Treatments for fibrosis development and progression: Lessons learned from preclinical models and potential impact on human conditions such as scleroderma, pulmonary fibrosis, hypertrophic scarring and tendinopathies

Abstract

Progressive fibrosis of a tissue or organ in response to a damaging insult may result in loss of organ function if the acute response is excessive, or a chronic fibrotic response is initiated due to the persistence of the insult. In the author’s laboratory over the past several years, a number of preclinical models of fibrosis or fibrogenic responses have been characterized for the effectiveness of various treatment approaches to either prevent or impede fibrosis development and progression to identify commonalities and translatable research directions that could provide insights into human diseases. These have mainly included either chemically induced pulmonary fibrosis models or overt physical injury models in rats, pigs and rabbits. Some preliminary studies in human populations have also been undertaken. The interventions evaluated have included fibrinolytic agents and drugs targeting specific cell populations. The results indicate that some approaches lend themselves to modifying fibrotic reactions in some models and not others, while others may have a more generalized impact on fibrogenic responses due to interference with abnormal cell functions in the injury environment.

Share and Cite:

Hart, D. (2013) Treatments for fibrosis development and progression: Lessons learned from preclinical models and potential impact on human conditions such as scleroderma, pulmonary fibrosis, hypertrophic scarring and tendinopathies. Journal of Biomedical Science and Engineering, 6, 1-9. doi: 10.4236/jbise.2013.68A2001.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Bagavant, H., et al. (2008) Lupus glomerulonephritis revisited 2004: Autoimmunity and end-organ damage. Scandinavian Journal of Immunology, 60, 52-63. doi:10.1111/j.0300-9475.2004.01463.x
[2] Krause, G., et al. (1992) LiCl prolongs survival and alters disease progression in the NZB/W model of SLE. Lithium, 3, 61-67.
[3] Hart, D.A., et al. (1994) Partial characterization of the enhanced survival of female NZB/W mice treated with lithium chloride. International Journal of Immunopharmacology, 16, 825-833. doi:10.1016/0192-0561(94)90056-6
[4] Lenz, S.P., Izui, S. and Hart, D.A. (1997) Evidence that lithium chloride treatment of female NZB/W mice does not influence autoantibody profiles in this murine model of systemic lupus erythematosus. Journal of Trace and Microprobe Techniques, 15, 109-116.
[5] Hart, D.A., et al. (1994) Partial reversal of established bleomycin-induced pulmonary fibrosis by rh-urokinase in a rat model. Clinical & Investigative Medicine, 17, 69-76.
[6] Gharaee-Kertmani, M., et al. (2008) The role of urokinase in idiopathic pulmonary fibrosis and implication for therapy. Expert Opinion on Investigational Drugs, 17, 905-916. doi:10.1517/13543784.17.6.905
[7] Azambuja E., et al. (2005) Bleomycin lung toxicity: Who are the patients with increased risk? Pulmonary Pharmacology & Therapeutics, 18, 363-366. doi:10.1016/j.pupt.2005.01.007
[8] Paun, A., et al. (2013) Association analysis reveals genetic variation altering bleomycin-induced pulmonary fibrosis in mice. American Journal of Respiratory Cell and Molecular Biology, 48, 330-336. doi:10.1165/rcmb.2012-0078OC
[9] Scriabine, A. and Rabin, D.U. (2009) New developments in the therapy of pulmonary fibrosis. Advances in Pharmacology, 57, 419-464. doi:10.1016/S1054-3589(08)57011-6
[10] Mouratis, M.A. and Aidinis, V. (2011) Modeling pulmonary fibrosis with bleomycin. Current Opinion in Pulmonary Medicine, 17, 355-361. doi:10.1097/MCP.0b013e328349ac2b
[11] Chambers, R.C. (2008) Procoagulant signaling mechanisms in lung inflammation and fibrosis: Novel opportunities for pharmacological intervention? British Journal of Pharmacology, 153, S367-S378. doi:10.1038/sj.bjp.0707603
[12] Chambers, R.C. and Laurent, G.J. (2002) Coagulation cascade proteases and tissue fibrosis. Biochemical Society Transactions, 30, 194-200. doi:10.1042/BST0300194
[13] Aksu, K., Donmez, A. and Keser, G. (2012) Inflammation-induced thrombosis: Mechanisms, disease associations and management. Current Pharmaceutical Design, 18, 1478-1493. doi:10.2174/138161212799504731
[14] Davalos, D. and Akassoplou, K. (2012) Fibrinogen as a key regulator of inflammation in disease. Seminars in Immunopathology, 34, 43-62. doi:10.1007/s00281-011-0290-8
[15] Ohba, T., et al. (1994) Scleroderma bronchoalveolar lavage fluid contains thrombin, a mediator of human lung fibroblast proliferation via induction of platelet-derived growth factor alpha-receptor. American Journal of Respiratory Cell and Molecular Biology, 10, 405-412. doi:10.1165/ajrcmb.10.4.7510986
[16] Imokawa, S., et al. (1997) Tissue factor expression and fibrin deposition in the lungs of patients with idiopathic pulmonary fibrosis and systemic sclerosis. American Journal of Respiratory and Critical Care Medicine, 156, 631-636. doi:10.1164/ajrccm.156.2.9608094
[17] Cash, H.A., et al., (1979) A rat model of chronic respiretory infection with Pseudomonas aeruginosa. American Review of Respiratory Disease, 119, 453-459.
