Inhaled asbestos exacerbates atherosclerosis in apolipoprotein E-deficient mice via CD4+ T cells.

Background: Associations between air pollution and morbidity/mortality from cardiovascular disease are recognized in epidemiologic and clinical studies, but the mechanisms by which inhaled fibers or particles mediate the exacerbation of atherosclerosis are unclear.

Objective And Methods: To determine whether lung inflammation after inhalation of a well-characterized pathogenic particulate, chrysotile asbestos, is directly linked to exacerbation of atherosclerosis and the mechanisms involved, we exposed apolipoprotein E-deficient (ApoE(-/-)) mice and ApoE(-/-) mice crossed with CD4(-/-) mice to ambient air, NIEHS (National Institute of Environmental Health Sciences) reference sample of chrysotile asbestos, or fine titanium dioxide (TiO(2)), a nonpathogenic control particle, for 3, 9, or 30 days.

Results: ApoE(-/-) mice exposed to inhaled asbestos fibers had approximately 3-fold larger atherosclerotic lesions than did TiO(2)-exposed ApoE(-/-) mice or asbestos-exposed ApoE(-/-)/CD4(-/-) double-knockout (DKO) mice.

Age affects ERK1/2 and NRF2 signaling in the regulation of GCLC expression.

We previously reported that activator protein-1 (AP-1) DNA binding activity was increased in vascular smooth muscle cells (VSMC) from old rats when exposed to high glucose or tumor necrosis factor (TNF-alpha) (Li et al., 2003. J Cell Physiol 197:418-425).

Age-related differences in MAP kinase activity in VSMC in response to glucose or TNF-alpha.

Aortic vascular smooth muscle cells (VSMC) were used to study the effect of age on responses to high glucose concentrations or the cytokine, tumor necrosis factor-alpha (TNF-alpha). Activator protein-1 (AP-1) binding to DNA increased more in VSMC from old versus young rats (P < 0.02) and was related to increased expression of its components, c-Fos, Fra-1, and JunD.

Mesothelial cell transformation requires increased AP-1 binding activity and ERK-dependent Fra-1 expression.

Mesothelioma is a unique and insidious tumor associated historically with occupational exposure to asbestos. The transcription factor, activator protein-1 (AP-1) is a major target of asbestos-induced signaling pathways. Here, we demonstrate that asbestos-induced mesothelial cell transformation is linked to increases in AP-1 DNA binding complexes and the AP-1 component, Fra-1.

In vitro and in vivo activation of extracellular signal-regulated kinases by coal dusts and quartz silica.

Alveolar type II epithelial cells are the main precursor cells that develop into carcinomas after inhalation of poorly soluble particles (PSP) at overload concentrations, but the mechanisms leading to initial proliferative events in these cells are unclear. In studies here, cell cycle kinetics, mitogen-activated protein kinase (MAPK) signaling events, and gene expression of activator protein-1 family members were investigated in murine alveolar type II epithelial cells (C10) or rats in vivo after exposure to several coal mine dusts (CMDs) of high or low quartz content. In contrast to results using unexposed C10 cells or cells exposed to the nonpathogenic particle glass beads, flow cytometry showed increased numbers of hypodiploid cells and cells in S phase after addition of DQ12 quartz or CMDs.

A mutant epidermal growth factor receptor targeted to lung epithelium inhibits asbestos-induced proliferation and proto-oncogene expression.

Asbestos is a ubiquitous naturally occurring fiber causing multiple cancers and fibroproliferativedisease. The mechanisms of epithelial cell hyperplasia, a hallmark of the initiation of lung cancers by asbestos, have been unclear. We demonstrate here that mice expressing a dominant-negative mutant epidermal growth factor receptor (EGFR) under the control of the human lung surfactant protein-C promoter exhibit decreased pulmonary epithelial cell proliferation without alterations in asbestos-induced inflammation.

Activation of NF-kappaB-dependent gene expression by silica in lungs of luciferase reporter mice.

Occupational exposure to crystalline silica is associated with the development of pulmonary inflammation and silicosis, yet how silica initiates pulmonary fibrosis and which cell types are involved are unclear. In studies here, we hypothesized that silica particles interact initially with pulmonary epithelial cells and alveolar macrophages (AMs) to cause transcriptional activation of nuclear factor (NF)-kappaB-regulated genes encoding inflammatory cytokines. Exposure of NF-kappaB luciferase reporter mice intratracheally to silica or lipopolysaccharide (LPS), but not the nonfibrogenic particle titanium dioxide (TiO(2)), increased immunoreactivity of luciferase protein in bronchiolar epithelial cells and AMs.

Ultrafine airborne particles cause increases in protooncogene expression and proliferation in alveolar epithelial cells.

Exposure to ambient particulate matter (PM) is linked to increases in respiratory morbidity and exacerbation of cardiopulmonary diseases. However, the important components of PM and their mechanisms of action in lung disease are unclear. We demonstrate the development of dose-related proliferation and apoptosis after exposure of an alveolar epithelial cell line (C10) to PM or to ultrafine carbon black (ufCB), a component of PM.