Recombinant Antithrombin Attenuates Acute Respiratory Distress Syndrome in Experimental Endotoxemia

Abstract

Sepsis-induced endothelial acute respiratory distress syndrome is related to microvascular endothelial dysfunction caused by endothelial glycocalyx disruption. Recently, recombinant antithrombin (rAT) was reported to protect the endothelial glycocalyx from septic vasculitis; however, the underlying mechanism remains unknown. Here, we investigated the effect of rAT administration on vascular endothelial injury under endotoxemia. Lipopolysaccharide (LPS; 20 mg/kg) was injected intraperitoneally into 10-week-old male C57BL/6 mice, and saline or rAT was administered intraperitoneally at 3 and 24 hours after LPS administration. Subsequently, serum and/or pulmonary tissues were examined for inflammation and cell proliferation and differentiation by histologic, ultrastructural, and microarray analyses. The survival rate was significantly higher in rAT-treated mice than in control mice 48 hours after LPS injection (75% versus 20%; P < 0.05). Serum interleukin-1β was increased but to a lesser extent in response to LPS injection in rAT-treated mice than in control mice. Lectin staining and ultrastructural studies showed a notable attenuation of injury to the endothelial glycocalyx after rAT treatment. Microarray analysis further showed an up-regulation of gene sets corresponding to DNA repair, such as genes involved in DNA helicase activity, regulation of telomere maintenance, DNA-dependent ATPase activity, and ciliary plasm, after rAT treatment. Thus, rAT treatment may promote DNA repair, attenuate inflammation, and promote ciliogenesis, thereby attenuating the acute respiratory distress syndrome caused by endothelial injury. Sepsis-induced endothelial acute respiratory distress syndrome is related to microvascular endothelial dysfunction caused by endothelial glycocalyx disruption. Recently, recombinant antithrombin (rAT) was reported to protect the endothelial glycocalyx from septic vasculitis; however, the underlying mechanism remains unknown. Here, we investigated the effect of rAT administration on vascular endothelial injury under endotoxemia. Lipopolysaccharide (LPS; 20 mg/kg) was injected intraperitoneally into 10-week-old male C57BL/6 mice, and saline or rAT was administered intraperitoneally at 3 and 24 hours after LPS administration. Subsequently, serum and/or pulmonary tissues were examined for inflammation and cell proliferation and differentiation by histologic, ultrastructural, and microarray analyses. The survival rate was significantly higher in rAT-treated mice than in control mice 48 hours after LPS injection (75% versus 20%; P < 0.05). Serum interleukin-1β was increased but to a lesser extent in response to LPS injection in rAT-treated mice than in control mice. Lectin staining and ultrastructural studies showed a notable attenuation of injury to the endothelial glycocalyx after rAT treatment. Microarray analysis further showed an up-regulation of gene sets corresponding to DNA repair, such as genes involved in DNA helicase activity, regulation of telomere maintenance, DNA-dependent ATPase activity, and ciliary plasm, after rAT treatment. Thus, rAT treatment may promote DNA repair, attenuate inflammation, and promote ciliogenesis, thereby attenuating the acute respiratory distress syndrome caused by endothelial injury. The diagnostic criteria for sepsis include organ failure caused by several factors, including endothelial cell injury.1Singer M. Deutschman C.S. Seymour C.W. Shankar-Hari M. Annane D. Bauer M. Bellomo R. Bernard G.R. Chiche J.D. Coopersmith C.M. Hotchkiss R.S. Levy M.M. Marshall J.C. Martin G.S. Opal S.M. Rubenfeld G.D. van der Poll T. Vincent J.L. Angus D.C. The third international consensus definitions for sepsis and septic shock (Sepsis-3).JAMA. 2016; 315: 801-810Crossref PubMed Scopus (13758) Google Scholar Endothelial cells are coated by the vascular endothelial glycocalyx present on the surface of endothelial cells, which plays a pivotal role in the maintenance of vascular homeostasis.2Chelazzi C. Villa G. Mancinelli P. De Gaudio A.R. Adembri C. Glycocalyx and sepsis-induced alterations in vascular permeability.Crit Care. 2015; 19: 26Crossref PubMed Scopus (239) Google Scholar In the healthy state, the glycocalyx is a critical determinant of vascular permeability.3Henry C.B. Duling B.R. Permeation of the luminal capillary glycocalyx is determined by hyaluronan.Am J Physiol. 