[18] Vogt, S.L., et al. (2011) The stringent response is essential for Pseudomonas aeruginosa virulence in the rat lung agar bead and Drosophila melanogaster feeding models of infection. Infection and Immunity, 79, 4094-4104. doi:10.1128/IAI.00193-11
[19] Hart, D.A., et al. (1993) Exogenous rh-urokinase modifies inflammation and Pseudomonas aeruginosa infection in a rat chronic pulmonary infection model. Canadian Journal of Microbiology, 39, 1127-1134. doi:10.1139/m93-170
[20] Hart, D.A. and Woods, D.E. (1994) Urokinase enhances the growth of Pseudomonas spp in vitro under nonshaking (oxygen limited) conditions. Canadian Journal of Microbiology, 40, 292-297. doi:10.1139/m94-047
[21] Hart, D.A. and Woods, D.E. (1994) Human urokinase, a serine proteinase, potentiates the in-vitro growth of microorganisms which commonly infect burn patients. Journal of Medical Microbiology, 41, 264-271. doi:10.1099/00222615-41-4-264
[22] Krieg, T. and Takehara, K. (2009) Skin disease: A cardinal feature of systemic sclerosis. Rheumatology (Oxford), 48, 14-18. doi:10.1093/rheumatology/kep108
[23] Matucci-Cerinic, M., et al. (2009) The complexity of managing systemic sclerosis: Screening and diagnosis. Rheumatology (Oxford), 48, 8-13. doi:10.1093/rheumatology/ken482
[24] Bussone, G. and Mouthon, L. (2011) Interstitial lung disease in systemic sclerosis. Autoimmunity Reviews, 10, 248-255. doi:10.1016/j.autrev.2010.09.012
[25] Valentini, G., et al., (2013) Early systemic sclerosis: Marker autoantibodies and videocapillaroscopy patterns are each associated with distinct clinical, functional and cellular activation markers. Arthritis Research & Therapy, 15, R63. (Epub ahead of print) doi:10.1186/ar4236
[26] Fritzler, M.J. and Hart, D.A. (1990) Prolonged improvement of Raynaud’s phenomenon and scleroderma after recombinant tissue plasminogen activator therapy. Arthritis & Rheumatism, 33, 274-276. doi:10.1002/art.1780330218
[27] Wilson, D., et al. (1995) The safety and efficacy of lowdose tissue plasminogen activator in the treatment of systemic sclerosis. The Journal of Dermatology, 22, 637-642.
