CORRESPONDENCE References 1. Noth I, Anstrom KJ, Calvert SB, de Andrade J, Flaherty KR, Glazer C, Kaner RJ, Olman MA; Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet). A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2012;186:88–95. 2. Chambers RC. Procoagulant signalling mechanisms in lung inflammation and fibrosis: novel opportunities for pharmacological intervention? Br J Pharmacol 2008;153:S367–S378. 3. Ohba T, McDonald JK, Silver RM, Strange C, LeRoy EC, Ludwicka A. Scleroderma BAL fluid contains thrombin, a mediator of human lung fibroblast proliferation via induction of the PDGF-alpha receptor. Am J Respir Cell Mol Biol 1994;10:405–412. ´ıguez NA, Cambrey AD, Harrison NK, Chambers RC, Gray 4. Hernandez-Rodr ´ AJ, Southcott AM, duBois RM, Black CM, Scully MF, McAnulty RJ, et al. Role of thrombin in pulmonary fibrosis. Lancet 1995;346:1071–1073. 5. Bogatkevich GS, Ludwicka-Bradley A, Nietert PJ, Akter T, van Ryn J, Silver RM. Antiinflammatory and antifibrotic effects of the oral direct thrombin inhibitor dabigatran etexilate in a murine model of interstitial lung disease. Arthritis Rheum 2011;63:1416–1425. 6. Yasui H, Gabazza EC, Tamaki S, Kobayashi T, Hataji O, Yuda H, Shimizu S, Suzuki K, Adachi Y, Taguchi O. Intratracheal administration of activated protein C inhibits bleomycin-induced lung fibrosis in the mouse. Am J Respir Crit Care Med 2001;163:1660–1668.
Copyright © 2014 by the American Thoracic Society
Reply From the Authors: We appreciate the insightful letter by Bogatkevich and colleagues, and strongly concur with their conclusions to carefully consider the potential unique antifibrotic effects of inhibiting individual components of the coagulation cascade, especially thrombin. Indeed, the unique effects of individual members of the coagulation cascade, compared with the cascade as a whole, deserve additional respect in light of the unsuccessful AntiCoagulant Effective in Idiopathic Pulmonary Fibrosis (ACE-IPF) trial (1, 2). At the time of our trial development, we were charged with designing a trial using available, FDA-approved, therapeutic interventions for pathways involved in fibrosis. We believe the ACE trial does demonstrate that the coagulation cascade (or other vitamin K–dependent proteins) plays a role in IPF, in that use of warfarin did lead to worsened outcomes (2). The notion of a more selective blockade of thrombin activity is an attractive idea. Our understanding of thrombin activity and protease-activated receptor (PAR)-mediated lung inflammation and fibrosis is growing rapidly. The authors of the letter to the editor have contributed significantly to this understanding through their findings that the thrombin inhibitor, dabigatran, has antifibrotic effects on lung fibroblasts and in a murine lung fibrosis model (3, 4). Moreover, Wygrecka and colleagues demonstrate that knockdown of PAR-1 and PAR-3 together, rather than PAR-1 alone, was necessary to inhibit thrombin-mediated epithelial to mesenchymal transition (5). The PARs remain an interesting antifibrotic target, and understanding their complex biological effects may be critical in the selection of a successful therapy. Given the availability of dabigatran etexilate, we would fully support a clinical trial to evaluate its activity. We hope that a validation of the biological effect on the correct target in vivo, would be a key part of any such clinical outcome trial in IPF, so that we can further advance this promising field. n Correspondence
Author disclosures are available with the text of this letter at www.atsjournals.org. Imre Noth, M.D. University of Chicago Chicago, Illinois Mitchell A. Olman, M.A., M.D. Cleveland Clinic Cleveland, Ohio
References 1. Chambers RC, Scotton CJ. Coagulation cascade proteinases in lung injury and fibrosis. Proc Am Thorac Soc 2012;9:96–101. 2. Noth I, Anstrom KJ, Calvert SB, de Andrade J, Flaherty KR, Glazer C, Kaner RJ, Olman MA; Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet). A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2012;186: 88–95. 3. Bogatkevich GS, Ludwicka-Bradley A, Silver RM. Dabigatran, a direct thrombin inhibitor, demonstrates antifibrotic effects on lung fibroblasts. Arthritis Rheum 2009;60:3455–3464. 4. Bogatkevich GS, Ludwicka-Bradley A, Nietert PJ, Akter T, van Ryn J, Silver RM. Antiinflammatory and antifibrotic effects of the oral direct thrombin inhibitor dabigatran etexilate in a murine model of interstitial lung disease. Arthritis Rheum 2011;63:1416–1425. 5. Wygrecka M, Didiasova M, Berscheid S, Piskulak K, Taborski B, Zakrzewicz D, Kwapiszewska G, Preissner KT, Markart P. Proteaseactivated receptors (PAR)-1 and -3 drive epithelial-mesenchymal transition of alveolar epithelial cells - potential role in lung fibrosis. Thromb Haemost 2013;110:295–307.
