Extracellular Superoxide Dismutase Inhibits Inflammation by Preventing Oxidative Fragmentation of Hyaluronan

Abstract

Extracellular superoxide dismutase (EC-SOD) is expressed at high levels in lungs. EC-SOD has a polycationic matrix-binding domain that binds to polyanionic constituents in the matrix. Previous studies indicate that EC-SOD protects the lung in both bleomycin- and asbestos-induced models of pulmonary fibrosis. Although the mechanism of EC-SOD protection is not fully understood, these studies indicate that EC-SOD plays an important role in regulating inflammatory responses to pulmonary injury. Hyaluronan is a polyanionic high molecular mass polysaccharide found in the extracellular matrix that is sensitive to oxidant-mediated fragmentation. Recent studies found that elevated levels of low molecular mass hyaluronan are associated with inflammatory conditions. We hypothesize that EC-SOD may inhibit pulmonary inflammation in part by preventing superoxide-mediated fragmentation of hyaluronan to low molecular mass fragments. We found that EC-SOD directly binds to hyaluronan and significantly inhibits oxidant-induced degradation of this glycosaminoglycan. In vitro human polymorphic neutrophil chemotaxis studies indicate that oxidative fragmentation of hyaluronan results in polymorphic neutrophil chemotaxis and that EC-SOD can completely prevent this response. Intratracheal injection of crocidolite asbestos in mice leads to pulmonary inflammation and injury that is enhanced in EC-SOD knock-out mice. Notably, hyaluronan levels are increased in the bronchoalveolar lavage fluid after asbestos-induced pulmonary injury, and this response is markedly enhanced in EC-SOD knock-out mice. These data indicate that inhibition of oxidative hyaluronan fragmentation probably represents one mechanism by which EC-SOD inhibits inflammation in response to lung injury. Extracellular superoxide dismutase (EC-SOD) is expressed at high levels in lungs. EC-SOD has a polycationic matrix-binding domain that binds to polyanionic constituents in the matrix. Previous studies indicate that EC-SOD protects the lung in both bleomycin- and asbestos-induced models of pulmonary fibrosis. Although the mechanism of EC-SOD protection is not fully understood, these studies indicate that EC-SOD plays an important role in regulating inflammatory responses to pulmonary injury. Hyaluronan is a polyanionic high molecular mass polysaccharide found in the extracellular matrix that is sensitive to oxidant-mediated fragmentation. Recent studies found that elevated levels of low molecular mass hyaluronan are associated with inflammatory conditions. We hypothesize that EC-SOD may inhibit pulmonary inflammation in part by preventing superoxide-mediated fragmentation of hyaluronan to low molecular mass fragments. We found that EC-SOD directly binds to hyaluronan and significantly inhibits oxidant-induced degradation of this glycosaminoglycan. In vitro human polymorphic neutrophil chemotaxis studies indicate that oxidative fragmentation of hyaluronan results in polymorphic neutrophil chemotaxis and that EC-SOD can completely prevent this response. Intratracheal injection of crocidolite asbestos in mice leads to pulmonary inflammation and injury that is enhanced in EC-SOD knock-out mice. Notably, hyaluronan levels are increased in the bronchoalveolar lavage fluid after asbestos-induced pulmonary injury, and this response is markedly enhanced in EC-SOD knock-out mice. These data indicate that inhibition of oxidative hyaluronan fragmentation probably represents one mechanism by which EC-SOD inhibits inflammation in response to lung injury. Hyaluronan/hyaluronic acid (HA) 2The abbreviations used are:HAhyaluronanEC-SODextracellular superoxide dismutasePMNhuman polymorphic neutrophilECMextracellular matrixROSreactive oxygen speciesBALFbronchoalveolar lavage fluid. is a negatively charged, high molecular mass polysaccharide found predominantly in the extracellular matrix (ECM). Under physiologic conditions, hyaluronan exists as a high molecular mass