A brief exposure to tryptase or thrombin potentiates fibrocyte differentiation in the presence of serum or serum amyloid P

Journal of Immunology

Volumn 194, Issue 1, 2015, Pages 142-150

  White, Michael J V ^a   Galvis Carvajal, Elkin ^a   Gomer, Richard H ^a  

^a TEXAS A AND M UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

COLLAGEN; GAMMA INTERFERON; PROTEINASE ACTIVATED RECEPTOR 1; PROTEINASE ACTIVATED RECEPTOR 2; SERUM AMYLOID P; THROMBIN; TRYPSIN; TRYPTASE; ALBUMINOID; LACTONE; N3-CYCLOPROPYL-7-((4-(1-METHYLETHYL)PHENYL)METHYL)-7H-PYRROLO(3, 2-F)QUINAZOLINE-1,3-DIAMINE; PYRIDINE DERIVATIVE; PYRROLE DERIVATIVE; QUINAZOLINE DERIVATIVE; VORAPAXAR;

ARTICLE; CELL ADHESION; CELL COUNT; CELL DIFFERENTIATION; CELL MIGRATION; CELL VIABILITY; COLLAGEN SYNTHESIS; CONTROLLED STUDY; FIBROBLAST; FIBROCYTE; HUMAN; HUMAN CELL; IN VITRO STUDY; PROTEIN CLEAVAGE; PROTEIN EXPRESSION; SCAR FORMATION; SIGNAL TRANSDUCTION; ANTAGONISTS AND INHIBITORS; BIOSYNTHESIS; CELL CULTURE; CELL MOTION; CYTOLOGY; DRUG EFFECTS; FIBROSIS; IMMUNOLOGY; METABOLISM; MONOCYTE; MONONUCLEAR CELL; PATHOLOGY; SCAR; WOUND HEALING;

ALBUMINS; CELL DIFFERENTIATION; CELL MOVEMENT; CELLS, CULTURED; CICATRIX; FIBROBLASTS; FIBROSIS; HUMANS; INTERFERON-GAMMA; LACTONES; LEUKOCYTES, MONONUCLEAR; MONOCYTES; PYRIDINES; PYRROLES; QUINAZOLINES; RECEPTOR, PAR-1; RECEPTOR, PAR-2; SERUM AMYLOID P-COMPONENT; SIGNAL TRANSDUCTION; THROMBIN; TRYPSIN; TRYPTASES; WOUND HEALING;

EID: 84919683468     PISSN: 00221767     EISSN: 15506606     Source Type: Journal    
DOI: 10.4049/jimmunol.1401777     Document Type: Article

References (105)

1. Sen, C. K., G. M. Gordillo, S. Roy, R. Kirsner, L. Lambert, T. K. Hunt, F. Gottrup, G. C. Gurtner, and M. T. Longaker. 2009. Human skin wounds: A major and snowballing threat to public health and the economy. Wound Repair Regen. 17: 763-771.
2. Sakai, N., T. Wada, H. Yokoyama, M. Lipp, S. Ueha, K. Matsushima, and S. Kaneko. 2006. Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis. Proc. Natl. Acad. Sci. USA 103: 14098-14103.
3. Wynn, T. A. 2004. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat. Rev. Immunol. 4: 583-594.
4. Reilkoff, R. A., R. Bucala, and E. L. Herzog. 2011. Fibrocytes: Emerging effector cells in chronic inflammation. Nat. Rev. Immunol. 11: 427-435.
5. Strieter, R. M., E. C. Keeley, M. D. Burdick, and B. Mehrad. 2009. The role of circulating mesenchymal progenitor cells, fibrocytes, in promoting pulmonary fibrosis. Trans. Am. Clin. Climatol. Assoc. 120: 49-59.
6. Abe, R., S. C. Donnelly, T. Peng, R. Bucala, and C. N. Metz. 2001. Peripheral blood fibrocytes: Differentiation pathway and migration to wound sites. J. Immunol. 166: 7556-7562.