Copyright © 2014 by the American Thoracic Society
Mesenchymal Stromal (Stem) Cell Therapy: An Emerging Immunomodulatory Strategy for the Adjunctive Treatment of Sepsis To the Editor: We read with considerable interest the Critical Care Perspective by Leentjens and colleagues regarding immunotherapy for the adjunctive treatment of sepsis (1). We were surprised that this perspective failed to include discussion of mesenchymal stromal (stem) cell (MSC) therapy as an emerging and innovative potential adjunctive treatment strategy for sepsis and its associated major end-organ complications, including the acute respiratory distress syndrome (ARDS), when administered in either a prophylactic (preventative) or treatment (importantly, after the onset of experimental sepsis) strategy (2–6). Although sepsis has traditionally been regarded as a syndrome characterized by an overwhelming proinflammatory host immune response, Leentjens and colleagues presented evidence that secondary infections (usually bacterial) occurring in the postinflammatory immunosuppressive or immunoparalysis stage of illness may play a more important role in ultimate clinical outcome of critically ill patients with sepsis than previously recognized. The authors argued that previous antiinflammatory strategies may have failed to 363
Copyright © 2014 by the American Thoracic Society
Reply From the Authors: We appreciate the insightful letter by Bogatkevich and colleagues, and strongly concur with their conclusions to carefully consider the potential unique antifibrotic effects of inhibiting individual components of the coagulation cascade, especially thrombin. Indeed, the unique effects of individual members of the coagulation cascade, compared with the cascade as a whole, deserve additional respect in light of the unsuccessful AntiCoagulant Effective in Idiopathic Pulmonary Fibrosis (ACE-IPF) trial (1, 2). At the time of our trial development, we were charged with designing a trial using available, FDA-approved, therapeutic interventions for pathways involved in fibrosis. We believe the ACE trial does demonstrate that the coagulation cascade (or other vitamin K–dependent proteins) plays a role in IPF, in that use of warfarin did lead to worsened outcomes (2). The notion of a more selective blockade of thrombin activity is an attractive idea. Our understanding of thrombin activity and protease-activated receptor (PAR)-mediated lung inflammation and fibrosis is growing rapidly. The authors of the letter to the editor have contributed significantly to this understanding through their findings that the thrombin inhibitor, dabigatran, has antifibrotic effects on lung fibroblasts and in a murine lung fibrosis model (3, 4). Moreover, Wygrecka and colleagues demonstrate that knockdown of PAR-1 and PAR-3 together, rather than PAR-1 alone, was necessary to inhibit thrombin-mediated epithelial to mesenchymal transition (5). The PARs remain an interesting antifibrotic target, and understanding their complex biological effects may be critical in the selection of a successful therapy. Given the availability of dabigatran etexilate, we would fully support a clinical trial to evaluate its activity. We hope that a validation of the biological effect on the correct target in vivo, would be a key part of any such clinical outcome trial in IPF, so that we can further advance this promising field. n Correspondence
Author disclosures are available with the text of this letter at www.atsjournals.org. Imre Noth, M.D. University of Chicago Chicago, Illinois Mitchell A. Olman, M.A., M.D. Cleveland Clinic Cleveland, Ohio
References 1. Chambers RC, Scotton CJ. Coagulation cascade proteinases in lung injury and fibrosis. Proc Am Thorac Soc 2012;9:96–101. 2. Noth I, Anstrom KJ, Calvert SB, de Andrade J, Flaherty KR, Glazer C, Kaner RJ, Olman MA; Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet). A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2012;186: 88–95. 3. Bogatkevich GS, Ludwicka-Bradley A, Silver RM. Dabigatran, a direct thrombin inhibitor, demonstrates antifibrotic effects on lung fibroblasts. Arthritis Rheum 2009;60:3455–3464. 4. Bogatkevich GS, Ludwicka-Bradley A, Nietert PJ, Akter T, van Ryn J, Silver RM. Antiinflammatory and antifibrotic effects of the oral direct thrombin inhibitor dabigatran etexilate in a murine model of interstitial lung disease. Arthritis Rheum 2011;63:1416–1425. 5. Wygrecka M, Didiasova M, Berscheid S, Piskulak K, Taborski B, Zakrzewicz D, Kwapiszewska G, Preissner KT, Markart P. Proteaseactivated receptors (PAR)-1 and -3 drive epithelial-mesenchymal transition of alveolar epithelial cells - potential role in lung fibrosis. Thromb Haemost 2013;110:295–307.
Copyright © 2014 by the American Thoracic Society
Mesenchymal Stromal (Stem) Cell Therapy: An Emerging Immunomodulatory Strategy for the Adjunctive Treatment of Sepsis To the Editor: We read with considerable interest the Critical Care Perspective by Leentjens and colleagues regarding immunotherapy for the adjunctive treatment of sepsis (1). We were surprised that this perspective failed to include discussion of mesenchymal stromal (stem) cell (MSC) therapy as an emerging and innovative potential adjunctive treatment strategy for sepsis and its associated major end-organ complications, including the acute respiratory distress syndrome (ARDS), when administered in either a prophylactic (preventative) or treatment (importantly, after the onset of experimental sepsis) strategy (2–6). Although sepsis has traditionally been regarded as a syndrome characterized by an overwhelming proinflammatory host immune response, Leentjens and colleagues presented evidence that secondary infections (usually bacterial) occurring in the postinflammatory immunosuppressive or immunoparalysis stage of illness may play a more important role in ultimate clinical outcome of critically ill patients with sepsis than previously recognized. The authors argued that previous antiinflammatory strategies may have failed to 363
