To better understand the role of disrupted transforming growth factor ␤ (TGF␤) signaling in fibrosis, we have selectively expressed a kinase-deficient human type II TGF␤ receptor (T␤RII⌬k) in fibroblasts of transgenic mice, using a lineage-specific expression cassette subcloned from the pro-␣2(I) collagen gene. Surprisingly, despite previous studies that characterized T␤RII⌬k as a dominant negative inhibitor of TGF␤ signaling, adult mice expressing this construct demonstrated TGF␤ overactivity and developed dermal and pulmonary fibrosis. Compared with wild type cells, transgenic fibroblasts proliferated more rapidly, produced more extracellular matrix, and showed increased expression of key markers of TGF␤ activation, including plasminogen activator inhibitor-1, connective tissue growth factor, Smad3, Smad4, and Smad7. Smad2/3 phosphorylation was increased in transgenic fibroblasts. Overall, the gene expression profile of explanted transgenic fibroblasts using cDNA microarrays was very similar to that of littermate wild type cells treated with recombinant TGF␤1. Despite basal up-regulation of TGF␤ signaling pathways, transgenic fibroblasts were relatively refractory to further stimulation with TGF␤1. Thus, responsiveness of endogenous genes to TGF␤ was reduced, and TGF␤-regulated promoter-reporter constructs transiently transfected into transgenic fibroblasts showed little activation by recombinant TGF␤1. Responsiveness was partially restored by overexpression of wild type type II TGF␤ receptors. Activation of MAPK pathways by recombinant TGF␤1 appeared to be less perturbed than Smad-dependent signaling. Our results show that expression of T␤RII⌬k selectively in fibroblasts leads to paradoxical ligand-dependent activation of downstream signaling pathways and causes skin and lung fibrosis. As well as confirming the potential for nonsignaling receptors to regulate TGF␤ activity, these findings support a direct role for perturbed TGF␤ signaling in fibrosis and provide a novel genetically determined animal model of fibrotic disease.Transforming growth factor ␤ (TGF␤) 1 isoforms ␤1-␤3 are important regulators of embryonic and postnatal cell differentiation and proliferation. They are also potent profibrotic factors in vitro. Transgenic and gene-targeted mutant mice have proven valuable for investigating the important roles of the TGF␤ family in growth and development. For example, mice lacking TGF␤1 show substantial embryonic lethality, and those that are born develop a fatal disseminated inflammatory illness within the first postnatal month. Conversely, mice lacking TGF␤2 all die neonatally with defective epithelial-mesenchymal interaction, whereas mice lacking TGF␤3 show a perinatal lethal phenotype with cleft palate (1). These different knock-out phenotypes suggest somewhat distinct biological functions in vivo, although all three TGF␤ isoforms signal though the same specific receptor complex, so differential effects are likely to reflect patterns of ligand expression or the influence of accessory receptors at the...

Objective. To determine the gene-expression profile in dermal fibroblasts from type 1 tight-skin (Tsk1) mice, and to examine the expression and potential fibrotic activity of monocyte chemoattractant protein 3 (MCP-3) in Tsk1 mouse and human systemic sclerosis (SSc) skin.Methods .

Untrained 32 f 4 was positively associated with the level of plasma anti-HSP-60 antibodies (~4 . 0 1 ) . These results suggest that BCG immunisation impairs endothelial responses and increases atherosclerosis in chronic low-level hypercholesterolaemic rabbits. This appears to be mediated, at least in part, by immune responses against mycobacterial targeting endogenous vascular HSP. Endurance-trained M28Background: The cardiovascular benefit of exercise has been partially attributed to its ability to enhance endothelial function and suppress postprandial lipaemia. However, the rapidity of onset and the longevity of these beneficial effects, in response to the commencement and cessation of exercise training respectively, are unclear. Subjects: 20 healthy men aged 20 to 40 with no CHD risk factors: 7 were untrained (UT) and did not exercise regularly; 13 were endurance-trained (ET) athletes who exercised at least 4 times a week. Methods: At screening, all subjects had anthropometric measurements made, their physical activity assessed by interview and their aerobic fitness determined by maximal treadmill exercise testing. At visit I , subjects underwent brachial artery reactivity (BAR) testing using ultrasound to determine their endotheliumdependent, flow-mediated dilation (FMD) following an overnight fast. BAR was repeated 3 hours later after an oral fat challenge was administered to induce postprandial lipaemia. Blood was sampled for fasting and postprandial lipid profile. For the subsequent 72 hours, ET men abstained from all planned exercise whereas UT men did 30 minutes of brisk walking with heart rate monitoring each day. After this period, all subjects returned for visit 2, when identical test procedures were carried out.