7. Bucala, R., L. A. Spiegel, J. Chesney, M. Hogan, and A. Cerami. 1994. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol. Med. 1: 71-81.
8. Moeller, A., S. E. Gilpin, K. Ask, G. Cox, D. Cook, J. Gauldie, P. J. Margetts, L. Farkas, J. Dobranowski, C. Boylan, et al. 2009. Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 179: 588-594.
9. Quan, T. E., S. E. Cowper, and R. Bucala. 2006. The role of circulating fibrocytes in fibrosis. Curr. Rheumatol. Rep. 8: 145-150.
10. Yang, L., P. G. Scott, C. Dodd, A. Medina, H. Jiao, H. A. Shankowsky, A. Ghahary, and E. E. Tredget. 2005. Identification of fibrocytes in postburn hypertrophic scar. Wound Repair Regen. 13: 398-404.
11. Pilling, D., V. Vakil, and R. H. Gomer. 2009. Improved serum-free culture conditions for the differentiation of human and murine fibrocytes. J. Immunol. Methods 351: 62-70.
12. Pilling, D., C. D. Buckley, M. Salmon, and R. H. Gomer. 2003. Inhibition of fibrocyte differentiation by serum amyloid P. J. Immunol. 171: 5537-5546.
13. Cox, N., D. Pilling, and R. H. Gomer. 2012. NaCl potentiates human fibrocyte differentiation. PLoS ONE 7: E45674.
14. Maharjan, A. S., D. Pilling, and R. H. Gomer. 2011. High and low molecular weight hyaluronic acid differentially regulate human fibrocyte differentiation. PLoS ONE 6: E26078.
15. Shao, D. D., R. Suresh, V. Vakil, R. H. Gomer, and D. Pilling. 2008. Pivotal Advance: Th-1 cytokines inhibit, and Th-2 cytokines promote fibrocyte differentiation. J. Leukoc. Biol. 83: 1323-1333.
16. Nelson, S. R., G. A. Tennent, D. Sethi, P. E. Gower, F. W. Ballardie, S. Amatayakul-Chantler, and M. B. Pepys. 1991. Serum amyloid P component in chronic renal failure and dialysis. Clin. Chim. Acta 200: 191-199.
17. Crawford, J. R., D. Pilling, and R. H. Gomer. 2012. FcgRI mediates serum amyloid P inhibition of fibrocyte differentiation. J. Leukoc. Biol. 92: 699-711.
18. Gomer, R. H., D. Pilling, L. M. Kauvar, S. Ellsworth, S. D. Ronkainen, D. Roife, and S. C. Davis. 2009. A serum amyloid P-binding hydrogel speeds healing of partial thickness wounds in pigs. Wound Repair Regen. 17: 397-404.
19. Naik-Mathuria, B., D. Pilling, J. R. Crawford, A. N. Gay, C. W. Smith, R. H. Gomer, and O. O. Olutoye. 2008. Serum amyloid P inhibits dermal wound healing. Wound Repair Regen. 16: 266-273.
20. Moreira, A. P., K. A. Cavassani, R. Hullinger, R. S. Rosada, D. J. Fong, L. Murray, D. P. Hesson, and C. M. Hogaboam. 2010. Serum amyloid P attenuates M2 macrophage activation and protects against fungal spore-induced allergic airway disease. J. Allergy Clin. Immunol. 126: 712-721.e7.
21. Murray, L. A., R. Rosada, A. P. Moreira, A. Joshi, M. S. Kramer, D. P. Hesson, R. L. Argentieri, S. Mathai, M. Gulati, E. L. Herzog, and C. M. Hogaboam. 2010. Serum amyloid P therapeutically attenuates murine bleomycin-induced pulmonary fibrosis via its effects on macrophages. PLoS ONE 5: E9683.
