Syndecans, Heparan Sulfate Proteoglycans, Maintain the Proteolytic Balance of Acute Wound Fluids

An imbalance between proteases and antiproteases is thought to play a role in the inflammatory injury that regulates wound healing. The activities of some proteases and antiproteases found in inflammatory fluids can be modified in vitro by heparin, a mast cell-derived glycosaminoglycan. Because syndecans, a family of cell surface heparan sulfate proteoglycans, are the major cellular source of heparin-like glycosaminoglycan, we asked whether syndecans modify protease activities in vivo.Syndecan-1 and syndecan-4 ectodomains are shed into acute human dermal wound fluids (Subramanian, S. V., Fitzgerald, M. L., and Bernfield, M. (1997) J. Biol. Chem. 272, 14713–14720). Moreover, purified syndecan-1 ectodomain binds cathepsin G (K d = 56 nm) and elastase (K d = 35 nm) tightly and reduces the affinity of these proteases for their physiological inhibitors. Purified syndecan-1 ectodomain protects cathepsin G from inhibition by α1-antichymotrypsin and squamous cell carcinoma antigen 2 and elastase from inhibition by α1-proteinase inhibitor by decreasing second order rate constants for protease-antiprotease associations (k ass) by 3700-, 32-, and 60-fold, respectively. Both enzymatic degradation of heparan sulfate and immunodepletion of the syndecan-1 and -4 in wound fluid reduce these proteolytic activities in the fluid, indicating that the proteases in the wound environment are regulated by interactions with syndecan ectodomains. Thus, syndecans are shed into acute wound fluids, where they can modify the proteolytic balance of the fluid. This suggests a novel physiological role for these soluble heparan sulfate proteoglycans. An imbalance between proteases and antiproteases is thought to play a role in the inflammatory injury that regulates wound healing. The activities of some proteases and antiproteases found in inflammatory fluids can be modified in vitro by heparin, a mast cell-derived glycosaminoglycan. Because syndecans, a family of cell surface heparan sulfate proteoglycans, are the major cellular source of heparin-like glycosaminoglycan, we asked whether syndecans modify protease activities in vivo. Syndecan-1 and syndecan-4 ectodomains are shed into acute human dermal wound fluids (Subramanian, S. V., Fitzgerald, M. L., and Bernfield, M. (1997) J. Biol. Chem. 272, 14713–14720). Moreover, purified syndecan-1 ectodomain binds cathepsin G (K d = 56 nm) and elastase (K d = 35 nm) tightly and reduces the affinity of these proteases for their physiological inhibitors. Purified syndecan-1 ectodomain protects cathepsin G from inhibition by α1-antichymotrypsin and squamous cell carcinoma antigen 2 and elastase from inhibition by α1-proteinase inhibitor by decreasing second order rate constants for protease-antiprotease associations (k ass) by 3700-, 32-, and 60-fold, respectively. Both enzymatic degradation of heparan sulfate and immunodepletion of the syndecan-1 and -4 in wound fluid reduce these proteolytic activities in the fluid, indicating that the proteases in the wound environment are regulated by interactions with syndecan ectodomains. Thus, syndecans are shed into acute wound fluids, where they can modify the proteolytic balance of the fluid. This suggests a novel physiological role for these soluble heparan sulfate proteoglycans. Multiple factors orchestrate the inflammatory response to tissue injury. These include proteases, antiproteases, cytokines, chemokines, and the growth factors derived from the plasma and cells associated with the injury, as well as from cells invading the injury site (1Clark R.A.F. The Molecular and Cellular Biology of Wound Repair. 2nd Ed. Plenum Press, New York1996Google Scholar). Emigrating polymorphonuclear leukocytes release proteolytic enzymes into the injury site, including the most potent serine proteases, neutrophil elastase and cathepsin G (CatG). 