1999; 277: H508-H514Crossref PubMed Google Scholar,4Vink H. Duling B.R. Capillary endothelial surface layer selectively reduces plasma solute distribution volume.Am J Physiol Heart Circ Physiol. 2000; 278: H285-H289Crossref PubMed Google Scholar Endothelial glycocalyx disruption causes injury to the microcirculation system, which functions to maintain blood flow and tissue perfusion, and thus, affects blood pressure and responses to inflammation. Disruption of the endothelial glycocalyx is also associated with lung injury and neutrophil adhesion during sepsis-induced acute respiratory distress syndrome.5Schmidt E.P. Yang Y. Janssen W.J. Gandjeva A. Perez M.J. Barthel L. Zemans R.L. Bowman J.C. Koyanagi D.E. Yunt Z.X. Smith L.P. Cheng S.S. Overdier K.H. Thompson K.R. Geraci M.W. Douglas I.S. Pearse D.B. Tuder R.M. The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis.Nat Med. 2012; 18: 1217-1223Crossref PubMed Scopus (553) Google Scholar Furthermore, lipopolysaccharide (LPS)-induced degradation of the endothelial glycocalyx is causally associated with microvascular endothelial dysfunction.6Inagawa R. Okada H. Takemura G. Suzuki K. Takada C. Yano H. Ando Y. Usui T. Hotta Y. Miyazaki N. Tsujimoto A. Zaikokuji R. Matsumoto A. Kawaguchi T. Doi T. Yoshida T. Yoshida S. Kumada K. Ushikoshi H. Toyoda I. Ogura S. Ultrastructural alteration of pulmonary capillary endothelial glycocalyx during endotoxemia.Chest. 2018; 154: 317-325Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Because an intact glycocalyx potentially protects against endothelial disorders,7Eskens B.J. Zuurbier C.J. van Haare J. Vink H. van Teeffelen J.W. Effects of two weeks of metformin treatment on whole-body glycocalyx barrier properties in db/db mice.Cardiovasc Diabetol. 2013; 12: 175Crossref PubMed Scopus (65) Google Scholar, 8Frati-Munari A.C. [Medical significance of endothelial glycocalyx].Arch Cardiol Mex. 2013; 83: 303-312Crossref PubMed Scopus (37) Google Scholar, 9Gunst J. Derese I. Aertgeerts A. Ververs E.J. Wauters A. Van den Berghe G. Vanhorebeek I. Insufficient autophagy contributes to mitochondrial dysfunction, organ failure, and adverse outcome in an animal model of critical illness.Crit Care Med. 2013; 41: 182-194Crossref PubMed Scopus (110) Google Scholar, 10Nieuwdorp M. van Haeften T.W. Gouverneur M.C. Mooij H.L. van Lieshout M.H. Levi M. Meijers J.C. Holleman F. Hoekstra J.B. Vink H. Kastelein J.J. Stroes E.S. Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo.Diabetes. 2006; 55: 480-486Crossref PubMed Scopus (426) Google Scholar protection of the endothelial glycocalyx could represent a novel therapeutic strategy to prevent the endothelial injury–induced organ failure that occurs during sepsis. However, thus far, no clinical strategies have been established for treating sepsis through endothelial glycocalyx protection. Although corticosteroids11Chappell D. Hofmann-Kiefer K. Jacob M. Rehm M. Briegel J. Welsch U. Conzen P. Becker B.F. TNF-alpha induced shedding of the endothelial glycocalyx is prevented by hydrocortisone and antithrombin.Basic Res Cardiol. 2009; 104: 78-89Crossref PubMed Scopus (221) Google Scholar and heparinoids12Song J.W. Zullo J.A. Liveris D. Dragovich M. Zhang X.F. Goligorsky M.S. Therapeutic restoration of endothelial glycocalyx in sepsis.J Pharmacol Exp Ther. 2017; 361: 115-121Crossref PubMed Scopus (68) Google Scholar have been suggested to protect the endothelial glycocalyx, definitive evidence of the clinical utility of these compounds for the treatment of sepsis is lacking. Antithrombin (AT)—a small protein molecule that inactivates several enzymes of the coagulation system—is a physiological serine-protease inhibitor that plays a crucial role in blood coagulation.13Rosenberg R.D. Damus P.S. The purification and mechanism of action of human antithrombin-heparin cofactor.J Biol Chem. 1973; 248: 6490-6505Abstract Full Text PDF PubMed Google Scholar AT inhibits the interaction between thrombin