title: Inhibition of gelatinase B (matrix metalloprotease-9) activity reduces cellular inflammation and restores function of transplanted pancreatic islets.
abstract: Islet transplantation provides an approach to compensate for loss of insulin-producing cells in patients with type 1 diabetes. However, the intraportal route of transplantation is associated with instant inflammatory reactions to the graft and subsequent islet destruction as well. Although matrix metalloprotease (MMP)-2 and -9 are involved in both remodeling of extracellular matrix and leukocyte migration, their influence on the outcome of islet transplantation has not been characterized. We observed comparable MMP-2 mRNA expressions in control and transplanted groups of mice, whereas MMP-9 mRNA and protein expression levels increased after islet transplantation. Immunostaining for CD11b (Mac-1)-expressing leukocytes (macrophage, neutrophils) and Ly6G (neutrophils) revealed substantially reduced inflammatory cell migration into islet-transplanted liver in MMP-9 knockout recipients. Moreover, gelatinase inhibition resulted in a significant increase in the insulin content of transplanted pancreatic islets and reduced macrophage and neutrophil influx compared with the control group. These results indicate that the increase of MMP-9 expression and activity after islet transplantation is directly related to enhanced leukocyte migration and that early islet graft survival can be improved by inhibiting MMP-9 (gelatinase B) activity.
authors.affiliation: Third Medical Department, Faculty of Medicine, Justus-Liebig University, Giessen, Germany.
authors.forename: Neelam
authors.initials: N
authors.lastname: Lingwal
authors.forename: Manju
authors.initials: M
authors.lastname: Padmasekar
authors.forename: Balaji
authors.initials: B
authors.lastname: Samikannu
authors.forename: Reinhard G
authors.initials: RG
authors.lastname: Bretzel
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Preissner
authors.forename: Thomas
authors.initials: T
authors.lastname: Linn
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002216:Captopril / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D006085:Graft Survival / Q000502:physiology*; D007249:Inflammation / Q000517:prevention & control; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008099:Liver / Q000601:surgery; D008264:Macrophages / Q000502:physiology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013552:Swine
chemical_list: D039481:CD11b Antigen; D007328:Insulin; D061965:Matrix Metalloproteinase Inhibitors; D002216:Captopril; D020780:Matrix Metalloproteinase 9