Liposomal prednisolone inhibits vascular inflammation and enhances venous outward remodeling in a murine arteriovenous fistula model

Arteriovenous fistulas (AVF) for hemodialysis access have a 1-year primary patency rate of only 60%, mainly as a result of maturation failure that is caused by insufficient outward remodeling and intimal hyperplasia. The exact pathophysiology remains unknown, but the inflammatory vascular response is thought to play an important role. In the present study we demonstrate that targeted liposomal delivery of prednisolone increases outward remodeling of the AVF in a murine model. Liposomes accumulate in the post-anastomotic area of the venous outflow tract in which the vascular pathology is most prominent in failed AVFs. On a histological level, we observed a reduction of lymphocytes and granulocytes in the vascular wall. In addition, a strong anti-inflammatory effect of liposomal prednisolone on macrophages was demonstrated in vitro. Therefore, treatment with liposomal prednisolone might be a valuable strategy to improve AVF maturation.

[1]  F. M. van der Sande,et al.  Prospective evaluation of failure modes in autogenous radiocephalic wrist access for haemodialysis. , 2003, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[2]  Z. Galis,et al.  This Review Is Part of a Thematic Series on Matrix Metalloproteinases, Which Includes the following Articles: Matrix Metalloproteinase Inhibition after Myocardial Infarction: a New Approach to Prevent Heart Failure? Matrix Metalloproteinases in Vascular Remodeling and Atherogenesis: the Good, the Ba , 2022 .

[3]  J. Jukema,et al.  Histopathologic alterations following local delivery of dexamethasone to inhibit restenosis in murine arteries. , 2005, Cardiovascular research.

[4]  G. Weissmann,et al.  A Mechanism for the Antiinflammatory Effects of Corticosteroids , 1993, Journal of Pediatric Gastroenterology and Nutrition.

[5]  C. Holland,et al.  Venous stenosis in a pig arteriovenous fistula model--anatomy, mechanisms and cellular phenotypes. , 2007, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[6]  A. Aydın,et al.  The relationship between arteriovenous fistula success and inflammation , 2013, Renal failure.

[7]  R. Schiffelers,et al.  Therapeutic Application of Long-Circulating Liposomal Glucocorticoids in Auto-Immune Diseases and Cancer , 2006, Journal of liposome research.

[8]  E. Lakatta,et al.  Matrix metalloproteinases promote arterial remodeling in aging, hypertension, and atherosclerosis. , 2015, Hypertension.

[9]  Hsin-Chieh Yeh,et al.  Effect of the 2011 vs 2003 duty hour regulation-compliant models on sleep duration, trainee education, and continuity of patient care among internal medicine house staff: a randomized trial. , 2013, JAMA internal medicine.

[10]  Prabir Roy-Chaudhury,et al.  Early arteriovenous fistula failure: a logical proposal for when and how to intervene. , 2006, Clinical journal of the American Society of Nephrology : CJASN.

[11]  Robert Langer,et al.  Impact of nanotechnology on drug delivery. , 2009, ACS nano.

[12]  J. Beijnen,et al.  Optimizing the therapeutic index of liposomal glucocorticoids in experimental arthritis. , 2011, International journal of pharmaceutics.

[13]  G. Storm,et al.  Liposomal Targeting of Prednisolone Phosphate to Synovial Lining Macrophages during Experimental Arthritis Inhibits M1 Activation but Does Not Favor M2 Differentiation , 2013, PloS one.

[14]  C. Libert,et al.  New insights into the anti-inflammatory mechanisms of glucocorticoids: an emerging role for glucocorticoid-receptor-mediated transactivation. , 2013, Endocrinology.

[15]  J. Grande,et al.  Increased venous proinflammatory gene expression and intimal hyperplasia in an aorto-caval fistula model in the rat. , 2003, The American journal of pathology.

[16]  T. Reil,et al.  Dexamethasone suppresses vascular smooth muscle cell proliferation. , 1999, The Journal of surgical research.

[17]  D. Mukhopadhyay,et al.  Adventitial Delivery of Lentivirus-shRNA-ADAMTS-1 Reduces Venous Stenosis Formation in Arteriovenous Fistula , 2014, PloS one.

[18]  D. Lasič Novel applications of liposomes. , 1998, Trends in biotechnology.

[19]  Zhao-Jun Liu,et al.  A New Arteriovenous Fistula Model to Study the Development of Neointimal Hyperplasia , 2012, Journal of Vascular Research.

[20]  G. Pasterkamp,et al.  Oral Matrix Metalloproteinase Inhibition and Arterial Remodeling After Balloon Dilation: An Intravascular Ultrasound Study in the Pig , 2001, Circulation.

[21]  Hermann Bondi,et al.  The good, the bad and the ugly , 1988, Nature.

[22]  P. Ravani,et al.  Biology of arteriovenous fistula failure. , 2007, Journal of nephrology.

[23]  Diederik F Van Wijk,et al.  Prednisolone-containing liposomes accumulate in human atherosclerotic macrophages upon intravenous administration. , 2015, Nanomedicine : nanotechnology, biology, and medicine.

[24]  J. Hamming,et al.  Doxycycline for Stabilization of Abdominal Aortic Aneurysms , 2013, Annals of Internal Medicine.

[25]  P. Quax,et al.  Short-term dexamethasone treatment inhibits vein graft thickening in hypercholesterolemic ApoE3Leiden transgenic mice. , 2006, Journal of vascular surgery.

[26]  P. Quax,et al.  Vascular remodeling and intimal hyperplasia in a novel murine model of arteriovenous fistula failure. , 2014, Journal of vascular surgery.

[27]  V. Fuster,et al.  Multimodal clinical imaging to longitudinally assess a nanomedical anti-inflammatory treatment in experimental atherosclerosis. , 2010, Molecular pharmaceutics.

[28]  D. Papahadjopoulos,et al.  Liposomes revisited , 1995, Science.

[29]  P. Quax,et al.  Arteriovenous access failure: more than just intimal hyperplasia? , 2013, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[30]  R. Gold,et al.  Drug targeting by long-circulating liposomal glucocorticosteroids increases therapeutic efficacy in a model of multiple sclerosis. , 2003, Brain : a journal of neurology.

[31]  M. Wauben,et al.  Complete remission of experimental arthritis by joint targeting of glucocorticoids with long-circulating liposomes. , 2003, Arthritis and rheumatism.

[32]  E. Topol,et al.  Local delivery of dexamethasone for prevention of neointimal proliferation in a rat model of balloon angioplasty. , 1994, The Journal of clinical investigation.

[33]  C. Meijer,et al.  Doxycycline for Stabilization of Abdominal Aortic Aneurysms: A Randomized Trial , 2014 .

[34]  J. Cidlowski,et al.  Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. , 2005, The New England journal of medicine.

[35]  L. Christophorou Science , 2018, Emerging Dynamics: Science, Energy, Society and Values.