1The abbreviations used are: CatG, neutrophil cathepsin G; α1-Achy, α1-antichymotrypsin; α1-PI, α1-proteinase inhibitor; SCCA2, squamous cell carcinoma antigen 2; Suc-AAPF-pNA, succinyl-Ala-Ala-Pro-Phe-para-nitroanilide; ACE, affinity co-electrophoresis; HS, heparan sulfate; Hase, heparinase; HSase, heparitinase; GAG, glycosaminoglycan; serpin, serine protease inhibitor; CBZ, benzyloxycarbonyl. These enzymes aid wound repair by digesting extracellular proteins, releasing growth factors from extracellular matrix, and remodeling the tissue (2Taylor J.C. Mittman C. Pulmonary Emphysema and Proteolysis. Academic Press Inc., New York, NY1987Google Scholar, 3Döring G. Am. J. Respir. Crit. Care Med. 1994; 150: S114-S117Crossref PubMed Google Scholar, 4Taipale J. Lohi J. Saarinen J. Kovanen P.T. Keski-Oja J. J. Biol. Chem. 1995; 270: 4689-4696Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar). However, these enzymes can also destroy tissues when proteolysis is prolonged, inappropriate, or excessive (5Bieth J.G. Mecham R.P. Biology of Extracellular Matrix: Regulation of Matrix Accumulation. Academic Press Inc., Orlando, FL1986: 217-320Google Scholar, 6Campbell E.J. Senior R.M. Welgus H.G. Chest. 1987; 92: 161-167Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). Enormous local concentrations of proteases, estimated to be in the millimolar range for elastase and cathepsin G, are released into extracellular spaces during the leukocyte activation associated with tissue injury (7Campbell E.J. Am. Rev. Respir. Dis. 1986; 134: 435-437Crossref PubMed Scopus (4) Google Scholar). Serine protease inhibitors (serpins), provide efficient control mechanisms to prevent undesirable extracellular protein degradation at the injury site (8Travis J. Salvesen G.S. Annu. Rev. Biochem. 1983; 52: 655-709Crossref PubMed Scopus (1484) Google Scholar). These antiproteases, mostly derived from plasma, share three principal properties: (i) they form 1:1 covalent complex with proteases, (ii) complex formation results in both inactivation of the protease and proteolytic cleavage of the serpin, and (iii) inhibition is essentially irreversible (9Gettins P.G.W. Patston P.A. Olson S.T. Serpins: Structure, Function and Biology. R. G. Landes Co., Austin, TX1996Google Scholar). The balance of proteases and antiproteases at the site of injury can regulate the extent of the inflammatory response during the repair process (10Potempa J. Korzus E. Travis J. J. Biol. Chem. 1994; 269: 15957-15960Abstract Full Text PDF PubMed Google Scholar, 11Grinnell F. Zhu M. J. Invest. Dermatol. 1996; 106: 335-341Abstract Full Text PDF PubMed Scopus (177) Google Scholar). Dermal wound repair requires harmonious protease-antiprotease interactions or proteolytic balance. Excessive elastase action in the wound bed can account for endothelial damage (12Coleridge-Smith P.D. Thomas P. Scurr J.H. Dormandy J.A. Br. Med. J. 1988; 296: 1726-1727Crossref PubMed Scopus (506) Google Scholar), degradation of the epidermal/dermal junction (13Briggaman R.A. Schechter N.M. Fraki J. Lazuras G.S. J. Exp. Med. 1984; 160: 1027-1042Crossref PubMed Scopus (171) Google Scholar), and the development of chronic skin ulcers (14Falanga V. J. Invest. Dermatol. 1993; 100: 721-725Abstract Full Text PDF PubMed Google Scholar). Physiological neutrophil elastase inhibitors include plasma-derived α2-macroglobulin and, most importantly, α1-proteinase inhibitor (also known as α1-PI, α1-antitrypsin, or α1-AT). The importance of α1-PI in regulating the response to tissue injury is emphasized by the extensive elastin and collagen fiber destruction leading to pulmonary emphysema in the lungs of individuals with congenital α1-PI deficiency (5Bieth J.G. Mecham R.P. Biology of Extracellular Matrix: Regulation of Matrix Accumulation. Academic Press Inc., Orlando, FL1986: 217-320Google Scholar). The major physiological cathepsin G inhibitor is α1-antichymotrypsin (α1-Achy), another plasma-derived serpin (15Beatty K. Bieth J. Travis J. J. Biol. Chem. 1980; 255: 3931-3934Abstract Full Text PDF PubMed Google Scholar). Inherited α1-Achy deficiency is pleiomorphic, but it is often associated with chronic active hepatitis and increased residual lung volumes (16Eriksson S. Lindmark B. Lilja H. Acta Med. Scand. 