Changes to the extracellular matrix (ECM) help direct the inflammatory response to tissue injury and resolution of inflammation. During inflammation, TNF-stimulated gene-6 (TSG-6) covalently modifies the ECM polysaccharide hyaluronic acid (HA) with the heavy chains (HCs) from the serum protein inter-alpha-inhibitor (I?I). This cross-linking of HA is exclusively carried out by TSG-6 and only occurs during tissue injury, where inflammatory mediators are present to induce TSG-6 secretion and leaky vessels allow serum I?I to enter tissue. While HA cross-linking is present in histopathological lesions of various chronic lung diseases, the presence and role of TSG-6 mediated cross-linking in acute lung injury remains undefined. This proposal will establish for the first time the role of HA cross-linking in directing leukocyte recruitment and delaying resolution during acute lung inflammation. The clinically relevant murine model of Pseudomonas aeruginosa (PA) induced acute lung injury and repair will be used to test the hypothesis that TSG-6 mediated HA cross-linking mediates the recruitment of pro-inflammatory macrophages to the airway (Aim 1) and prolongs inflammation (Aim 2).
In Aim 1, we will utilize mice deficient for TSG-6 and I?I as well as TSG-6 supplementation in I?I mice to specifically determine the role of TSG-6 mediated HA cross-linking in the recruitment of pro-inflammatory macrophages.
In Aim 2, we will utilize TSG-6 loss of function approaches (TSG-6 null mice and neutralization antibody) to determine the effect of inhibiting TSG-6 on the rate of epithelial repair following PA infection. Completion of these aims will establish a new understanding of the role of TSG-6 induction in the lung and its evolutionarily conserved modifying of HA during inflammation that may yield new therapeutic strategies for lung repair.

Public Health Relevance

Acute lung injury is a major cause of morbidity and mortality in critically ill patients. We have discovered that the extracellular sugar molecule hyaluronic acid present throughout lung tissue is extensively modified during acute lung injury and propose that this hyaluronic acid modification mediates the recruitment of inflammatory cells and delays repair following bacterial infection of the lungs. Completion of this study provides a new mechanism by which the extracellular matrix directs the lung?s response to acute injury and repair.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30HL136169-01A1
Application #
9470535
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Tigno, Xenia
Project Start
2018-02-01
Project End
2021-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206