22. Murray, L. A., Q. Chen, M. S. Kramer, D. P. Hesson, R. L. Argentieri, X. Peng, M. Gulati, R. J. Homer, T. Russell, N. van Rooijen, et al. 2011. TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P. Int. J. Biochem. Cell Biol. 43: 154-162.
23. Pilling, D., D. Roife, M. Wang, S. D. Ronkainen, J. R. Crawford, E. L. Travis, and R. H. Gomer. 2007. Reduction of bleomycin-induced pulmonary fibrosis by serum amyloid P. J. Immunol. 179: 4035-4044.
24. Jager, P. L., B. P. Hazenberg, E. J. Franssen, P. C. Limburg, M. H. van Rijswijk, and D. A. Piers. 1998. Kinetic studies with iodine-123-labeled serum amyloid P component in patients with systemic AA and AL amyloidosis and assessment of clinical value. J. Nucl. Med. 39: 699-706.
25. Duitman, J., R. R. Ruela-de-Sousa, K. Shi, O. J. De Boer, K. S. Borensztajn, S. Florquin, M. P. Peppelenbosch, and C. A. Spek. 2014. Protease activated receptor- 1 deficiency diminishes bleomycin-induced skin fibrosis. Mol. Med. 20: 410-416.
26. Undas, A., K. Brummel, J. Musial, K. G. Mann, and A. Szczeklik. 2001. Blood coagulation at the site of microvascular injury: Effects of low-dose aspirin. Blood 98: 2423-2431.
27. Moffatt, J. D., R. Lever, and C. P. Page. 2004. Effects of inhaled thrombin receptor agonists in mice. Br. J. Pharmacol. 143: 269-275.
28. Scotton, C. J., M. A. Krupiczojc, M. Königshoff, P. F. Mercer, Y. C. Lee, N. Kaminski, J. Morser, J. M. Post, T. M. Maher, A. G. Nicholson, et al. 2009. Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury. J. Clin. Invest. 119: 2550-2563.
29. Howell, D. C., N. R. Goldsack, R. P. Marshall, R. J. McAnulty, R. Starke, G. Purdy, G. J. Laurent, and R. C. Chambers. 2001. Direct thrombin inhibition reduces lung collagen, accumulation, and connective tissue growth factor mRNA levels in bleomycin-induced pulmonary fibrosis. Am. J. Pathol. 159: 1383-1395.
30. Bogatkevich, G. S., A. Ludwicka-Bradley, P. J. Nietert, T. Akter, J. van Ryn, and R. M. Silver. 2011. Antiinflammatory and antifibrotic effects of the oral direct thrombin inhibitor dabigatran etexilate in a murine model of interstitial lung disease. Arthritis Rheum. 63: 1416-1425.
31. Vu, T. K., D. T. Hung, V. I. Wheaton, and S. R. Coughlin. 1991. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64: 1057-1068.
32. Coughlin, S. R. 1999. How the protease thrombin talks to cells. Proc. Natl. Acad. Sci. USA 96: 11023-11027.
33. López-Pedrera, C., M. A. Aguirre, P. Buendía, N. Barbarroja, P. Ruiz-Limón, E. Collantes-Estevez, F. Velasco, M. Khamashta, and M. J. Cuadrado. 2010. Differential expression of protease-Activated receptors in monocytes from patients with primary antiphospholipid syndrome. Arthritis Rheum. 62: 869-877.
34. Gallwitz, M., M. Enoksson, M. Thorpe, and L. Hellman. 2012. The extended cleavage specificity of human thrombin. PLoS ONE 7: E31756.
35. Hermes, B., I. Feldmann-Böddeker, P.Welker, B. Algermissen, M. U. Steckelings, J. Grabbe, and B. M. Henz. 2000. Altered expression of mast cell chymase and tryptase and of c-Kit in human cutaneous scar tissue. J. Invest. Dermatol. 114: 51-55.
