Indiana University-Purdue University Indianapolis (IUPUI) / 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.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/19248 |
| Date | 04 1900 |
| Creators | Ni, Kevin Chen |
| Contributors | Petrache, Irina, Evans-Molina, Carmella, Dong, X. Charlie, Goebl, Mark G., Wek, Ronald C. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
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