The perinatal lung is at risk for a variety of injuries that can lead to chronic lung disease, in part because if immature defenses, and in part, because of the potentially deleterious effects of ventilator interventions. Premature infants ventilated with supplemental oxygen can acquire injured lungs that exhibit edema, inflammation, and alveolar destruction. These responses can lead to fibrosis and abnormal lung growth. We have recently found that members of the syndecan family of cell surface heparan sulfate proteoglycans we be induced by an antibiotic peptide derived from neutrophils, and can be shed into the fluids in injured tissues, including the tracheal aspirates of ventilated infants. This proposal is based on the hypothesis that the response of the lung to injury is mediated by a variety of cellular effectors whose action can be modified by binding to heparin-like glycosaminoglycans, and that the soluble syndecans can regulate the actions of these effectors. We will evaluate the mechanisms by which the syndecan ectodomains are shed from the cell surface and establish whether the soluble syndecan ectodomains modify the activity of bFGF and HB-EGF, proteases and antiproteases, and the chemokines IP-10 and CATP III. We will assess the syndecan inductive activity of various antibiotic peptides, of purifies wound fluid peptides and recombonant analogs in an attempt of clarify the molecules involved and the mechanism of induction. We will analyze pulmonary secretions of ventilated infants for syndecans and for agents that promote syndecan shedding and syndecan induction. These results will be correlated with clinical and outcome data to gain an insight into the role of the syndecans in the response of the perinatal lung to injury. Elucidating the factors that regulate the activity of the cellular effectors involved in the response to lung injury should lead to novel preventive and therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
1P50HL056398-02
Application #
6273188
Study Section
Project Start
1998-02-01
Project End
1998-11-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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