bay-12-9566 and Disease-Models--Animal

Azithromycin has become a standard of care in therapy of bronchiolitis obliterans following lung transplantation. Matrix metalloprotease-9 broncho-alveolar lavage levels increase in airway neutrophilia and bronchiolitis obliterans. Interleukin-17 may play a role in lung allograft rejection, and interleukin-12 is downregulated in bronchiolitis obliterans. Whether these mechanisms can be targeted by azithromycin remains unclear.. Bronchiolitis obliterans was induced by transplantation of Fischer F344 rat left lungs to Wistar Kyoto rats. Allografts with azithromycin therapy from day 1 to 28 or 56 and mono- or combination therapy with the broad-spectrum matrix metalloprotease inhibitor tanomastat from day 1 to 56 were compared to control allografts and isografts. Graft histology was assessed, and tissue cytokine expression studied using Western blotting and immunofluorescence.. The chronic airway rejection score in the azithromycin group did not change between 4 and 8 weeks after transplantation, whereas it significantly worsened in control allografts (P = .041). Azithromycin+tanomastat prevented complete allograft fibrosis, which occurred in 40% of control allografts. Azithromycin reduced interleukin-17 expression (P = .049) and the number of IL-17(+)/CD8(+) lymphocytes at 4 weeks, and active matrix metalloprotease-9 at 8 weeks (P = .017), and increased interleukin-12 expression (P = .025) at 8 weeks following transplantation versus control allografts.. The expression of interleukin-17 and matrix metalloprotease-9 in bronchiolitis obliterans may be attenuated by azithromycin, and the decrease in interleukin-12 expression was prevented by azithromycin. Combination of azithromycin with a matrix metalloprotease inhibitor is worth studying further because it prevented complete allograft fibrosis in this study.

Topics: Animals; Azithromycin; Biphenyl Compounds; Bronchiolitis Obliterans; Disease Models, Animal; Drug Therapy, Combination; Fibrosis; Graft Survival; Interleukin-12; Interleukin-17; Lung; Lung Transplantation; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Phenylbutyrates; Rats, Inbred F344; Rats, Inbred WKY; Time Factors

Previous work has shown that integrin alpha1-null Alport mice exhibit attenuated glomerular disease with decreased matrix accumulation and live much longer than strain-matched Alport mice. However, the mechanism underlying this observation is unknown. Here we show that glomerular gelatinase expression, specifically matrix metalloproteinase-2 (MMP-2), MMP-9, and MMP-14, was significantly elevated in both integrin alpha1-null mice and integrin alpha1-null Alport mice relative to wild-type mice; however, only MMP-9 was elevated in glomeruli of Alport mice that express integrin alpha1. Similarly, cultured mesangial cells from alpha1-null mice showed elevated expression levels of all three MMPs, whereas mesangial cells from Alport mice show elevated expression levels of only MMP-9. In both glomeruli and cultured mesangial cells isolated from integrin alpha1-null mice, activation of the p38 and ERK branches of the mitogen-activated protein kinase pathway was also observed. The use of small molecule inhibitors demonstrated that the activation of the p38, but not ERK, pathway was linked to elevated MMP-2, -9, and -14 expression levels in mesangial cells from integrin alpha1-null mice. In contrast, elevated MMP-9 levels in mesangial cells from Alport mice were linked to ERK pathway activation. Blockade of gelatinase activity using a small molecule inhibitor (BAY-12-9566) ameliorated progression of proteinuria and restored the architecture of the glomerular basement membrane in alpha1 integrin-null Alport mice, suggesting that elevated gelatinase activity exacerbates glomerular disease progression in these mice.

Topics: Animals; Autoantigens; Biphenyl Compounds; Cells, Cultured; Collagen Type IV; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Integrin alpha1beta1; Matrix Metalloproteinases; Mesangial Cells; Mice; Mice, Knockout; Nephritis, Hereditary; Organic Chemicals; p38 Mitogen-Activated Protein Kinases; Phenylbutyrates; Tissue Inhibitor of Metalloproteinases

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Biphenyl Compounds; Cathepsins; Disease Models, Animal; Enzyme Inhibitors; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Mice; Neoplasms; Organic Chemicals; Phenylbutyrates; Plasminogen Activators; Plasminogen Inactivators; Predictive Value of Tests; Prognosis; Tissue Inhibitor of Metalloproteinases; Treatment Failure; Urokinase-Type Plasminogen Activator

Tumor growth is angiogenesis dependent. We hypothesized that nonneoplastic tissue growth also depends on neovascularization. We chose adipose tissue as an experimental system because of its remodeling capacity. Mice from different obesity models received anti-angiogenic agents. Treatment resulted in dose-dependent, reversible weight reduction and adipose tissue loss. Marked vascular remodeling was evident in adipose tissue sections, which revealed decreased endothelial proliferation and increased apoptosis in treated mice compared with controls. Continuous treatment maintained mice near normal body weights for age without adverse effects. Metabolic adaptations in food intake, metabolic rate, and energy substrate utilization were associated with anti-angiogenic weight loss. We conclude that adipose tissue mass is sensitive to angiogenesis inhibitors and can be regulated by its vasculature.

Topics: Adipose Tissue; Angiogenesis Inhibitors; Angiostatins; Animals; Antineoplastic Agents; Biphenyl Compounds; Body Composition; Body Weight; Collagen; Cyclohexanes; Disease Models, Animal; Endostatins; Energy Metabolism; Male; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Obesity; Organic Chemicals; Peptide Fragments; Phenylbutyrates; Plasminogen; Sesquiterpenes; Thalidomide; Time Factors