[28] Lotti, T., Campanile, G. and Matucci-Cerinic, M. (1994) Cutaneous and plasma fibrinolytic activities are not deficient in patients with systemic sclerosis. Journal of the American Academy of Dermatology, 30, 813-814. doi:10.1016/S0190-9622(08)81531-9
[29] Ames, P.R., et al. (1997) The coagulation/fibrinolysis balance in systemic sclerosis: evidence for a haematological stress syndrome. British Journal of Rheumatology, 36, 1045-1050. doi:10.1093/rheumatology/36.10.1045
[30] Herrick, A.L., et al. (1996) Von willebrand factor, thrombomodulin, thromboxane, beta-thromboglobin and markers of fibrinolysis in primary Raynaud’s phenomenon and systemic sclerosis. Annals of the Rheumatic Diseases, 55, 122-127. doi:10.1136/ard.55.2.122
[31] Bandinelli, F, et al. (2005) The fibrinolytic system components are increased in systemic sclerosis and modulated by Alprotadil (alpha1 ciclodestryn). Clinical and Experimental Rheumatology, 23, 671-677.
[32] Shimizu, Y., et al. (1994) Neural blockade, urokinase and prostaglandin E1 combination therapy for acute digital ischemia of progressive systemic sclerosis. The Journal of Dermatology, 21, 755-759.
[33] Ciompi, M.L., et al. (1996) A placebo-controlled study of urokinase therapy in systemic sclerosis. Biomedicine & Pharmacotherapy, 50, 363-368. doi:10.1016/S0753-3322(96)89669-7
[34] Bazzichi, L., et al. (2003) Clinical improvement in systemic sclerosis resulting from urokinase therapy explained by light and electron microscopy skin examination. Scandinavian Journal of Rheumatology, 32, 261-267. doi:10.1080/03009740310003875
[35] Klimiuk, P.S., et al. (1992) A double blind placebo controlled trial of recombinant tissue plasminogen activator in the treatment of digital ischemia in systemic sclerosis. The Journal of Rheumatology, 19, 716-720.
[36] Fritzler, M.J., Hart, D.A., et al. (1995) Antibodies to fibrin bound tissue type plasminogen activator in systemic sclerosis. The Journal of Rheumatology, 22, 1688-1693.
[37] Kessler-Becker, D., et al. (2004) High plasminogen activator inhibitor type 2 expression is a hallmark of scleroderma fibroblasts in vitro. Experimental Dermatology, 13, 708-714. doi:10.1111/j.0906-6705.2004.00222.x
[38] Postiglione, L., et al. (2010) The plasminogen activator system in fibroblasts from systemic sclerosis. International Journal of Immunopathology and Pharmacology, 23, 891-900.
[39] Manetti, M., et al. (2011) A genetic variation located in the promoter region of the UPAR (CD87) gene is associated with the vascular complications of systemic sclerosis. Arthritis & Rheumatism, 63, 247-256. doi:10.1002/art.30101
[40] Gallant, C.L., Olson, M.E. and Hart, D.A. (2004) Molecular, histologic, and gross phenotype of skin wound healing in red Duroc pigs reveals an abnormal healing phenotype of hypercontracted, hyperpigmented scarring. Wound Repair and Regeneration, 12, 305-319. doi:10.1111/j.1067-1927.2004.012311.x
[41] Gallant-Behm, C.L. and Hart, D.A. (2006) Genetic analysis of skin wound healing and scarring in a porcine model. Wound Repair and Regeneration, 14, 46-54. doi:10.1111/j.1524-475X.2005.00087.x
[42] Gallant-Behm, C.L, Olson, M.E. and Hart, D.A. (2005) Cytokine and growth factor mRNA expression patterns associated with the hypercontracted, hyperpigmented healing phenotype of red Duroc pigs: A model of abnormal human scar development? Journal of Cutaneous Medicine and Surgery, 9, 165-177. doi:10.1007/s10227-005-0105-4
[43] Gallant-Behm, C.L., et al. (2007) Genetic involvement in skin wound healing and scarring in domestic pigs: Assessment of molecular expression patterns in (Yorkshire x Red Duroc) x Yorkshire backcross animals. Journal of Investigative Dermatology, 127, 233-244. doi:10.1038/sj.jid.5700482
[44] Zhu, K.Q., et al. (2007) Review of the female Duroc /Yorkshire pig model of human fibroproliferative scarring. Wound Repair and Regeneration, 17, S32-S39. doi:10.1111/j.1524-475X.2007.00223.x
[45] Engrav, L.H., Garner, W.L. and Tredget, E.E. (2007) Hypertrophic scar, wound contraction and hyper-pigmentation. Journal of Burn Care & Research, 28, 593-597. doi:10.1097/BCR.0B013E318093E482
[46] Gallant-Behm, C.L., Hildebrand, K.A. and Hart, D.A. (2008) The mast cell stabilizer ketotifen prevents development of excessive skin wound contraction and fibrosis in red Duroc pigs. Wound Repair and Regeneration, 16, 226-233. doi:10.1111/j.1524-475X.2008.00363.x
[47] de Hemptinne, I., et al. (2008) Dermal fibroblasts from red Duroc and Yorkshire pigs exhibit intrinsic differences in the contraction of collagen gels. Wound Repair and Regeneration, 16, 132-142. doi:10.1111/j.1524-475X.2007.00340.x
[48] Ohtola, J., et al. (2008) Beta-catenin has sequential roles in the survival and specification of ventral dermis. Development, 135, 2321-2329. doi:10.1242/dev.021170
[49] Hildebrand, K.A., et al. (2004) Myofibroblast numbers are elevated in human elbow contractures after trauma. Clinical Orthopaedics and Related Research, 419, 189-197.
