Anti-inflammatory effects of non-anticoagulant heparinoids in vitro and in a rat renal transplantation model

Talsma, D. (Ditmer) (2013) Anti-inflammatory effects of non-anticoagulant heparinoids in vitro and in a rat renal transplantation model. thesis, Medicine.

Text TalsmaD.pdf Restricted to Registered users only Download (433kB)

Abstract

Introduction: Chronic transplant dysfunction (CTD) is histologically characterized by tissue remodeling including interstitial fibrosis, tubular atrophy, glomerulosclerosis, and transplant vasculopathy, along with a chronic inflammatory component including complement activation and leukocyte infiltration. Currently, there is no treatment to reduce the tissue remodeling in CTD. We earlier showed upregulation of matrix proteoglycans (PGs) in CTD, and now hypothesize that heparinoids, via PG-ligand interaction inhibition can reduce complement activation and leukocyte recruitment and could be a target of intervention. Methods: Heparinoid effectivity to diminish chemokine (CCL2), leukocyte adhesion molecule (L-selectin) and complement (properdin and factor H) binding to immobilized heparan sulfate PG’s was evaluated in an ELISA in vitro approach. The in vivo anti-inflammatory effects of these heparinoids on development of CTD was tested in a rat CTD model. Results: ELISA results showed the binding of L-selectin, CCL-2 and properdin to heparan sulfate PG perlecan. Factor H did not interact with perlecan, however bound with heparin-albumin. The interaction of L-selectin, CCL2 and properdin with perlecan could be dose-dependently inhibited by heparin and two non-anticoagulant heparinoids, namely N-acetyl heparin and RO-heparin. Results showed CCL-2 to be most sensitive for heparinoid inhibition, followed by properdin and L-selectin. In the rat CTD model daily s.c. treatment with the non-anticoagulant RO-heparin reduced tubulo-interstitial inflammation with CD45+ cells by 50% ( p=0.0175). Unexpectedly, RO-heparin increased properdin deposition in the transplanted kidneys. Terminal complement MAC complex formation was non-significantly reduced in all heparin treated groups. Conclusion: Our data show that (non-anticoagulant) heparin(oids) can reduce chemokine, adhesion molecule, and complement binding to heparan sulfate PG’s in vitro, and are effective in reducing inflammation in rat CTD. We therefore suggest (non-anticoagulant) glycomimetics to be a promising therapeutic modality to reduce CTD and possibly other fibrotic diseases.

Item Type:	Thesis (Thesis)
Supervisor name:	Born, Jaap van den
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 11:02
Last Modified:	25 Jun 2020 11:02
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/2262

Actions (login required)

View Item