polymer in excess of 106 Da. It does not induce inflammatory or proliferative genes as a native high molecular mass polymer. However, recent studies have found that low molecular mass hyaluronan fragments accumulate in tissues after injury (1Hernnas J. Nettelbladt O. Bjermer L. Sarnstrand B. Malmstrom A. Hallgren R. Eur. Respir. J. 1992; 5: 404-410PubMed Google Scholar, 2Hallgren R. Samuelsson T. Laurent T.C. Modig J. Am. Rev. Respir. Dis. 1989; 139: 682-687Crossref PubMed Scopus (126) Google Scholar). These low molecular mass hyaluronan fragments have been shown to be capable of activating macrophages and inducing the expression of genes whose functions are relevant to chronic inflammation (3McKee C.M. Penno M.B. Cowman M. Burdick M.D. Strieter R.M. Bao C. Noble P.W. J. Clin. Invest. 1996; 98: 2403-2413Crossref PubMed Scopus (700) Google Scholar). Hyaluronan turnover and degradation increase during inflammation, and lower molecular mass species of hyaluronan accumulate. Importantly, this accumulation is detected prior to the influx of inflammatory cells and deposition of collagen, which suggests that low molecular mass hyaluronan accumulation is an early event in the development of inflammatory pulmonary disease (4Nettelbladt O. Bergh J. Schenholm M. Tengblad A. Hallgren R. Am. Rev. Respir. Dis. 1989; 139: 759-762Crossref PubMed Scopus (75) Google Scholar). Although the mechanisms of hyaluronan turnover and degradation are still unknown, it is generally accepted that free radicals, especially the highly reactive hydroxyl radical, play an important role in the degradation process of hyaluronan (5Casalino-Matsuda S.M. Monzon M.E. Forteza R.M. Am. J. Respir. Cell Mol. Biol. 2006; 34: 581-591Crossref PubMed Scopus (138) Google Scholar, 6Pascal M. Abdallahi O.M. Elwali N.E. Mergani A. Qurashi M.A. Magzoub M. Reggi de M. Gharib B. Trans. R. Soc. Trop. Med. Hyg. 2000; 94: 66-70Abstract Full Text PDF PubMed Google Scholar). Uchiyama et al. (7Uchiyama H. Dobashi Y. Ohkouchi K. Nagasawa K. J. Biol. Chem. 1990; 265: 7753-7759Abstract Full Text PDF PubMed Google Scholar) showed that the oxidative reductive depolymerization reaction of hyaluronan proceeds essentially by random destruction of unit monosaccharides due to oxygen-derived free radicals, followed by secondary hydrolytic cleavage of the resulting unstable glycosidic substituents. hyaluronan extracellular superoxide dismutase human polymorphic neutrophil extracellular matrix reactive oxygen species bronchoalveolar lavage fluid. Asbestos is a group of naturally occurring mineral fibers that are associated with the development of both malignant (lung cancer, mesothelioma) and nonmalignant (asbestosis) diseases in the lung and pleura (8Mossman B.T. Gee J.B. N. Engl. J. Med. 1989; 320: 1721-1730Crossref PubMed Scopus (337) Google Scholar, 9Mossman B.T. Gee J.B. Am J. Public Health. 1997; 87 (author reply 690–681): 689-690Crossref PubMed Google Scholar). Both acute and chronic inflammatory responses are involved in asbestos-induced lung injury. Although the mechanisms of asbestos-induced lung injury are not fully understood, numerous studies suggest that reactive oxygen species may contribute to ECM degradation and enhanced inflammation and abnormal repair in asbestos-induced lung injury models (10Fattman C.L. Chang L.Y. Termin T.A. Petersen L. Enghild J.J. Oury T.D. Free Radic. Biol. Med. 2003; 35: 763-771Crossref PubMed Scopus (104) Google Scholar, 11Fattman C.L. Tan R.J. Tobolewski J.M. Oury T.D. Free Radic. Biol. Med. 2006; 40: 601-607Crossref PubMed Scopus (77) Google Scholar). An important factor in determining the surface and biological reactivity of asbestos fibers is their ability to participate in redox reactions that generate free radicals. Free radicals generated from asbestos fibers and/or damage by fibers are linked to cell signaling, inflammation, and a plethora of other responses associated with the pathogenesis of asbestos-associated diseases (10Fattman C.L. Chang L.Y. Termin T.A. Petersen L. Enghild J.J. Oury T.D. Free Radic. Biol. Med. 2003; 35: 763-771Crossref PubMed Scopus (104) Google Scholar, 12Shukla A. Gulumian M. Hei T.K. Kamp D. Rahman Q. Mossman B.T. Free Radic. Biol. Med. 2003; 34: 1117-1129Crossref PubMed Scopus (238) Google Scholar, 13Tan R.J. Fattman C.L. Watkins S.C. Oury T.D. J. Appl. Physiol. 