36. Pesci, A., M. Majori, M. L. Piccoli, A. Casalini, A. Curti, D. Franchini, and M. Gabrielli. 1996. Mast cells in bronchiolitis obliterans organizing pneumonia. Mast cell hyperplasia and evidence for extracellular release of tryptase. Chest 110: 383-391.
37. Wygrecka, M., B. K. Dahal, D. Kosanovic, F. Petersen, B. Taborski, S. Von Gerlach, M. Didiasova, D. Zakrzewicz, K. T. Preissner, R. T. Schermuly, and P. Markart. 2013. Mast cells and fibroblasts work in concert to aggravate pulmonary fibrosis: Role of transmembrane SCF and the PAR-2/PKC-A/Raf-1/p44/ 42 signaling pathway. Am. J. Pathol. 182: 2094-2108.
38. Eklund, A., M. van Hage-Hamsten, C. M. Sköld, and S. G. Johansson. 1993. Elevated levels of tryptase in bronchoalveolar lavage fluid from patients with sarcoidosis. Sarcoidosis 10: 12-17.
39. Walls, A. F., A. R. Bennett, R. C. Godfrey, S. T. Holgate, and M. K. Church. 1991. Mast cell tryptase and histamine concentrations in bronchoalveolar lavage fluid from patients with interstitial lung disease. Clin. Sci. 81: 183-188.
40. Andersson, C. K., A. Andersson-Sjöland, M. Mori, O. Hallgren, A. Pardo, L. Eriksson, L. Bjermer, C. G. Löfdahl, M. Selman, G. Westergren-Thorsson, and J. S. Erjefält. 2011. Activated MCTC mast cells infiltrate diseased lung areas in cystic fibrosis and idiopathic pulmonary fibrosis. Respir. Res. 12: 139.
41. Rodriguez, J., N. Gupta, R. D. Smith, and P. A. Pevzner. 2008. Does trypsin cut before proline? J. Proteome Res. 7: 300-305.
42. Molino, M., E. S. Barnathan, R. Numerof, J. Clark, M. Dreyer, A. Cumashi, J. A. Hoxie, N. Schechter, M. Woolkalis, and L. F. Brass. 1997. Interactions of mast cell tryptase with thrombin receptors and PAR-2. J. Biol. Chem. 272: 4043-4049.
43. Huang, C., G. T. De Sanctis, P. J. O'Brien, J. P. Mizgerd, D. S. Friend, J. M. Drazen, L. F. Brass, and R. L. Stevens. 2001. Evaluation of the substrate specificity of human mast cell tryptase beta I and demonstration of its importance in bacterial infections of the lung. J. Biol. Chem. 276: 26276-26284.
44. Oh, S. W., C. I. Pae, D. K. Lee, F. Jones, G. K. Chiang, H. O. Kim, S. H. Moon, B. Cao, C. Ogbu, K. W. Jeong, et al. 2002. Tryptase inhibition blocks airway inflammation in a mouse asthma model. J. Immunol. 168: 1992-2000.
45. Krishna, M. T., A. Chauhan, L. Little, K. Sampson, R. Hawksworth, T. Mant, R. Djukanovic, T. Lee, and S. Holgate. 2001. Inhibition of mast cell tryptase by inhaled APC 366 attenuates allergen-induced late-phase airway obstruction in asthma. J. Allergy Clin. Immunol. 107: 1039-1045.
46. Saw, S., S. L. Kale, and N. Arora. 2012. Serine protease inhibitor attenuates ovalbumin induced inflammation in mouse model of allergic airway disease. PLoS ONE 7: E41107.
47. McLarty, J. L., G. C. Meléndez, G. L. Brower, J. S. Janicki, and S. P. Levick. 2011. Tryptase/Protease-Activated receptor 2 interactions induce selective mitogen-Activated protein kinase signaling and collagen synthesis by cardiac fibroblasts. Hypertension 58: 264-270.
