An imbalance between proteinases and antiproteinases is thought to mediate, in part, the inflammatory injury that leads to chronic lung disease in mechanically ventilated pre-term infants. The activities of some proteinases and proteinase inhibitors found in inflammatory fluids can be modifiedin vitro by heparin, a mast cell-derived glycosaminoglycan (GAG). The major cellular source of heparin-like GAG is the syndecan family of transmembrane heparan sulfate proteoglycans, found on the surface of several cell types in the lung.

To determine whether such modifications of these activities occursin vivo, we asked whether syndecans (i) were shed into inflammatory fluids, including tracheal aspirates from ventilated infants (TA), (ii) mimic the action of heparin on proteinases and antiproteinases, and (iii) alter the proteolytic balance of inflammatory fluids. Immunoblots showed that the extracellular domains (ectodomains) of both syndecan-1 and -4 are shed into dermal wound fluid (WF) and into TA. Interestingly, these same syndecans are induced at the cell surface by a neutrophil-derived peptide (Gallo et al, PNAS 1994). Purified syndecan-1 ectodomain mimics the ability of heparin (a) to protect cathepsin G from the inhibition by either alphal-antichymotrypsin or by SCCA2, a newly described serpin found in TA, and (b) to augment the inhibition of thrombin by antithrombin III. Heparinase (degrades heparin-like GAG) treatment of WF reduces while heparitinase (produces heparin-like GAG from syndecan heparan sulfate chains) enhances the proteinase activity of both the elastase and cathepsin G present in WF. Thus, syndecans are shed into inflammatory fluids where they can alter the proteolytic balance of proteases and antiproteases. Attempts to modify proteinase-mediated lung injury should consider the role of syndecan expression and shedding. (Supported by NIH grant HL46491).