Both the identity and source of the rodent collagenase(s) that mediates matrix remodeling in liver fibrosis remain elusive. We have recently demonstrated an unequivocal role for scar-associated macrophages (SAMs) in the spontaneous resolution of liver fibrosis and sought to determine whether SAMs are the source of matrix metalloproteinase (MMP) 13 (collagenase 3), considered to be the primary interstitial collagenase in rodents. In this study, we demonstrate an association between MMP13 expression and the presence of SAMs in the regression of experimental liver fibrosis. mmp13 gene expression was restricted to regions of fibrosis that were rich in SAMs. Both MMP13 mRNA and protein colocalized to large phagocytes within and directly apposed to hepatic scars. Using the CD11b-DTR-transgenic mouse to deplete SAMs in a model of chronic CCl4 injury, we found that SAM depletion resulted in a 5-fold reduction in mmp13 message (p = 0.005). Furthermore, resolution of CCl4-induced fibrosis was retarded in MMP13-deficient mice. Thus, SAMs selectively, during resolution of fibrosis induce and use the major collagenase MMP13 to mediate the resorption of interstitial matrix and successfully remodel the fibrotic liver.

The non-dipping phenomenon is closely related to a high incidence of CV diseases, a poor long-term survival and profound autonomic dysfunction. ABPM is useful in predicting long-term CV prognosis in HD patients.

Recent progress with specific markers of lymphatic vessel endothelium allowed recognition of lymphangiogenic events in various disease states; however, there is little information concerning this process in human chronic renal diseases. To determine this we measured expression of the lymphatic marker D2-40 and vascular endothelial growth factor-C (VEGF-C), a major growth factor in lymphangiogenesis, in 124 human renal biopsy specimens. In the kidneys of control subjects and in uninjured areas of pathologic specimens, lymphatic vessels were detected only around the arcuate and interlobular arteries. An increase in the number of lymphatic vessels was found at the site of tubulointerstitial lesions correlating with the degree of tissue damage and more strongly correlating with areas of fibrosis than inflammation. On serial sections, lymphatic vessel proliferation was found in the tubulointerstitial area at the site of tuft adhesions to Bowman's capsule. Lymphatic growth was associated with VEGF-C expression in inflammatory mononuclear cells and tubular epithelial cells, mainly of proximal tubules. Lymphangiogenesis and VEGF-C expression was elevated in diabetic nephropathy in comparison to other renal diseases. Our results indicate that lymphangiogenesis is a common feature in the progression of the tubulointerstitial fibrosis.

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