48. White, M. J., M. Glenn, and R. H. Gomer. 2013. Trypsin potentiates human fibrocyte differentiation. PLoS ONE 8: E70795.
49. Pilling, D., T. Fan, D. Huang, B. Kaul, and R. H. Gomer. 2009. Identification of markers that distinguish monocyte-derived fibrocytes from monocytes, macrophages, and fibroblasts. PLoS ONE 4: E7475.
50. Schwartz, L. B., and T. R. Bradford. 1986. Regulation of tryptase from human lung mast cells by heparin. Stabilization of the active tetramer. J. Biol. Chem. 261: 7372-7379.
51. Ahn, H. S., C. Foster, G. Boykow, A. Stamford, M. Manna, and M. Graziano. 2000. Inhibition of cellular action of thrombin by N3-cyclopropyl-7-[[4-(1- methylethyl)phenyl]methyl]-7H-pyrrolo[3, 2-f]quinazoline-1, 3-diamine (SCH 79797), a nonpeptide thrombin receptor antagonist. Biochem. Pharmacol. 60: 1425-1434.
52. Chackalamannil, S., Y. Wang, W. J. Greenlee, Z. Hu, Y. Xia, H. S. Ahn, G. Boykow, Y. Hsieh, J. Palamanda, J. Agans-Fantuzzi, et al. 2008. Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. J. Med. Chem. 51: 3061-3064.
53. Maharjan, A. S., D. Roife, D. Brazill, and R. H. Gomer. 2013. Serum amyloid P inhibits granulocyte adhesion. Fibrogenesis Tissue Repair 6: 2.
54. Kamentsky, L., T. R. Jones, A. Fraser, M. A. Bray, D. J. Logan, K. L. Madden, V. Ljosa, C. Rueden, K. W. Eliceiri, and A. E. Carpenter. 2011. Improved structure, function and compatibility for CellProfiler: Modular high-throughput image analysis software. Bioinformatics 27: 1179-1180.
55. Anigstein, D. M., L. Anigstein, and D. W. Micks, inventors. Wound healing agent obtained from blood and method of preparation. United States patent application, Publication No. US2912359 A. 1959.
56. Fortney, D. Z., and D. R. Durham, inventors; W. R. Grace and Company, assignee. Compositions containing protease produced by vibrio and method of use in debridement and wound healing. United States patent application 07/ 567, 884, Publication No. US5145681 A. 1996.
57. Martin, G. J., and B. J. Morton, inventors; The National Drug Company, assignee. Wound healing composition. United States patent application, Publication No. US3003917 A. 1961.
58. Carson, S. N., C. Wiggins, K. Overall, and J. Herbert. 2003. Using a castor oilbalsam of Peru-trypsin ointment to assist in healing skin graft donor sites. Ostomy Wound Manage. 49: 60-64.
59. Cetrulo, G. I. 1953. Use of trypsin intravenously in a gunshot wound. J. Am. Med. Assoc. 152: 605-606.
60. Pritchard, D. I., K. M. Shakesheff, A. J. Horobin, and A. Brown, inventors. Treatment of wounds. United States patent application 13/083, 495, Publication No. US20110280858 A1. 2011.
61. Huttunen, M., and I. T. Harvima. 2005. Mast cell tryptase and chymase in chronic leg ulcers: Chymase is potentially destructive to epithelium and is controlled by proteinase inhibitors. Br. J. Dermatol. 152: 1149-1160.
62. Harvima, I. T., R. J. Harvima, T. O. Eloranta, and J. E. Fräki. 1988. The allosteric effect of salt on human mast cell tryptase. Biochim. Biophys. Acta 956: 133-139.
63. Iizaka, S., H. Sanada, G. Nakagami, R. Sekine, H. Koyanagi, C. Konya, and J. Sugama. 2010. Estimation of protein loss from wound fluid in older patients with severe pressure ulcers. Nutrition 26: 890-895.