2004; 97: 2006-2013Crossref PubMed Scopus (68) Google Scholar, 14Ghio A.J. Kadiiska M.B. Xiang Q.H. Mason R.P. Free Radic. Biol. Med. 1998; 24: 11-17Crossref PubMed Scopus (33) Google Scholar, 15Oury T.D. Schaefer L.M. Fattman C.L. Choi A. Weck K.E. Watkins S.C. Am. J. Physiol. 2002; 283: L777-L784PubMed Google Scholar, 16Kinnula V.L. Fattman C.L. Tan R.J. Oury T.D. Am. J. Respir. Crit. Care Med. 2005; 172: 417-422Crossref PubMed Scopus (338) Google Scholar, 17Porter D.W. Millecchia L.L. Willard P. Robinson V.A. Ramsey D. McLaurin J. Khan A. Brumbaugh K. Beighley C.M. Teass A. Castranova V. Toxicol. Sci. 2006; 90: 188-197Crossref PubMed Scopus (64) Google Scholar). The oxidative stress-related nature of asbestos-associated lung injury makes it a good model to study the possible relationship between free radical-induced hyaluronan degradation and the possible protective effects of antioxidants in vivo. In fact, studies show that asbestos-induced lung injury is associated with excessive ECM turnover, and hyaluronan is one of the ECM components that accumulates in asbestos-induced lung injury (18Bjermer L. Lundgren R. Hallgren R. Thorax. 1989; 44: 126-131Crossref PubMed Scopus (111) Google Scholar, 19Dorger M. Allmeling A.M. Kiefmann R. Munzing S. Messmer K. Krombach F. Toxicol. Appl. Pharmacol. 2002; 181: 93-105Crossref PubMed Scopus (30) Google Scholar). Recent studies suggest that low molecular mass hyaluronan accumulates in sites of injury and induces chemokine gene expression in human alveolar macrophages from patients with idiopathic pulmonary fibrosis (3McKee C.M. Penno M.B. Cowman M. Burdick M.D. Strieter R.M. Bao C. Noble P.W. J. Clin. Invest. 1996; 98: 2403-2413Crossref PubMed Scopus (700) Google Scholar). Failure to remove ECM degradation products from the site of tissue injury results in the host succumbing to persistent inflammation that can progress to fibrosis. Extracellular superoxide dismutase (EC-SOD) is the predominant extracellular SOD, and it is expressed at especially high levels in mammalian with other tissues C.L. Schaefer L.M. Oury T.D. Free Radic. Biol. Med. 2003; 35: PubMed Scopus Google Scholar). the superoxide free radical, which suggests that it may play an important role in pulmonary diseases by oxidative R.J. Fattman C.L. Watkins S.C. Oury T.D. J. Appl. Physiol. 2004; 97: 2006-2013Crossref PubMed Scopus (68) Google Scholar, C.L. Schaefer L.M. Oury T.D. Free Radic. Biol. Med. 2003; 35: PubMed Scopus Google Scholar). Previous studies have found that EC-SOD protects mice from bleomycin- and asbestos-induced lung (10Fattman C.L. Chang L.Y. Termin T.A. Petersen L. Enghild J.J. Oury T.D. Free Radic. Biol. Med. 2003; 35: 763-771Crossref PubMed Scopus (104) Google Scholar, 11Fattman C.L. Tan R.J. Tobolewski J.M. Oury T.D. Free Radic. Biol. Med. 2006; 40: 601-607Crossref PubMed Scopus (77) Google Scholar, R.P. M. K. Am. J. Physiol. Cell Mol. Physiol. 2002; PubMed Scopus Google Scholar) and that it is significantly from the lung in response to these R.J. Fattman C.L. Watkins S.C. Oury T.D. J. Appl. Physiol. 2004; 97: 2006-2013Crossref PubMed Scopus (68) Google Scholar, C.L. S.M. Enghild J.J. Oury T.D. Free Radic. Biol. Med. PubMed Scopus Google Scholar). EC-SOD knock-out mice show enhanced lung injury and inflammation with mice in both and lung (10Fattman C.L. Chang L.Y. Termin T.A. Petersen L. Enghild J.J. Oury T.D. Free Radic. Biol. Med. 2003; 35: 763-771Crossref PubMed Scopus (104) Google Scholar, 13Tan R.J. Fattman C.L. Watkins S.C. Oury T.D. J. Appl. Physiol. 