and activated coagulation factors and has been reported to account for 75% to 80% of the inhibitory activity directed toward thrombin.14Stein P.E. Carrell R.W. What do dysfunctional serpins tell us about molecular mobility and disease?.Nat Struct Biol. 1995; 2: 96-113Crossref PubMed Scopus (395) Google Scholar Similarly, AT binds to heparin sulfate on endothelial cells and to syndecan-4 on neutrophils to subsequently attenuate inflammation by more than 120% of the level activated by LPS.15Wiedermann C.J. Clinical review: molecular mechanisms underlying the role of antithrombin in sepsis.Crit Care. 2006; 10: 209Crossref PubMed Scopus (64) Google Scholar AT also has been reported to attenuate endothelial glycocalyx injury caused by LPS administration,16Iba T. Levy J.H. Hirota T. Hiki M. Sato K. Murakami T. Nagaoka I. Protection of the endothelial glycocalyx by antithrombin in an endotoxin-induced rat model of sepsis.Thromb Res. 2018; 171: 1-6Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar and a nonfucosylated recombinant AT (rAT) was found to maintain vascular structure.17Iba T. Hirota T. Sato K. Nagaoka I. Protective effect of a newly developed fucose-deficient recombinant antithrombin against histone-induced endothelial damage.Int J Hematol. 2018; 107: 528-534Crossref PubMed Scopus (8) Google Scholar However, the mechanisms underlying these effects are unknown. Therefore, our aim was to assess the state of the pulmonary endothelial glycocalyx after LPS injection in rAT-treated mice. The present study conformed to the NIH’s Guide for the Care and Use of Laboratory Animals and was approved by the Institutional Animal Research Committee of Gifu University (30-190, Gifu, Japan).18Committee for the Update of the Guide for the Care and Use of Laboratory AnimalsNational Research CouncilGuide for the Care and Use of Laboratory Animals: Eighth Edition. National Academies Press, Washington, DC2011Crossref Google Scholar Ten-week-old, male C57BL/6 mice were obtained from Chubu Kagaku Shizai, Co., Ltd. (Nagoya, Japan). After a 16-hour starvation period, the mice were injected intraperitoneally with LPS (20 mg/kg; MilliporeSigma, Burlington, MA) and with rAT (750 IU/kg; Kyowa Kirin, Co., Ltd., Tokyo, Japan) for certain assays at 3 and 24 hours after LPS injection. The survival rate was evaluated every 12 hours after LPS administration; the mice that survived were euthanized, and lung specimens were obtained. There was no significant difference in the survival rate between male and female mice in a preliminary study. Therefore, male mice were used for this experiment. were as K. Okada H. Takemura G. Takada C. H. Yano H. I. Zaikokuji R. A. H. A. S. Suzuki A. Miyazaki N. T. N. T. Doi T. Yoshida T. Kumada K. Ushikoshi H. Yoshida S. Ogura S. protects against acute respiratory distress syndrome of pulmonary endothelial J PubMed Scopus Google Scholar Serum was to and for and The clinical of lung was as K. Okada H. Takemura G. Takada C. H. Yano H. I. Zaikokuji R. A. H. A. S. Suzuki A. Miyazaki N. T. N. T. Doi T. Yoshida T. Kumada K. Ushikoshi H. Yoshida S. Ogura S. protects against acute respiratory distress syndrome of pulmonary endothelial J PubMed Scopus Google treatment the increased and in Exp Res. Google Scholar were in a to and the analysis of glycocalyx of staining was a Japan) and as K. Okada H. Takemura G. Takada C. H. Yano H. I. Zaikokuji R. A. H. A. S. Suzuki A. Miyazaki N. T. N. T. Doi T. Yoshida T. Kumada K. Ushikoshi H. Yoshida S. Ogura S. protects against acute respiratory distress syndrome of pulmonary endothelial J PubMed Scopus Google Scholar which of the endothelial H. A. H. Y. S. T. of endothelial glycocalyx layer with Res 2016; PubMed Scopus Google Scholar was injected into the The lung of was in Tokyo, Japan) and with The were at of tissues to were with a The of was in in the were with against the endothelial cell cell and The of the was the or staining was used to analysis of the endothelial glycocalyx was as H. Takemura G. Suzuki K. K. Takada C. Hotta Y. Miyazaki N. Tsujimoto A. I. Ando Y. Zaikokuji R. Matsumoto A. H. Y. Usui T. Doi T. Yoshida T. Yoshida S. Ushikoshi H. Toyoda I. Ogura S. of capillary endothelial glycocalyx under and experimental