bxl628 and Chronic-Disease

Benign prostatic hyperplasia (BPH) is a common disorder affecting 50-80% of the aged male population. Androgens and age have been traditionally considered the main determinants of prostate enlargement, but in the last years a potentially important role of chronic inflammation in BPH pathogenesis has emerged. Bacterial and non-infectious chronic prostatitis could represent inciting factors leading to tissue hyperproliferation, possibly via the recently demonstrated antigen-presenting capacity of prostatic stromal cells, enabling them to induce and sustain intraglandular immune responses. The prostate growth-promoting chemokine IL-8 could represent a direct link between chronic prostate inflammation and autocrine/paracrine stromal cell proliferation, in agreement with its marked secretion induced in BPH stromal cells by a combination of Th1 and Th17 cell-derived inflammatory cytokines. BPH stromal cells express the vitamin D receptor (VDR), which is up-regulated by exposure to inflammatory stimuli. The non-hypercalcaemic VDR agonist elocalcitol, shown to arrest BPH development by decreasing the intra-prostatic androgen signalling without directly interfering with systemic androgen action, exerts immunoregulatory and anti-inflammatory properties in different prostatic pathology characterized by growth and inflammation. The mechanism of action of VDR agonists supports an important role of chronic inflammation in BPH pathogenesis and strengthens the concept of these agents as a therapeutic option for pharmacological treatment of BPH.

Topics: Androgens; Anti-Inflammatory Agents; Calcitriol; Chemokines; Chronic Disease; Cytokines; Humans; Inflammation; Interleukin-8; Male; Prostate; Prostatic Hyperplasia; Prostatitis; Receptors, Calcitriol; Signal Transduction; Stromal Cells

Vitamin D receptor (VDR) agonists are immunomodulatory agents that have been shown to prolong allograft survival in several transplantation models, but calcemic liability remains an issue.. To study the effect of VDR agonists on acute rejection, the authors have used the heterotopic vascularized heart model, and to assess their long-term effects, the aortic allograft model, which shows immune-mediated intimal thickening similar to the vascular lesions of human chronic allograft rejection. VDR agonists were administered orally from days -1 to 30, or until allografts were rejected. Aortic allograft recipients were killed at day 60 posttransplantation, and the transplanted aorta was analyzed by histology, immunohistochemistry, and gene microarray.. A significant delay in acute rejection was induced by calcitriol and, more markedly, by the less calcemic analogue BXL-628. BXL-628 was also more effective in inhibiting intimal hyperplasia, leading to approximately 80% reduction compared with vehicle-treated controls, an effect significantly superior to dexamethasone administration. Leukocyte recruitment to the graft was significantly inhibited by BXL-628 treatment, with a profound reduction in the number of CD11b macrophages and CD11c dendritic cells infiltrating the adventitia of transplanted aortas. A significant reduction of transcripts coding for several muscle-related genes was observed in aortic allografts from BXL-628-treated mice compared with controls.. These results show that the nonhypercalcemic VDR agonist BXL-628 inhibits, as a monotherapy, acute and chronic graft rejection in mouse models.

Topics: Acute Disease; Animals; Aorta; Calcitriol; Cell Division; Chronic Disease; Disease Models, Animal; Graft Rejection; Graft Survival; Heart Transplantation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Receptors, Calcitriol; Time Factors; Transplantation, Homologous