64. Laiho, K. 2004. Albumin as a marker of plasma transudation in experimental skin lesions. Int. J. Legal Med. 118: 282-288.
65. Ossovskaya, V. S., and N. W. Bunnett. 2004. Protease-Activated receptors: Contribution to physiology and disease. Physiol. Rev. 84: 579-621.
66. Hoekstra, W. J., B. L. Hulshizer, D. F. McComsey, P. Andrade-Gordon, J. A. Kauffman, M. F. Addo, D. Oksenberg, R. M. Scarborough, and B. E. Maryanoff. 1998. Thrombin receptor (PAR-1) antagonists. Heterocyclebased peptidomimetics of the SFLLR agonist motif. Bioorg. Med. Chem. Lett. 8: 1649-1654.
67. Kanke, T., H. Ishiwata, M. Kabeya, M. Saka, T. Doi, Y. Hattori, A. Kawabata, and R. Plevin. 2005. Binding of a highly potent protease-Activated receptor-2 (PAR2) activating peptide, [3H]2-furoyl-LIGRL-NH2, to human PAR2. Br. J. Pharmacol. 145: 255-263.
68. Vassallo, R. R., Jr., T. Kieber-Emmons, K. Cichowski, and L. F. Brass. 1992. Structure-function relationships in the activation of platelet thrombin receptors by receptor-derived peptides. J. Biol. Chem. 267: 6081-6085.
69. Gardell, L. R., J. N. Ma, J. G. Seitzberg, A. E. Knapp, H. H. Schiffer, A. Tabatabaei, C. N. Davis, M. Owens, B. Clemons, K. K. Wong, et al. 2008. Identification and characterization of novel small-molecule protease-Activated receptor 2 agonists. J. Pharmacol. Exp. Ther. 327: 799-808.
70. Ishida, Y., T. Kondo, T. Takayasu, Y. Iwakura, and N. Mukaida. 2004. The essential involvement of cross-talk between IFN-gamma and TGF-beta in the skin wound-healing process. J. Immunol. 172: 1848-1855.
71. Shigehara, K., N. Shijubo, M. Ohmichi, R. Takahashi, S. Kon, H. Okamura, M. Kurimoto, Y. Hiraga, T. Tatsuno, S. Abe, and N. Sato. 2001. IL-12 and IL- 18 are increased and stimulate IFN-gamma production in sarcoid lungs. J. Immunol. 166: 642-649.
72. Kawao, N., Y. Sakaguchi, A. Tagome, R. Kuroda, S. Nishida, K. Irimajiri, H. Nishikawa, K. Kawai, M. D. Hollenberg, and A. Kawabata. 2002. Proteaseactivated receptor-2 (PAR-2) in the rat gastric mucosa: Immunolocalization and facilitation of pepsin/pepsinogen secretion. Br. J. Pharmacol. 135: 1292-1296.
73. Altrogge, L. M., and D. Monard. 2000. An assay for high-sensitivity detection of thrombin activity and determination of proteases activating or inactivating protease-Activated receptors. Anal. Biochem. 277: 33-45.
74. Dong, Y., C. Q. Zeng, J. M. Ball, M. K. Estes, and A. P. Morris. 1997. The rotavirus enterotoxin NSP4 mobilizes intracellular calcium in human intestinal cells by stimulating phospholipase C-mediated inositol 1, 4, 5-trisphosphate production. Proc. Natl. Acad. Sci. USA 94: 3960-3965.
75. Dawes, K. E., A. J. Gray, and G. J. Laurent. 1993. Thrombin stimulates fibroblast chemotaxis and replication. Eur. J. Cell Biol. 61: 126-130.
76. Pilcher, B. K., D. W. Kim, D. H. Carney, and J. J. Tomasek. 1994. Thrombin stimulates fibroblast-mediated collagen lattice contraction by its proteolytically activated receptor. Exp. Cell Res. 211: 368-373.