Care. 2017; PubMed Scopus Google Scholar Because is to between the glycocalyx and staining by the glycocalyx is was used in during glycocalyx tissues used for microarray analysis were obtained from or rAT-treated mice at hours after LPS and was as K. Okada H. Takemura G. Takada C. H. Yano H. I. Zaikokuji R. A. H. A. S. Suzuki A. Miyazaki N. T. N. T. Doi T. Yoshida T. Kumada K. Ushikoshi H. Yoshida S. Ogura S. protects against acute respiratory distress syndrome of pulmonary endothelial J PubMed Scopus Google Scholar analysis was by the Research Gifu University Tokyo, Japan). The obtained were and as K. Okada H. Takemura G. Takada C. H. Yano H. I. Zaikokuji R. A. H. A. S. Suzuki A. Miyazaki N. T. N. T. Doi T. Yoshida T. Kumada K. Ushikoshi H. Yoshida S. Ogura S. protects against acute respiratory distress syndrome of pulmonary endothelial J PubMed Scopus Google Scholar microarray were in the are as the was used for two and survival were the P < was were an experimental LPS (20 mg/kg) was injected intraperitoneally into 10-week-old C57BL/6 male mice. 48 hours after LPS the survival rate of rAT-treated mice 24 of was significantly higher than that of control mice of the adverse effects of was injected into the mice LPS The survival rate of the mice was at 48 hours after injection. However, adverse effects of including and were In the serum of control mice, the of and at and 12 hours after LPS and to at 48 hours after injection However, in rAT-treated mice, the was significantly at hours after LPS administration in rAT the was at 12 hours after LPS administration with saline injected mice in rAT the was significantly at 12 hours after LPS administration with saline injected mice pulmonary injury was at 48 hours after LPS injection a clinical treatment the increased and in Exp Res. Google M. J. the of PubMed Scopus Google Scholar and neutrophil were caused by LPS injection However, at 48 hours after LPS pulmonary was in the rAT-treated mice to that in the mice and and neutrophil also was significantly in the rAT-treated mice with that in the mice and that rAT treatment the pulmonary injury that occurs after LPS administration. staining was to endothelial glycocalyx which the of the endothelial H. A. H. Y. S. T. of endothelial glycocalyx layer with Res 2016; PubMed Scopus Google Scholar and the staining staining was in mice after LPS administration than in mice injected with LPS and however, in rAT-treated mice, the staining after LPS injection was increased to that in the mice and that rAT treatment endothelial glycocalyx injury in lung are as which are by an and a as by and After LPS were in the pulmonary capillary with induced which subsequently to the injury of the surface of the vascular and However, rAT administration this injury and to the endothelial glycocalyx, analysis was after The endothelial glycocalyx and a and the surface of the vascular in mice and After LPS the endothelial glycocalyx was and was in mice and the was in rAT-treated mice and In the surface of pulmonary and the endothelial capillary in mice and After LPS the surface of the vascular and showed a and the endothelial in mice and endothelial was in rAT-treated mice and further that the endothelial glycocalyx a and the surface of the vascular and as also in After LPS the endothelial glycocalyx was thus, the was in mice and However, in rAT-treated mice, the was and the endothelial glycocalyx injury was and that rAT treatment endothelial glycocalyx injury under endotoxemia. analysis was on and rAT-treated mice. In gene and of and of gene a significant up-regulation of gene sets related to DNA helicase activity was with regulation of telomere maintenance DNA-dependent ATPase activity and ciliary in rAT-treated mice < versus these that rAT treatment against DNA was examined the gene analysis that rAT treatment could cell was at a higher level in rAT-treated mice after LPS injection than in mice after LPS administration and in mice and was in several of cells such as cells, and endothelial Therefore, for further for and a of endothelial cells, was which showed of and in rAT-treated mice further the DNA repair, assays were with staining for and is a protein in the and of and the of the cell