1986; 220: 447-453Crossref PubMed Scopus (43) Google Scholar). Another serpin that inhibits cathepsin G is the squamous cell carcinoma antigen 2 (SCCA2), a newly described product of skin and respiratory tract epithelia (17Schick C. Kamachi Y. Bartuski A.J. Cataltepe S. Schechter N.M. Pemperton P.A. Silverman G.A. J. Biol. Chem. 1997; 272: 1849-1855Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar). Although the activity of one class of serpins is accelerated by binding to heparin or other glycosaminoglycans (GAGs) (9Gettins P.G.W. Patston P.A. Olson S.T. Serpins: Structure, Function and Biology. R. G. Landes Co., Austin, TX1996Google Scholar, 18Pratt C.W. Whinna H.C. Church F.C. J. Biol. Chem. 1992; 267: 8795-8801Abstract Full Text PDF PubMed Google Scholar), α1-PI and α1-Achy belong to the class of serpins that function independently of heparin and other GAGs. However, heparin can bind with high affinity to both neutrophil elastase and cathepsin G (19Frommherz K.J. Faller B. Bieth J.G. J. Biol. Chem. 1991; 266: 15356-15362Abstract Full Text PDF PubMed Google Scholar, 20Ermolieff J. Boudier C. Laine A. Meyer B. Bieth J.G. J. Biol. Chem. 1994; 269: 29502-29508Abstract Full Text PDF PubMed Google Scholar). This binding inhibits the enzymatic activities, but most importantly, it reduces the ability of the enzymes to interact with serpins (19Frommherz K.J. Faller B. Bieth J.G. J. Biol. Chem. 1991; 266: 15356-15362Abstract Full Text PDF PubMed Google Scholar, 20Ermolieff J. Boudier C. Laine A. Meyer B. Bieth J.G. J. Biol. Chem. 1994; 269: 29502-29508Abstract Full Text PDF PubMed Google Scholar). The heparin used clinically and in these studies is a product derived from of the heparin mast cells Biol. Google Scholar). The major physiological source of the heparin-like GAG, heparan is found in at the cell surface and in the extracellular M. J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google Scholar). cellular heparan sulfate from the syndecan family of cell surface proteoglycans. This family known as syndecan in of and and well extracellular of syndecans heparan syndecan-1 and can also bind of the factors that orchestrate the inflammatory response to tissue injury as well as a of extracellular and their heparan sulfate and are in and M. R. M. J. E.J. Annu. Rev. Biol. 1992; PubMed Scopus Google Scholar). is regulated during wound wound from the wound of cell surface syndecan-1 K. S. M. M. M. J. Biol. 1991; PubMed Scopus Google Scholar). syndecan-1 the endothelial and syndecan-4 the dermal that form the tissue K. S. M. M. M. J. Biol. 1991; PubMed Scopus Google Scholar, C. R. M. J. Invest. Dermatol. 1996; Full Text PDF PubMed Scopus Google Scholar), to action of M. C. E. M. M. S. A. 1994; PubMed Scopus Google Scholar). cell can be the plasma the soluble ectodomains into the M. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). This is accelerated by activation of protease and growth growth family and by the action of proteases in wound repair M. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). Moreover, soluble syndecan-1 and -4 ectodomains are in acute dermal wound fluids M. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). Although syndecan and are regulated during the response to tissue injury, the role these play in response is of the response to tissue injury is the and of proteolytic balance at the wound The action of the major proteases, neutrophil elastase and cathepsin G, be by their major α1-PI and α1-Achy, for wound repair to of balance can prevent leading to chronic in the skin are to (14Falanga V. J. Invest. Dermatol. 