No abstract

A disintegrin and metalloproteinase domain 10 (ADAM10) is a metalloprotease involved in cleavage of various cell surface molecules, such as adhesion molecules, chemokines, and growth factor receptors. Although we have previously shown an association of ADAM10 expression with atherosclerotic plaque progression, a causal role of ADAM10 in atherosclerosis has not been investigated. Bone marrow from conditional knockout mice lacking Adam10 in the myeloid lineage or from littermate controls was transplanted into lethally irradiated low density lipoprotein receptor Ldlr(-/-) mice on an atherogenic diet. Myeloid Adam10 deficiency did not affect plaque size, but it increased plaque collagen content. Matrix metalloproteinase 9 and 13 expression and matrix metalloproteinase 2 gelatinase activity were significantly impaired in Adam10-deficient macrophages, whereas their capacity to stimulate collagen production was unchanged. Furthermore, relative macrophage content in advanced atherosclerotic lesions was decreased. In vitro, Adam10-deficient macrophages showed reduced migration toward monocyte chemoattractant protein-1 and transmigration through collagen. In addition, Adam10-deficient macrophages displayed increased anti-inflammatory phenotype with elevated IL-10, and reduced production of proinflammatory tumor necrosis factor, IL-12, and nitric oxide in response to lipopolysaccharide. These data suggest a critical role of Adam10 for leukocyte recruitment, inflammatory mediator production, and extracellular matrix degradation. Thereby, myeloid ADAM10 may play a causal role in modulating atherosclerotic plaque stability.

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Visual interstitial fibrosis assessment as continuous variable in protocol renal transplant biopsiesAims: In current renal transplant pathology practice, interstitial fibrosis is visually assessed in categories according to the Banff classification. As this has a moderate reproducibility, which is little ameliorated by morphometric analysis, we investigated whether visual renal fibrosis assessment is feasible on a continuous scale, i.e. as a percentage of affected area of the cortex. Methods and results: Protocol renal biopsies taken at transplantation (n = 125), three (n = 73) and 12 months (n = 88) after transplantation were visually scored in categories (Banff) and percentages for interstitial fibrosis (ci). Interobserver variation (ICC and weighted j) was assessed, and morphometric analysis on Sirius red-stained sections was performed. Correlations between the different methods and their association with donor age and eGFR 1 and 5 years post-transplant were analysed using Pearson's or Spearman's rho. Interobserver agreement was equivalent for Banff and %ci (j = 0.713 versus ICC = 0.792), and for Banff IF/TA and %IF/TA (j = 0.615 versus ICC = 0.743). Both Banff and %ci were associated with Sirius red morphometry in 3 and 12 months. With all three methods, a significant correlation was found between donor age and fibrosis in the implantation biopsy and between fibrosis in the 12 months' biopsy and eGFR at 1 and 5 years (eGFR at 1 year: Sirius red q = 0.487, %ci q = 0.393, Banff q = 0.413, all P < 0.01, eGFR at 5 years: Sirius red q = 0.392, %ci q = 0.333, Banff q = 0.435, all P < 0.01). Conclusion: Interstitial fibrosis assessment on a continuous scale can be used next to scoring in categories according to the Banff classification in protocol renal transplant biopsies.