Y. K. K. M. Y. T. F. K. M. S. of and DNA by human with protein to PubMed Scopus Google Scholar is related to the activation of the DNA K. L. M. K. T. Y. R. role of on for and DNA PubMed Scopus Google Scholar cell in rAT-treated mice were with in the and Furthermore, in rAT-treated mice, cell were than in the saline and cells and cells include several of cells, endothelial cells, which was to assess the gene related to ciliary staining with an showed that was to cells After LPS in rAT-treated mice, the on cells, the of the layer was and in the showed that rAT treatment injury on cells after LPS injection. study showed that with saline rAT treatment pulmonary endothelial glycocalyx injury in mice after LPS injection. Although studies have that rAT T. Levy J.H. Hirota T. Hiki M. Sato K. Murakami T. Nagaoka I. Protection of the endothelial glycocalyx by antithrombin in an endotoxin-induced rat model of sepsis.Thromb Res. 2018; 171: 1-6Abstract Full Text Full Text PDF PubMed Scopus (31) Google T. Hirota T. Sato K. Nagaoka I. Protective effect of a newly developed fucose-deficient recombinant antithrombin against histone-induced endothelial damage.Int J Hematol. 2018; 107: 528-534Crossref PubMed Scopus (8) Google Scholar the novel of the present study is that rAT administration causes the of DNA of DNA helicase activity, regulation of telomere maintenance, and DNA-dependent ATPase The of this study showed that rAT treatment the of the and neutrophil in the are in with of that AT inflammation by with endothelial cells and C.J. Clinical review: molecular mechanisms underlying the role of antithrombin in sepsis.Crit Care. 2006; 10: 209Crossref PubMed Scopus (64) Google Scholar a crucial role in endothelial injury. causes of neutrophil and neutrophil in pulmonary and neutrophil is by of the lung and K.H. responses of the endothelial and of the lung in to PubMed Scopus Google B.R. D. J.C. C.M. of capillary and neutrophil to neutrophil through Physiol PubMed Scopus Google Scholar in acute respiratory distress a alteration to sepsis is the of neutrophils in the J. of neutrophils to acute lung Med. PubMed Scopus Google Scholar neutrophil disruption organ failure by attenuating endothelial injury under septic T. Okada H. Takemura G. Suzuki K. Takada C. H. Suzuki A. K. A. S. H. Yano H. I. Zaikokuji R. A. A. S. Miyazaki N. Hotta Y. N. T. K. Doi T. Yoshida T. Ushikoshi H. Yoshida S. Y. Ogura S. endotoxin-induced injury degradation of capillary PubMed Scopus Google K. Okada H. Takemura G. Takada C. A. Yano H. Zaikokuji R. K. H. K. S. A. T. S. Miyazaki N. Kawaguchi T. T. Yoshida T. Ushikoshi H. Yoshida S. Y. Ogura S. the pulmonary endothelial glycocalyx in experimental J Full Text Full Text PDF PubMed Scopus Google Scholar Although the endothelial glycocalyx is present on healthy endothelial cells and plays a critical role in vascular C. Villa G. Mancinelli P. De Gaudio A.R. Adembri C. Glycocalyx and sepsis-induced alterations in vascular permeability.Crit Care. 2015; 19: 26Crossref PubMed Scopus (239) Google H. Takemura G. Suzuki K. K. Takada C. Hotta Y. Miyazaki N. Tsujimoto A. I. Ando Y. Zaikokuji R. Matsumoto A. H. Y. Usui T. Doi T. Yoshida T. Yoshida S. Ushikoshi H. Toyoda I. Ogura S. of capillary endothelial glycocalyx under and experimental Care. 2017; PubMed Scopus Google B.F. D. Jacob M. Endothelial glycocalyx and vascular the Res Cardiol. PubMed Scopus Google Scholar, J.H. of capillary and layer as by Google Scholar, M. S. M. Welsch U. Conzen P. Jacob M. Becker B.F. Endothelial glycocalyx as an barrier of or in the vascular PubMed Scopus Google Scholar, S. Vink H. van The endothelial and PubMed Scopus Google Scholar, and the glycocalyx model of an for J 2012; Full Text Full Text PDF PubMed Scopus Google Scholar neutrophils and the endothelial glycocalyx and subsequently organ study also that disruption of the endothelial glycocalyx affects the of acute respiratory distress syndrome.5Schmidt E.P. Yang Y. Janssen W.J. Gandjeva A. Perez M.J. Barthel L. Zemans R.L. Bowman J.C. Koyanagi D.E. Yunt Z.X. Smith L.P. Cheng S.S. Overdier K.H. Thompson K.R. Geraci M.W. Douglas I.S. Pearse D.B. Tuder R.M. The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis.Nat Med. 2012; 18: 