77. Chambers, R. C., K. Dabbagh, R. J. McAnulty, A. J. Gray, O. P. Blanc-Brude, and G. J. Laurent. 1998. Thrombin stimulates fibroblast procollagen production via proteolytic activation of protease-Activated receptor 1. Biochem. J. 333: 121-127.
78. Scheel, G., B. Rahfoth, J. Franke, and P. Grau. 1991. Acceleration of wound healing by local application of fibronectin. Arch. Orthop. Trauma Surg. 110: 284-287.
79. Kallis, Y. N., C. J. Scotton, A. C. Mackinnon, R. D. Goldin, N. A. Wright, J. P. Iredale, R. C. Chambers, and S. J. Forbes. 2014. Proteinase activated receptor 1 mediated fibrosis in a mouse model of liver injury: A role for bone marrow derived macrophages. PLoS ONE 9: E86241.
80. Knight, V., J. Tchongue, D. Lourensz, P. Tipping, and W. Sievert. 2012. Protease-Activated receptor 2 promotes experimental liver fibrosis in mice and activates human hepatic stellate cells. Hepatology 55: 879-887.
81. Lindner, J. R., M. L. Kahn, S. R. Coughlin, G. R. Sambrano, E. Schauble, D. Bernstein, D. Foy, A. Hafezi-Moghadam, and K. Ley. 2000. Delayed onset of inflammation in protease-Activated receptor-2-deficient mice. J. Immunol. 165: 6504-6510.
82. Damiano, B. P., W. M. Cheung, R. J. Santulli, W. P. Fung-Leung, K. Ngo, R. D. Ye, A. L. Darrow, C. K. Derian, L. de Garavilla, and P. Andrade-Gordon. 1999. Cardiovascular responses mediated by protease-Activated receptor-2 (PAR-2) and thrombin receptor (PAR-1) are distinguished in mice deficient in PAR-2 or PAR-1. J. Pharmacol. Exp. Ther. 288: 671-678.
83. Pawlinski, R., M. Tencati, C. R. Hampton, T. Shishido, T. A. Bullard, L. M. Casey, P. Andrade-Gordon, M. Kotzsch, D. Spring, T. Luther, et al. 2007. Protease-Activated receptor-1 contributes to cardiac remodeling and hypertrophy. Circulation 116: 2298-2306.
84. Alberte, R. S., and W. P. Roschek, inventors. Tryptase enzyme inhibiting aminopyridines. United States patent application 12/608, 618, Publication No. US20100113523∗010.
85. Kido, H., and H. Nakai, inventors. Tryptase inhibitor and novel guanidino derivatives. United States patent application 09/155, 868, Publication No. US6388122 B1. 2002.
86. Choi-Sledeski, Y. M., G. Liang, and P. W.-K. Shum, inventors. Tropinone benzylamines as beta-tryptase inhibitors. United States patent application 13/ 488, 538, Publication No. US2012023∗012.
87. Van Ryn, J., P. Garin-Chesa, and F. Solca, inventors. Combination therapy in treatment of cancer and fibrotic diseases. United States patent application 14/ 073, 030, Publication No. US20140066456 A1. 2014.
88. Cohen S., and M. Nasoff, inventors. Antagonists of protease activated receptor- 1 (par1). United States patent application EP20070810611, Publication No. EP2043686 A4. 2008.
89. Boyd, J. W., P. Meo, M. Higginbottom, I. Simpson, D. M. Mountford, and E. D. Savory, inventors. Protease activated receptor 2 (PAR2) antagonists. United States patent application PCT/GB2012/050177, Publication No. EP2668157 A1. 2012.
90. Cairns, J. A. 2005. Inhibitors of mast cell tryptase beta as therapeutics for the treatment of asthma and inflammatory disorders. Pulm. Pharmacol. Ther. 18: 55-66.
