Role of p53-fibrinolytic system cross-talk in the regulation of quartz-induced lung injury.

Silica is the major component of airborne dust generated by wind, manufacturing and/or demolition. Chronic occupational inhalation of silica dust containing crystalline quartz is by far the predominant form of silicosis in humans. Silicosis is a progressive lung disease that typically arises after a very long latency and is a major occupational concern with no known effective treatment. The mechanism of silicosis is not clearly understood. However, silicosis is associated with increased cell death, expression of redox enzymes and pro-fibrotic cytokines and chemokines. Since alveolar epithelial cell (AEC) death and disruption of alveolar fibrinolysis is often associated with both acute and chronic lung injuries, we explored whether p53-mediated changes in the urokinase-type plasminogen activator (uPA) system contributes to silica-induced lung injury. We further sought to determine whether caveolin-1 scaffolding domain peptide (CSP), which inhibits p53 expression, mitigates lung injury associated with exposure to silica. Lung tissues and AECs isolated from wild-type (WT) mice exposed to silica exhibit increased apoptosis, p53 and PAI-1, and suppression of uPA expression. Treatment of WT mice with CSP inhibits PAI-1, restores uPA expression and prevents AEC apoptosis by suppressing p53, which is otherwise induced in mice exposed to silica. The process involves CSP-mediated inhibition of serine-15 phosphorylation of p53 by inhibition of protein phosphatase 2A-C (PP2A-C) interaction with silica-induced caveolin-1 in AECs. These observations suggest that changes in the p53-uPA fibrinolytic system cross-talk contribute to lung injury caused by inhalation of silica dust containing crystalline quartz and is protected by CSP by targeting this pathway.

Hypothyroidism among former workers of a nuclear weapons facility.

BACKGROUND: Ionizing radiation alters thyroid function, and workers at a nuclear weapons facility may be exposed to above environmental levels of radiation. METHODS: Hypothyroid status was determined for 622 former workers of a nuclear weapons facility located in Texas, using a combination of measured thyroid stimulating hormone (TSH) levels and thyroid medication history, as part of an on-going health surveillance program. We classified 916 unique job titles into 35 job categories. RESULTS: According to the most stringent TSH definition used in this study (0.3-3.0 IU/ml), 174 (28.0%) former workers were considered to be hypothyroid; of these 66 (41.8%) were females and 108 (23.3%) were males. In logistic regression analysis adjusted for age, gender, and smoking status, only having worked as a material handler (n = 18) exhibited an elevated risk of developing hypothyroidism compared to other jobs (OR 3.88, 95% CI 1.43-11.07). This is one of the jobs with suspected exposure to radiation. No excess risk of hypothyroidism was observed for any of the other job categories. CONCLUSIONS: There is suggestive evidence that only material handlers at this nuclear weapons facility may have elevated risk of hypothyroidism; further evaluation of thyroid health in this population is warranted.

Transdermal progesterone: effects on menopausal symptoms and on thrombotic, anticoagulant, and inflammatory factors in postmenopausal women.

Conventional hormone replacement therapy increases a woman's risk of thrombotic events as evidenced in large prospective clinical trials, including HERS I and the Women's Health Initiative. A possible mechanism for this is the unfavorable net effects of conjugated equine estrogens and medroxyprogesterone acetate on factors involved in hemostatic balance and inflammation. The objective of this study was to examine the short-term effects of transdermal progesterone on menopausal symptoms and serum levels of hemostatic, inflammatory, and immune signaling factors. In a prospective, randomized, double-blinded, placebo-controlled, crossover study, 30 healthy postmenopausal women received either 20 mg/day of transdermal progesterone or placebo for 4 weeks, followed by a 4-week washout period, and were then crossed over to receive either placebo or active drug for an additional 4 weeks. Baseline, 4-week follow-up, and end-of-study values were obtained for the Greene Climacteric Scale, and for serum levels of total factor VII:C, factor VIIa, factor V, fibrinogen, antithrombin III, plasminogen activator inhibitor-1, C-reactive protein, interleukin-6, matrix metalloproteinase-9, and tumor necrosis factor-a. Transdermal progesterone significantly improved Greene Climacteric Scale scores. In sharp contrast to previous studies of conventional hormone replacement therapy, no detrimental effect was observed on any of the hemostatic or inflammatory components examined. Administration of transdermal progesterone at a daily dose of 20 mg significantly relieves menopausal symptoms in postmenopausal women without adversely altering prothrombotic potential. We suggest, therefore, that this treatment be seriously considered as an effective and safe alternative clinical therapy for women suffering from menopausal symptoms.