Anti-inflammatory pharmacotherapy with ketoprofen ameliorates experimental lymphatic vascular insufficiency in mice
Kenta Nakamura, Kavita Radhakrishnan, Yat Man Wong, Stanley G Rockson, Kenta Nakamura, Kavita Radhakrishnan, Yat Man Wong, Stanley G Rockson
Abstract
Background: Disruption of the lymphatic vasculature causes edema, inflammation, and end-tissue destruction. To assess the therapeutic efficacy of systemic anti-inflammatory therapy in this disease, we examined the impact of a nonsteroidal anti-inflammatory drug (NSAID), ketoprofen, and of a soluble TNF-alpha receptor (sTNF-R1) upon tumor necrosis factor (TNF)-alpha activity in a mouse model of acquired lymphedema.
Methods and findings: Lymphedema was induced by microsurgical ablation of major lymphatic conduits in the murine tail. Untreated control mice with lymphedema developed significant edema and extensive histopathological inflammation compared to sham surgical controls. Short-term ketoprofen treatment reduced tail edema and normalized the histopathology while paradoxically increasing TNF-alpha gene expression and cytokine levels. Conversely, sTNF-R1 treatment increased tail volume, exacerbated the histopathology, and decreased TNF-alpha gene expression. Expression of vascular endothelial growth factor-C (VEGF-C), which stimulates lymphangiogenesis, closely correlated with TNF-alpha expression.
Conclusions: Ketoprofen therapy reduces experimental post-surgical lymphedema, yet direct TNF-alpha inhibition does not. Reducing inflammation while preserving TNF-alpha activity appears to optimize the repair response. It is possible that the observed favorable responses, at least in part, are mediated through enhanced VEGF-C signaling.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
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References
- Nakamura K, Rockson SG. The role of the lymphatic circulation in the natural history and expression of cardiovascular disease. Int J Cardiol 2008
- Rockson SG. Diagnosis and management of lymphatic vascular disease. J Am Coll Cardiol. 2008;52:799–806.
- Szuba A, Skobe M, Karkkainen MJ, Shin WS, Beynet DP, et al. Therapeutic lymphangiogenesis with human recombinant VEGF-C. Faseb J. 2002;16:1985–1987.
- Cheung L, Han J, Beilhack A, Joshi S, Wilburn P, et al. An experimental model for the study of lymphedema and its response to therapeutic lymphangiogenesis. BioDrugs. 2006;20:363–370.
- Tabibiazar R, Cheung L, Han J, Swanson J, Beilhack A, et al. Inflammatory Manifestations of Experimental Lymphatic Insufficiency. PLoS Med. 2006;3:e254.
- Saito Y, Nakagami H, Morishita R, Takami Y, Kikuchi Y, et al. Transfection of human hepatocyte growth factor gene ameliorates secondary lymphedema via promotion of lymphangiogenesis. Circulation. 2006;114:1177–1184.
- Yoon YS, Murayama T, Gravereaux E, Tkebuchava T, Silver M, et al. VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema. J Clin Invest. 2003;111:717–725.
- Nakamura K, Rockson SG. Molecular Targets for Therapeutic Lymphangiogenesis in Lymphatic Dysfunction and Disease. Lymphat Res Biol (in press) 2008
- Nakamura K, Rockson SG. Biomarkers of lymphatic function and disease: state of the art and future directions. Mol Diagn Ther. 2007;11:227–238.
- Skobe M, Hamberg LM, Hawighorst T, Schirner M, Wolf GL, et al. Concurrent induction of lymphangiogenesis, angiogenesis, and macrophage recruitment by vascular endothelial growth factor-C in melanoma. Am J Pathol. 2001;159:893–903.
- Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. Embo J. 2001;20:672–682.
- Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med. 2001;7:186–191.
- Olszewski WL, Engeset A, Romaniuk A, Grzelak I, Ziolkowska A. Immune cells in peripheral lymph and skin of patients with obstructive lymphedema. Lymphology. 1990;23:23–33.
- Rockson SG. Lymphedema. Am J Med. 2001;110:288–295.
- Schneider M, Ny A, Ruiz de Almodovar C, Carmeliet P. A new mouse model to study acquired lymphedema. PLoS Med. 2006;3:e264.
- Jin da P, An A, Liu J, Nakamura K, Rockson SG. Therapeutic responses to exogenous VEGF-C administration in experimental lymphedema: immunohistochemical and molecular characterization. Lymphat Res Biol. 2009;7:47–57.
- Appleyard CB, McCafferty DM, Tigley AW, Swain MG, Wallace JL. Tumor necrosis factor mediation of NSAID-induced gastric damage: role of leukocyte adherence. Am J Physiol. 1996;270:G42–48.
- Hosack D, Dennis G, Sherman B, Lane H, Lempicki R. Identifying biological themes within lists of genes with EASE. Genome Biology. 2003;4:R70.
- Ulfgren AK, Andersson U, Engstrom M, Klareskog L, Maini RN, et al. Systemic anti-tumor necrosis factor alpha therapy in rheumatoid arthritis down-regulates synovial tumor necrosis factor alpha synthesis. Arthritis Rheum. 2000;43:2391–2396.
- Bush KA, Walker JS, Frazier J, Kirkham BW. Effects of a PEGylated soluble TNF receptor type 1 (PEG sTNF-RI) on cytokine expression in adjuvant arthritis. Scand J Rheumatol. 2002;31:198–204.