1993; 100: 721-725Abstract Full Text PDF PubMed Google Scholar). that activities of the major proteases in acute wound fluids can be modified in vitro by heparin, soluble syndecan ectodomains be in and the proteolytic balance in in vivo. found syndecan-1 and -4 ectodomains in acute human dermal wound also found that purified syndecan-1 ectodomain binds to both neutrophil elastase and cathepsin G, their affinity for serpins and these enzymes from their physiological inhibitors. Moreover, both degradation of heparan sulfate and of syndecan-1 and -4 from wound fluids reduce proteolytic activities in the fluid. Thus, syndecan ectodomains the proteolytic balance in acute wound fluids, a novel physiological role for soluble heparan sulfate proteoglycans. binding from and from human neutrophil cathepsin G and human plasma α1-PI from human neutrophil elastase from and human plasma α1-Achy from Purified protein a from (17Schick C. Kamachi Y. Bartuski A.J. Cataltepe S. Schechter N.M. Pemperton P.A. Silverman G.A. J. Biol. Chem. 1997; 272: 1849-1855Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar). for cathepsin G and for from and for elastase from Molecular from and sulfate heparan sulfate and from The syndecan-1 ectodomain purified to from the of cells M. A. S. M. J. Biol. 1987; PubMed Scopus Google Scholar). of syndecan-1 protein of H. V. M. Fitzgerald, S. and M. Bernfield, for for ectodomains of human syndecan-1 and -4 in as in by for at with and for purified with with and New to and with used the human syndecan-1 ectodomain C. R. M. J. Invest. Dermatol. 1996; Full Text PDF PubMed Scopus Google from and human and C. R. M. J. Invest. Dermatol. 1996; Full Text PDF PubMed Scopus Google human and and from of to human syndecan-1 used for of and of by and with of of with human syndecan-1 with human syndecan-1 ectodomain purified from of human This as with a to a protein with and as described M. S. A. 1988; PubMed Scopus Google Scholar). cells with and syndecan-1 ectodomain from purified by and M. A. S. M. J. Biol. 1987; PubMed Scopus Google Scholar). of ectodomain to elastase and cathepsin G by as described M. H. M. J. Biol. Chem. 1994; 269: Scholar, S. A. 1991; PubMed Scopus Google Scholar). with concentrations of protease in syndecan-1 ectodomain these the of syndecan-1 with sulfate or heparin to The syndecan-1 a The and used to the of the major syndecan-1 in These as a function of and used to the d as described S. A. 1991; PubMed Scopus Google Scholar). The of proteases and serpins by the of and E. Biochem. PubMed Scopus Google Scholar). by that used in of The of α1-PI and cathepsin G the α1-Achy the cathepsin G. for cathepsin G, and for inhibition by with concentrations of syndecan-1 in the and for at The inhibitor and residual activity by the and at with a or at with a The concentrations for cathepsin G cathepsin G, α1-Achy or SCCA2, and The concentrations for elastase and some syndecan-1 to as with or in of for at and for concentrations of syndecan-1 ectodomain or heparin with protease for at with concentrations of serpin in the and the residual activities with The concentrations for cathepsin G cathepsin G and in cathepsin G The concentrations for elastase elastase and in elastase The rate for the of serpins with and enzymes second order rate (15Beatty K. Bieth J. Travis J. J. Biol. Chem. 1980; 255: 3931-3934Abstract Full Text PDF PubMed Google Scholar). nm) of with or the syndecan-1 ectodomain and inhibitor at for of The by the of for the and the release of or The residual activities used to the of E. used for of in the and of syndecan-1 The rate of in the of is described as where the of the of a second order rate (k human dermal wound fluids from by E. and Wound fluids at from in the fluids for at and to cells and for at and to The at wound fluid and as described M. C. E. M. M. S. A. 1994; PubMed Scopus Google Scholar, K. E. P. J. 1992; 52: Full