[50] Hildebrand, K.A., Zhang, M. and Hart, D.A. (2005) High rate of joint capsule matrix turnover in chronic human elbow contractures. Clinical Orthopaedics and Related Research, 439, 228-234.
[51] Hildebrand, K.A., Zhang, M. and Hart, D.A. (2007) Myofibroblast upregulators are elevated in joint capsules in posttraumatic contractures. Clinical Orthopaedics and Related Research, 456, 85-91.
[52] Lindenhovius, A.L. and Jupiter, J.B. (2007) The posttraumatic stiff elbow: A review of the literature. Journal of Hand Surgery, 32, 1605-1623. doi:10.1016/j.jhsa.2007.09.015
[53] Charalambous, C.P. and Morrey, B.E. (2012) Posttraumatic elbow stiffness. The Journal of Bone & Joint Surgery, 94, 1428-1437. doi:10.2106/JBJS.K.00711
[54] Hildebrand, K.A., Zhang, M. and Hart, D.A. (2006) Joint capsule matrix turnover in a rabbit model of chronic joint contractures: Correlation with human contractures. Journal of Orthopaedic Research, 24, 1036-1043. doi:10.1002/jor.20128
[55] Hildebrand, K.A., et al. (2008) Cellular, matrix, and growth factor components of the joint capsule are modified early in the process of posttraumatic contracture formation in a rabbit model. Acta Orthopaedica, 79, 116-125. doi:10.1080/17453670710014860
[56] Hildebrand, K.A., et al. (2008) Joint capsule mast cells and neuropeptides are increased within four weeks of injury and remain elevated in chronic stages of posttraumatic contractures. Journal of Orthopaedic Research, 26, 1313-1319. doi:10.1002/jor.20652
[57] Monument, M.J., Hart, D.A., et al. (2010) The mast cell stabilizer ketotifen fumarate lessens contracture severity and myofibroblast hyperplasia: A study in a rabbit model of posttraumatic joint contractures. The Journal of Bone & Joint Surgery, 92, 1468-1477. doi:10.2106/JBJS.I.00684
[58] Monument, M.J., Hart, D.A., et al. (2012) The mast cell stabilizer ketotifen reduces joint capsule fibrosis in a rabbit model of post-traumatic contractures. Inflammation Research, 61, 285-292. doi:10.1007/s00011-011-0409-3
[59] Gruber, B.L. and Kaufman, L.D. (1990) Ketotifen-induced remission of progressive early diffuse scleroderma: Evidence for the role of mast cells in disease pathogenesis. The American Journal of Medicine, 89, 392-395. doi:10.1016/0002-9343(90)90360-P
[60] Gruber, B.L. and Kaufman, L.D. (1991) A double-blind randomized controlled trial of ketotifen versus placebo in early diffuse scleroderma. Arthritis & Rheumatism, 34, 362-366. doi:10.1002/art.1780340315
[61] Yukawa, S., et al. (2010) Involvement of mast cells in systemic sclerosis. Nihon Rinsho Meneki Gakkai Kaishi, 33, 81-86. doi:10.2177/jsci.33.81
[62] Walker, M., Harley, R. and LeRoy, E.C. (1990) Ketotifen prevents skin fibrosis in the tight skin mouse. The Journal of Rheumatology, 17, 57-59.