2004; 97: 2006-2013Crossref PubMed Scopus (68) Google Scholar). Although the mechanisms in which EC-SOD inflammation in response to lung are not in the extracellular matrix and ability to to negatively components in the matrix suggest that one mechanism may be to prevent oxidative of these matrix These of EC-SOD to the that one mechanism in which EC-SOD may prevent inflammation is by to hyaluronan and preventing oxidant-induced of low molecular mass hyaluronan fragments. of EC-SOD to Hyaluronan EC-SOD from as C.L. Enghild J.J. Schaefer L.M. Oury T.D. 2000; PubMed Scopus Google Scholar). by of from to of and of to the of Tengblad A. PubMed Scopus Google Scholar) and et al. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (77) Google Scholar). to with of in of at EC-SOD in of and to the The with of and the with in or by with of of and by of EC-SOD with of EC-SOD to at has T.D. Enghild J.J. J. 1996; PubMed Scopus Google Scholar). with at and the by and to EC-SOD of Hyaluronan by generated by the it both superoxide and hydroxyl radicals. The reaction mechanism has been Y. N. Y. T. Free Radic. Biol. Med. PubMed Scopus Google Scholar, F. J. T. C. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). The reaction proceeds at at to lower the reaction of high molecular mass hyaluronan from in the of to 106 to of and human EC-SOD from human T.D. Enghild J.J. J. 1996; PubMed Scopus Google Scholar) or at the of by the of The reaction to at and the reaction by a or in the at with fragments by from and used as used to the as C.L. S.M. Enghild J.J. Oury T.D. Free Radic. Biol. Med. PubMed Scopus Google Scholar). EC-SOD detected with EC-SOD as C.L. Tan R.J. Tobolewski J.M. Oury T.D. Free Radic. Biol. Med. 2006; 40: 601-607Crossref PubMed Scopus (77) Google Scholar). neutrophil chemotaxis a used to the of human a in response to hyaluronan with in the or of as from of from as by the at the of A. J. J. 1990; PubMed Scopus Google Scholar). The in cell used at a of with of high molecular mass hyaluronan at and with after to the of with to the K. T.A. Y. J. 2006; PubMed Scopus Google Scholar). The lower of and of with or the of EC-SOD generated a as C.L. Schaefer L.M. Oury T.D. Free Radic. Biol. Med. 2003; 35: PubMed Scopus Google Scholar). are generated by to and superoxide by a EC-SOD it to prior to the of The at and and cell a the of not with hyaluronan to that responses not secondary to the of and of from the reaction to that chemotaxis not in response to and by the of Care and and EC-SOD knock-out mice with the of and mice with of crocidolite asbestos in or of by as C.L. Tan R.J. Tobolewski J.M. Oury T.D. Free Radic. Biol. Med. 2006; 40: 601-607Crossref PubMed Scopus (77) Google Scholar, 13Tan R.J. Fattman C.L. Watkins S.C. Oury T.D. J. Appl. Physiol. 2004; 97: 2006-2013Crossref PubMed Scopus (68) Google Scholar). by and at used after bronchoalveolar lavage fluid by and of of from of that the cell a The at of Hyaluronan and hyaluronan the hyaluronan The of hyaluronan in the a of of Hyaluronan in tissues with from at followed by of by the at with with molecular mass hyaluronan and a or with and with and to a and The with of to hyaluronan the by the of molecular mass hyaluronan Hyaluronan in the the from Hyaluronan by an determining the of and to the The reaction by an used this L. Am. J. Respir. Crit. Care Med. 2005; 172: PubMed Scopus Google Scholar). The the as a the Hyaluronan detected by hyaluronan M. R. T. N. T. 2004; PubMed Scopus Google Scholar, S. Y. T. T. PubMed Scopus Google Scholar, M.A. R. 1992; PubMed Scopus Google Scholar). with of and the with an of and The to at the with at The with at the with and with in at The with acid and with in and with and the detected as a and the with an are expressed as and of followed by group the is at EC-SOD to has a polycationic matrix-binding which has high polyanionic components in the as hyaluronan is a polyanionic in the that EC-SOD may directly to hyaluronan and that this may hyaluronan from oxidative EC-SOD can to EC-SOD to a hyaluronan The by and the by that EC-SOD directly binds to hyaluronan in vitro The of EC-SOD to study the of the EC-SOD matrix-binding domain in hyaluronan this domain by with as T.D. Enghild J.J. J. 1996; PubMed Scopus Google Scholar). with a EC-SOD which the matrix-binding this of EC-SOD to