1217-1223Crossref PubMed Scopus (553) Google Scholar from endothelial cells is through with AT and sulfate on endothelial inhibits and to endothelial cells and Furthermore, AT binds to syndecan-4 on the surface of neutrophils and subsequently inhibits neutrophil R.D. Damus P.S. The purification and mechanism of action of human antithrombin-heparin cofactor.J Biol Chem. 1973; 248: 6490-6505Abstract Full Text PDF PubMed Google C.J. Clinical review: molecular mechanisms underlying the role of antithrombin in sepsis.Crit Care. 2006; 10: 209Crossref PubMed Scopus (64) Google Scholar Similarly, AT was reported to the of and from endothelial cells by through AT was found to attenuate acute lung injury by mobility S. H. Matsumoto S. T. antithrombin inhibits and endotoxin-induced acute lung injury in Care Med. PubMed Scopus Google Scholar study showed that rAT treatment the endothelial glycocalyx injury that occurs with endotoxemia. Because attenuation of inflammation protect the endothelial glycocalyx T. Okada H. Takemura G. Suzuki K. Takada C. H. Suzuki A. K. A. S. H. Yano H. I. Zaikokuji R. A. A. S. Miyazaki N. Hotta Y. N. T. K. Doi T. Yoshida T. Ushikoshi H. Yoshida S. Y. Ogura S. endotoxin-induced injury degradation of capillary PubMed Scopus Google K. Okada H. Takemura G. Takada C. A. Yano H. Zaikokuji R. K. H. K. S. A. T. S. Miyazaki N. Kawaguchi T. T. Yoshida T. Ushikoshi H. Yoshida S. Y. Ogura S. the pulmonary endothelial glycocalyx in experimental J Full Text Full Text PDF PubMed Scopus Google Scholar the effect of rAT as of the effects of rAT treatment The of DNA after rAT administration was by the of our gene which showed the up-regulation of gene sets related to DNA helicase activity, regulation of telomere maintenance, and DNA-dependent ATPase activity in rAT-treated mice. which is related to the cell was at higher in pulmonary endothelial cells in rAT-treated mice than in mice. that DNA was more in endothelial cells in rAT-treated mice than in control mice. several of DNA including of of DNA by of of and of In acute respiratory distress neutrophils to the and pulmonary tissue The acute respiratory distress J Med. 2000; PubMed Scopus Google Scholar Thus, the DNA of endothelial cells is under rAT treatment promote DNA is a protein involved in the and of DNA and the of the cell Y. K. K. M. Y. T. F. K. M. S. of and DNA by human with protein to PubMed Scopus Google Scholar is related to the activation of the DNA K. L. M. K. T. Y. R. role of on for and DNA PubMed Scopus Google Scholar rAT treatment the cell and with the of Because these are to DNA repair, these that rAT treatment may DNA in several cell in the rAT treatment endothelial glycocalyx injury caused by septic Because the endothelial glycocalyx on the surface of endothelial cells and is by endothelial effects of under on endothelial glycocalyx an in J 2017; Full Text Full Text PDF PubMed Scopus Google Scholar DNA of endothelial cells associated with endothelial glycocalyx in septic rAT treatment also the gene related to ciliary are present in cells that are and are into two and on the respiratory the respiratory in the that and of the Y. I. H. A. are on in the and the respiratory Biol. 2012; PubMed Scopus Google Scholar The showed that were present on the respiratory the respiratory and that rAT treatment respiratory cells and the of Because are present on of cells, blood cells, the up-regulation of the gene related to ciliary also could by endothelial However, of this further is a with the that developed in an experimental The of the study was to the between septic and endothelial glycocalyx injury. Thus, we used an However, this animal model certain septic such as a of our study. In cells, the and endothelial cells is to a Furthermore, we gene from further about the of the gene study is study also the adverse effects of rAT in healthy mice. Because the in healthy mice, is that rAT adverse effects such as or with rAT protects the endothelial glycocalyx is for vascular against injury by the caused by several factors including and the restoration of endothelial Because rAT is used in clinical administration as a novel strategy for the treatment of septic

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