[63] Zhu, Z., et al. (2013) The molecular mechanism of hypertrophic scar. Journal of Cell Communication and Signaling. Epub ahead of print.
[64] Tredget, E.E., et al. (1997) Determination of plasma NT-methylhistamine in vivo by isotope dilution using benchtop gas chromatography-mass spectrometry. Sciences and Applications, 694, 1-9. doi:10.1016/S0378-4347(97)00122-9
[65] Wilder-Smith, E.P., Seet, R.C. and Lim, E.C. (2006) Diagnosing carpel tunnel syndrome-clinical criteria and ancillary tests. Nature Clinical Practice. Neurology, 2, 366-374.
[66] Kuhnel, W., et al. (1987) A morphological study of the periand epineurium in the compression zone of the median nerve in carpal tunnel syndrome. Acta Anatomica (Basal), 129, 81-91.
[67] Scott, A., et al. (2008) Increased mast cell numbers in human patellar tendinosis: Correlation with symptom duration and vascular hyperplasia. British Journal of Sports Medicine, 42, 753-757. doi:10.1136/bjsm.2007.040212
[68] Medsger Jr., T.A. (2003) Natural history of systemic sclerosis and the assessment of disease activity, severity, functional status, and psychologic well being. Rheumatic Disease Clinics of North America, 29, 255-273. doi:10.1016/S0889-857X(03)00023-1
[69] Murrell, G.A., Francis, M.J. and Howlett, C.R. (1989) Dupuytren’s contracture. Fine structure in relation to etiology. Journal of Bone and Joint Surgery British, 71, 367-373.
[70] Dolmans, G.H., de Bock, G.H. and Werker, P.M. (2012) Dupuytren diathesis and genetic risk. Journal of Hand Surgery, 37, 2106-2111. doi:10.1016/j.jhsa.2012.07.017
[71] Hu, F.Z., et al. (2005) Mapping of an autosomal dominant gene for Dupuytren’s contracture to chromosome 16q in a Swedish family. Clinical Genetics, 68, 424-429. doi:10.1111/j.1399-0004.2005.00504.x
[72] Shubert, T.E., et al. (2006) Dupuytren’s contracture is associated with sprouting of substance P positive nerve fibres and infiltration by mast cells. Annals of the Rheumatic Diseases, 65, 414-415. doi:10.1136/ard.2005.044016
[73] Azzopardi, E. and Boyce, D.E. (2012) Clostridium histolyticum collagenase in the treatment of Dupuytren’s contracture. British Journal of Hospital Medicine (London), 73, 432-436.
[74] Hentz, V.R., et al. (2012) Advances in the management of Dupuytren’s disease: Collagenase. Hand Clinics, 28, 551-563. doi:10.1016/j.hcl.2012.08.003
[75] Pullar, T. and Capell, H.A. (1985) A rheumatological dilemma: Is it possible to modify the course of rheumatoid arthritis? Can we answer the question? Annals of the Rheumatic Diseases, 44, 134-140. doi:10.1136/ard.44.2.134
[76] Teh, L.G., Madhok, R. and Capell, H.A. (1984) Does the addition of ketotifen to non-steroidal anti-inflammatory drugs confer and additional benefit to rheumatoid arthritis? British Journal of Clinical Pharmacology, 17, 157-159. doi:10.1111/j.1365-2125.1984.tb02330.x
[77] Kolb, M., et al. (2001) Proteoglycans decorin and biglycan differentially modulate TGF-beta-mediated fibrotic responses in the lung. American Journal of Physiology. Lung Cellular and Molecular Physiology, 280, L1327-L1334.
[78] Gagliardini, E. and Benigni, A. (2006) Role of anti-TGF-beta antibodies in the treatment of renal injury. Cytokine & Growth Factor Reviews, 17, 89-96. doi:10.1016/j.cytogfr.2005.09.005
[79] Boffa, J.J. and Ronco, P. (2007) Strategies to reverse fibrotic lesions of the kidney. La Presse Médicale, 26, 1857-1864. doi:10.1016/j.lpm.2007.04.033

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.