- Edwards CK., 3rd PEGylated recombinant human soluble tumour necrosis factor receptor type I (r-Hu-sTNF-RI): novel high affinity TNF receptor designed for chronic inflammatory diseases. Ann Rheum Dis. 1999;58(Suppl 1):I73–81.
- Maini RN, Taylor PC. Anti-cytokine therapy for rheumatoid arthritis. Annu Rev Med. 2000;51:207–229.
- Ghezzi P, Melillo G, Meazza C, Sacco S, Pellegrini L, et al. Differential contribution of R and S isomers in ketoprofen anti-inflammatory activity: role of cytokine modulation. J Pharmacol Exp Ther. 1998;287:969–974.
- Tsuboi I, Tanaka H, Nakao M, Shichijo S, Itoh K. Nonsteroidal anti-inflammatory drugs differentially regulate cytokine production in human lymphocytes: up-regulation of TNF, IFN-gamma and IL-2, in contrast to down-regulation of IL-6 production. Cytokine. 1995;7:372–379.
- Santucci L, Fiorucci S, Giansanti M, Brunori PM, Di Matteo FM, et al. Pentoxifylline prevents indomethacin induced acute gastric mucosal damage in rats: role of tumour necrosis factor alpha. Gut. 1994;35:909–915.
- Jorres A, Dinter H, Topley N, Gahl GM, Frei U, et al. Inhibition of tumour necrosis factor production in endotoxin-stimulated human mononuclear leukocytes by the prostacyclin analogue iloprost: cellular mechanisms. Cytokine. 1997;9:119–125.
- Kunkel SL, Spengler M, Kwon G, May MA, Remick DG. Production and regulation of tumor necrosis factor alpha. A cellular and molecular analysis. Methods Achiev Exp Pathol. 1988;13:240–259.
- Renz H, Gong JH, Schmidt A, Nain M, Gemsa D. Release of tumor necrosis factor-alpha from macrophages. Enhancement and suppression are dose-dependently regulated by prostaglandin E2 and cyclic nucleotides. J Immunol. 1988;141:2388–2393.
- Sironi M, Gadina M, Kankova M, Riganti F, Mantovani A, et al. Differential sensitivity of in vivo TNF and IL-6 production to modulation by anti-inflammatory drugs in mice. Int J Immunopharmacol. 1992;14:1045–1050.
- Tannenbaum CS, Hamilton TA. Lipopolysaccharide-induced gene expression in murine peritoneal macrophages is selectively suppressed by agents that elevate intracellular cAMP. J Immunol. 1989;142:1274–1280.
- Meyer AM, Ramzan NN, Heigh RI, Leighton JA. Relapse of inflammatory bowel disease associated with use of nonsteroidal anti-inflammatory drugs. Dig Dis Sci. 2006;51:168–172.
- Hub E, Rot A. Binding of RANTES, MCP-1, MCP-3, and MIP-1alpha to cells in human skin. Am J Pathol. 1998;152:749–757.
- Scavelli C, Weber E, Agliano M, Cirulli T, Nico B, et al. Lymphatics at the crossroads of angiogenesis and lymphangiogenesis. J Anat. 2004;204:433–449.
- Pan D, Suzuki Y, Yang PC, Rockson SG. Indirect magnetic resonance lymphangiography to assess lymphatic function in experimental murine lymphedema. Lymphat Res Biol. 2006;4:211–216.
- Ristimaki A, Narko K, Enholm B, Joukov V, Alitalo K. Proinflammatory cytokines regulate expression of the lymphatic endothelial mitogen vascular endothelial growth factor-C. J Biol Chem. 1998;273:8413–8418.
- Cha HS, Bae EK, Koh JH, Chai JY, Jeon CH, et al. Tumor necrosis factor-alpha induces vascular endothelial growth factor-C expression in rheumatoid synoviocytes. J Rheumatol. 2007;34:16–19.
- Paavonen K, Mandelin J, Partanen T, Jussila L, Li TF, et al. Vascular endothelial growth factors C and D and their VEGFR-2 and 3 receptors in blood and lymphatic vessels in healthy and arthritic synovium. J Rheumatol. 2002;29:39–45.
- Wauke K, Nagashima M, Ishiwata T, Asano G, Yoshino S. Expression and localization of vascular endothelial growth factor-C in rheumatoid arthritis synovial tissue. J Rheumatol. 2002;29:34–38.
- Mouta C, Heroult M. Inflammatory triggers of lymphangiogenesis. Lymphat Res Biol. 2003;1:201–218.
- Baluk P, Yao LC, Feng J, Romano T, Jung SS, et al. TNF-alpha drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice. J Clin Invest. 2009;119:2954–2964.
- Goldman J, Le TX, Skobe M, Swartz MA. Overexpression of VEGF-C causes transient lymphatic hyperplasia but not increased lymphangiogenesis in regenerating skin. Circ Res. 2005;96:1193–1199.
- Sitzia J. Volume measurement in lymphoedema treatment: examination of formulae. Eur J Cancer Care (Engl) 1995;4:11–16.
- Pan D, Han J, Wilburn P, Rockson SG. Validation of a new technique for the quantitation of edema in the experimental setting. Lymphat Res Biol. 2006;4:153–158.
- Sanders JE, Goldstein BS, Leotta DF, Richards KA. Image processing techniques for quantitative analysis of skin structures. Comput Methods Programs Biomed. 1999;59:167–180.
- Chen MM, Ashley EA, Deng DX, Tsalenko A, Deng A, et al. Novel role for the potent endogenous inotrope apelin in human cardiac dysfunction. Circulation. 2003;108:1432–1439.
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