the hyaluronan it to to the as by in the that the matrix-binding domain of EC-SOD is the to Hyaluronan to and EC-SOD of hyaluronan to generated by the of molecular mass in these that the or does not induce hyaluronan the generated by the the molecular of the These studies indicate that to degradation of hyaluronan in a and The used in the of the hyaluronan molecular mass from high to the used in the hyaluronan that is to be in the of the and the of the EC-SOD matrix-binding a of high molecular mass hyaluronan to in the or of human EC-SOD and Notably, with EC-SOD found to inhibit hyaluronan degradation in a of EC-SOD can prevent hyaluronan degradation in The EC-SOD gene is to SOD, especially in the of the site R.J. Free Radic. Biol. Med. 2002; PubMed Scopus Google with the matrix-binding and it is not as as EC-SOD at preventing hyaluronan are to the protection effects suggests that the EC-SOD matrix-binding domain the protective effects by EC-SOD by Hyaluronan human to a and a the hyaluronan fragmentation to an increase in chemotaxis the with and EC-SOD this response hyaluronan with hyaluronan chemotaxis by human EC-SOD between the and hyaluronan with both and EC-SOD chemotaxis with high molecular mass hyaluronan or in the of hyaluronan and in of EC-SOD gene knock-out mice and mice an in model to the role of EC-SOD in hyaluronan degradation in response to free radical-induced lung injury. Previous studies from found that EC-SOD gene knock-out mice show lung injury with mice after asbestos C.L. Tan R.J. Tobolewski J.M. Oury T.D. Free Radic. Biol. Med. 2006; 40: 601-607Crossref PubMed Scopus (77) Google Scholar, 13Tan R.J. Fattman C.L. Watkins S.C. Oury T.D. J. Appl. Physiol. 2004; 97: 2006-2013Crossref PubMed Scopus (68) Google Scholar). In of fluid a of inflammatory in fluid from mice with that in EC-SOD knock-out mice These results indicate that EC-SOD knock-out mice have enhanced asbestos-induced lung inflammation, which is with studies C.L. Tan R.J. Tobolewski J.M. Oury T.D. Free Radic. Biol. Med. 2006; 40: 601-607Crossref PubMed Scopus (77) Google Scholar). Hyaluronan in EC-SOD in in both and levels significantly elevated in the of EC-SOD knock-out mice with and with mice fluid hyaluronan levels significantly elevated in both EC-SOD knock-out mice and mice after asbestos injury Notably, fluid hyaluronan levels elevated to an in EC-SOD knock-out mice with the mice. of hyaluronan in the lung tissue that the hyaluronan in EC-SOD knock-out mice has a lower molecular mass with mice with the and The hyaluronan in fluid are lower in the lung and due to the low of fluid is to the of hyaluronan in lung tissues the hyaluronan by with the hyaluronan and the results are from the results in to a that asbestos injury leads to fragmentation of hyaluronan in vivo. that hyaluronan in the of mice has a with hyaluronan in the of mice. Although of hyaluronan are to from the it that the hyaluronan in with is the hyaluronan in from to is not preventing of the of fragmentation between and knock-out mice. However, these results indicate that hyaluronan is after asbestos injury with the increased hyaluronan accumulation in the and in EC-SOD knock-out mice with that EC-SOD plays an important role in preventing asbestos-induced lung injury by fragmentation of Hyaluronan and in the of Hyaluronan levels by Although hyaluronan in both fluid and especially in EC-SOD knock-out mice with results from lung show increase in pulmonary hyaluronan suggests that increased hyaluronan levels are not due to in In between mice and EC-SOD knock-out mice in the Notably, is between mice and mice suggests that lower molecular mass hyaluronan after asbestos injury is not due to increased In this a possible mechanism by which EC-SOD inhibits inflammation after asbestos-induced lung injury. EC-SOD in L. Clin. PubMed Scopus (337) Google Scholar). It shown to be the predominant superoxide dismutase in extracellular and it is highly expressed in the lung and other of the in T.D. Free Radic. Biol. 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