Text PDF PubMed Scopus Google Scholar). for and the of by the and wound fluids from a for with and for with for syndecan-1 and for by a with or respectively. by to the human wound fluids with and for at in to heparan sulfate in the fluid. heparin to to or fluids, the and activities in the by the for and for at with a or at with a human dermal wound fluids by for with a of of to syndecan-1 and and syndecan-4 and or with of and protein and for activity in elastase by elastase and with at with a Because heparin can elastase and cathepsin G inhibition by plasma-derived serpins (19Frommherz K.J. Faller B. Bieth J.G. J. Biol. Chem. 1991; 266: 15356-15362Abstract Full Text PDF PubMed Google Scholar, 20Ermolieff J. Boudier C. Laine A. Meyer B. Bieth J.G. J. Biol. Chem. 1994; 269: 29502-29508Abstract Full Text PDF PubMed Google Scholar), we that the soluble syndecan ectodomains in wound fluid syndecan-1 ectodomain purified from the of cells with of purified human neutrophil cathepsin G and and α1-PI and The syndecan-1 ectodomain to cathepsin G and elastase at of binding to the antiproteases at concentrations S. A. 1991; PubMed Scopus Google of syndecan-1 ectodomain with cathepsin G and elastase binding and d of 56 for cathepsin G and 35 for elastase and binding to the proteases, sulfate or indicating that the binding is to the heparan sulfate syndecan-1 and The with both enzymes in syndecan-1 ectodomain binding at concentrations the d that are of the ectodomain that in their for the proteases whether the binding of the syndecan-1 ectodomain to the proteases their rate of with a serpin, rate constants (k ass) for these interactions in the and of soluble syndecan-1 ectodomain The protease and serpin form a 1:1 Because heparin or the syndecan-1 ectodomain second order (15Beatty K. Bieth J. Travis J. J. Biol. Chem. 1980; 255: 3931-3934Abstract Full Text PDF PubMed Google Scholar). nm) of protease and serpin in the or of the syndecan-1 ectodomain at concentrations in complex formation by and the activity as described The for the from for cathepsin G with α1-antichymotrypsin and with in the of the syndecan-1 ectodomain The for elastase with α1-proteinase inhibitor by the syndecan-1 ectodomain second order rate constants also for complex formation in the of a heparin to that of the syndecan-1 ectodomain the concentrations the soluble syndecan-1 ectodomain the of at as as The rate for cathepsin G and α1-antichymotrypsin to a extent in the of soluble syndecan-1 ectodomain in the of heparin syndecan-1 ectodomain reduces rate of in a The of the purified syndecan-1 ectodomain protease activity in the and of The ectodomain with cathepsin G or elastase for and for protease activity with or concentrations of serpins Syndecan-1 ectodomain cathepsin G activity in a inhibition at 2 as protein However, the syndecan-1 ectodomain the ability of both α1-Achy and to cathepsin G activity the of these serpins the but with concentrations of their activity is and The syndecan-1 ectodomain in cathepsin G inhibition by = by α1-Achy = with elastase The ectodomain elastase inhibition of the ectodomain also the ability of α1-PI to the protease = These results that syndecan-1 ectodomain reduces the activities of cathepsin G and elastase to extent to that with heparin (19Frommherz K.J. Faller B. Bieth J.G. J. Biol. Chem. 1991; 266: 15356-15362Abstract Full Text PDF PubMed Google Scholar, 20Ermolieff J. Boudier C. Laine A. Meyer B. Bieth J.G. J. Biol. Chem. 1994; 269: 29502-29508Abstract Full Text PDF PubMed Google Scholar). Moreover, binding of the syndecan-1 ectodomain to the proteases protects from inhibition by serpins the syndecan-1 ectodomain are for ability to the proteases from the antiproteases, syndecan-1 with heparin-like of of both and HSase, or sulfate for at with or ectodomain that or with of these enzymes and with and the residual activity by the and elastase or cathepsin G they the activity of these