
• LaI inter alpha inhibitor
• Respiratory infection

Language dc:language.iso

en

Identifier URI

http://dx.doi.org/10.7912/C2/1790

OAI identifier oai:identifier

oai:scholarworks.indianapolis.iu.edu:1805/19248