91. University of Utah. Dabigatran's effect on changes in atrial fibrosis in patients with atrial fibrillation. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2012- [cited 2014 Sep 14]. Available from: Http: //clinicaltrials.gov/show/NCT01546883. NLM Identifier: NCT01546883.
92. Lohman, R. J., A. J. Cotterell, G. D. Barry, L. Liu, J. Y. Suen, D. A. Vesey, and D. P. Fairlie. 2012. An antagonist of human protease activated receptor-2 attenuates PAR2 signaling, macrophage activation, mast cell degranulation, and collagen-induced arthritis in rats. FASEB J. 26: 2877-2887.
93. Datta, A., C. J. Scotton, and R. C. Chambers. 2011. Novel therapeutic approaches for pulmonary fibrosis. Br. J. Pharmacol. 163: 141-172.
94. Haudek, S. B., J. Cheng, J. Du, Y. Wang, J. Hermosillo-Rodriguez, J. Trial, G. E. Taffet, and M. L. Entman. 2010. Monocytic fibroblast precursors mediate fibrosis in angiotensin-II-induced cardiac hypertrophy. J. Mol. Cell. Cardiol. 49: 499-507.
95. Kong, P., P. Christia, and N. G. Frangogiannis. 2014. The pathogenesis of cardiac fibrosis. Cell. Mol. Life Sci. 71: 549-574.
96. Möllmann, H., H. M. Nef, S. Kostin, C. Von Kalle, I. Pilz, M.Weber, J. Schaper, C. W. Hamm, and A. Elsässer. 2006. Bone marrow-derived cells contribute to infarct remodelling. Cardiovasc. Res. 71: 661-671.
97. Akin, C., and D. D. Metcalfe. 2004. Systemic mastocytosis. Annu. Rev. Med. 55: 419-432.
98. Chiu, A., N. M. Nanaji, M. Czader, G. Gheorghe, D. M. Knowles, A. Chadburn, and A. Orazi. 2009. The stromal composition of mast cell aggregates in systemic mastocytosis. Mod. Pathol. 22: 857-865.
99. Li, C. Y., and J. Y. Baek. 2002. Mastocytosis and fibrosis: Role of cytokines. Int. Arch. Allergy Immunol. 127: 123-126.
100. Schwartz, L. B., K. Sakai, T. R. Bradford, S. Ren, B. Zweiman, A. S. Worobec, and D. D. Metcalfe. 1995. The alpha form of human tryptase is the predominant type present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis. J. Clin. Invest. 96: 2702-2710.
101. Matito, A., J. M. Morgado, I. Á lvarez-Twose, L. Sánchez-Munoz, C. E. Pedreira, M. Jara-Acevedo, C. Teodosio, P. Sánchez-López, E. Fernández- Núnez, R. Moreno-Borque, et al. 2013. Serum tryptase monitoring in indolent systemic mastocytosis: Association with disease features and patient outcome. PLoS ONE 8: E76116.
102. Iizaka, S., H. Sanada, Y. Matsui, M. Furue, T. Tachibana, T. Nakayama, J. Sugama, K. Furuta, M. Tachi, K. Tokunaga, and Y. Miyachi. 2011. Serum albumin level is a limited nutritional marker for predicting wound healing in patients with pressure ulcer: Two multicenter prospective cohort studies. Clin. Nutr. 30: 738-745.
103. Anthony, D., L. Rafter, T. Reynolds, and M. Aljezawi. 2011. An evaluation of serum albumin and the sub-scores of the Waterlow score in pressure ulcer risk assessment. J. Tissue Viability 20: 89-99.
104. Williams, D. F., N. A. Stotts, and K. Nelson. 2000. Patients with existing pressure ulcers admitted to acute care. J. Wound Ostomy Continence Nurs. 27: 216-226.
105. James, T. J., M. A. Hughes, G. W. Cherry, and R. P. Taylor. 2000. Simple biochemical markers to assess chronic wounds. Wound Repair Regen. 8: 264-269.