proteases in that by and with both and by the ability of syndecan-1 to cathepsin G antiproteases α1-Achy and and However, of syndecan-1 with or the ability of syndecan-1 to elastase from inhibition by α1-PI or sulfate from syndecan-1 and syndecan-1 ectodomain in the proteases from inhibition by antiproteases Thus, the soluble syndecan-1 ectodomain protects cathepsin G and elastase antiproteases heparan sulfate Wound fluids during dermal wound repair syndecan-1 and of human acute dermal wound fluids, to to human syndecan-1 and to human syndecan-4 syndecan-1 and However, the of syndecan-1 and -4 to these M. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar), and in human plasma M. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). asked whether these syndecan ectodomains modify the balance between the proteases and their inhibitors in the wound fluid. we heparin to wound fluids and the heparan sulfate in the fluid. of as as 2 heparin increased that heparin the balance in of the protease the heparan sulfate with the as in activity This enzymatic degradation activity in wound fluids heparin to the the balance in of the protease and the of activity Thus, the activity of proteases and their inhibitors is in wound fluid, and balance can be by the heparan sulfate in the fluid. whether the syndecan ectodomains the active heparan sulfate in the fluid, wound fluids with the syndecan-1 and -4 ectodomains as a with concentrations of and the activity of syndecan-1 and -4 ectodomains from of wound fluids activity heparin to the balance in of the proteases and the of to that in These that soluble syndecan ectodomains the proteolytic balance of wound fluids but complex with the protease in the of syndecan-1 and -4 from human acute dermal wound fluids reduces their acute wound fluid with purified human syndecan-1 and and syndecan-4 and or with concentrations of the for activity by the and the of acute wound fluids activity immunodepletion of syndecan-1 and -4 in a is we provide into the of protease-antiprotease balance during tissue injury. that syndecan-1 and cell surface heparan sulfate proteoglycans, are shed into wound fluids as soluble ectodomains. These acute dermal wound fluids the proteases cathepsin G and as well as the plasma-derived antiproteases α1-PI and Both degradation of in the wound fluid and immunodepletion of syndecan-1 and -4 from the wound fluids the protease-antiprotease balance of the fluid. vitro studies that balance results from binding of the the ectodomains to cathepsin G and This reduces the ability of the to protease These results that syndecan-1 and -4 are shed into inflammatory fluids, where they modify the proteolytic balance of the The also a novel physiological role for soluble heparan sulfate and to the protease balance of inflammatory Wound repair requires and of a of including chemokines, growth extracellular cell proteins, proteases, and of these bind heparin and heparan sulfate physiological and with high K. 1994; Full Text PDF Scopus (343) Google Scholar). repair of skin injury, cellular of syndecan-1 and -4 is K. S. M. M. M. J. Biol. 1991; PubMed Scopus Google Scholar, C. R. M. J. Invest. Dermatol. 1996; Full Text PDF PubMed Scopus Google Scholar), and cell surface syndecan-1 and -4 are to soluble by cleavage of their extracellular a process known as M. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). studies that syndecan is a regulated process that is by released at the site of tissue injury M. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). a cell surface into a soluble The of these soluble ectodomains are cell can as for growth the action of requires a growth sulfate complex R. H. G. J. Biol. 1996; PubMed Scopus Google Scholar). However, the soluble ectodomains their HS, they can bind the as the cell surface syndecans, to be inhibitors of these the other the soluble ectodomains heparin-like into the wound These can interact with and in the The inflammatory of tissue repair is by plasma and the of that and the remodeling enzymes elastase and cathepsin G. Although heparin binds and activity of some serpins (9Gettins P.G.W. Patston P.A. Olson S.T. Serpins: Structure, Function and Biology. R. G. Landes Co., Austin, TX1996Google Scholar), heparin interact with the serpins that regulate these the enzymes bind heparin, reduces their affinity for the serpin and protects from inhibition (19Frommherz K.J. Faller B. Bieth J.G. J. Biol. Chem. 1991; 266: 15356-15362Abstract Full Text PDF PubMed Google Scholar, 20Ermolieff J. Boudier C. Laine A. Meyer B. Bieth J.G. J. Biol. Chem. 1994; 269: 29502-29508Abstract Full Text PDF PubMed Google Scholar). results that the the soluble syndecan ectodomains action of heparin and regulate the activity of the proteases in the wound environment the syndecan-1 ectodomain are at as in decreasing the protease-antiprotease as of heparin The binding of the syndecan-1 ectodomain for the protease that for heparin with heparin (19Frommherz K.J. Faller B. Bieth J.G. J. Biol. Chem. 1991; 266: 15356-15362Abstract Full Text PDF PubMed Google Scholar, 20Ermolieff J. Boudier C. Laine A. Meyer B. Bieth J.G. J. Biol. Chem. 1994; 269: 29502-29508Abstract Full Text PDF PubMed Google Scholar), the between the syndecan-1 ectodomain and protease inhibits the protease activity but the of protease binding to the serpin is for growth and cell into the wound site, and extracellular degradation P. Welgus H.G. R.A.F. The Molecular and Cellular Biology of Wound Repair. 2nd Ed. Plenum Press, New Scholar). An imbalance of proteolytic activity wound repair and R. Full Text PDF PubMed Scopus Google R. 1996; PubMed Scopus Google Scholar). the soluble ectodomains also heparin to the activity of serpins protease and the ectodomain regulate of proteolysis during wound in with their physiological and their activity is regulated to provide activity for This activity results from a and activation by degradation and The of syndecan ectodomains in regulating proteolytic balance including the of elastase activity and the of degradation in wound fluids F. Zhu M. J. Invest. Dermatol. 1996; 106: 335-341Abstract Full Text PDF PubMed Scopus (177) Google Scholar). that both degradation and immunodepletion of syndecan ectodomains reduce the proteolytic activity of acute wound fluids and that these soluble to proteolytic activity in the wound in proteolytic balance are thought to be one acute and chronic F. Zhu M. J. Invest. Dermatol. 1996; 106: 335-341Abstract Full Text PDF PubMed Scopus (177) Google Scholar, K. J. Invest. Dermatol. 1995; Full Text PDF PubMed Scopus Google Scholar). The high of proteolytic activity in chronic wound fluid to the that proteases to the of chronic to when with and growth factors F. C. A. J. Invest. Dermatol. 1992; Full Text PDF PubMed Scopus Google Scholar, P. 1997; PubMed Scopus Google Scholar). in the of syndecan ectodomains to of proteolytic balance and to development of chronic proteolytic activity is for wound of the tissue injury is in the repair the at the wound and a of serine proteases and to and the An imbalance of proteases and serpins to chronic inflammatory as pulmonary and the development of of and in the in (9Gettins P.G.W. Patston P.A. Olson S.T. Serpins: Structure, Function and Biology. R. G. Landes Co., Austin, TX1996Google Scholar). or syndecans a role in regulating proteolytic activities in these is but in of found that syndecan-1 and -4 ectodomains human acute wound fluids to proteolytic balance. Although the ectodomains of other heparan sulfate that can be as and P. G. H. J. 1992; PubMed Scopus Google and J.C. E. R. B. G. A. J. Biol. 1995; PubMed Scopus Google Scholar, proteolytic balance in the wound environment the to with from growth to skin Thus, syndecan and be in and to modify the response to tissue injury. and for wound fluid Silverman and for and and for