Frontiers in occupational and environmental lung disease research.

Chest. 2012 Mar;141(3):772-81

Authors: Muzaffar SA, Christiani DC

Abstract
Two central challenges in the field of occupational and environmental epidemiology include accurately measuring biologic responses to exposure and preventing subsequent disease. As exposure-related lung diseases continue to be identified, advances in exposure biology have introduced toxicogenomic approaches that detect biomarkers of exposure at the gene, protein, and metabolite levels. Moreover, genetic epidemiology research has focused more recently on common, low-penetrant (ie, low-relative-risk) genetic variants that may interact with commonly encountered exposures. A number of such gene by environment interactions have been identified for airways and interstitial lung diseases, with the goal of preventing disease among susceptible populations that may not otherwise have been identified. Exhaled breath condensate analysis has provided another noninvasive means of assessing toxicant exposures and systemic effects. As these technologies become more refined, clinicians and public health practitioners will need to appreciate the social implications of the individual- and population-level risks conferred by certain genetic polymorphisms or by biomarker evidence of exposure. At present, the primary approach to occupational and environmental lung disease prevention remains elimination or reduction of known hazardous exposures and requires continued application of local and international resources toward exposure control.

PMID: 22396562 [PubMed - in process]

Chemoprevention of Asbestos-linked Cancers: A Systematic Review.

Anticancer Res. 2012 Mar;32(3):1005-13

Authors: Neri M, Ugolini D, Boccia S, Canessa PA, Cesario A, Leoncini G, Mutti L, Bonassi S

Abstract
Asbestos has been used extensively and, in spite of many countries having banned most of its uses, professional, domestic and environmental exposure has not ceased worldwide. Inhaled asbestos fibers can lead to malignant mesothelioma, lung cancer and non-cancerous conditions, while the substance persists indefinitely in the lung and pleural tissue, resulting in continuous damage. Exposed individuals may be offered medical surveillance or compensation, but nothing is currently being done to lower their specific cancer risk: chemoprevention seems a promising approach. A web search and a PubMed review of the literature on chemoprevention trials in individuals exposed to asbestos have been conducted. Forty-six articles on five projects were found and newly reviewed but, surprisingly, no novel trials have been set up for twenty years, although considerable advances have been gained in cancer chemoprevention. A re-consideration of possibilities offered by chemoprevention should be encouraged. New trials based on the most recently characterized molecules should be planned, taking into account specific issues such as the need for a very large number of participants and a long follow up or, alternatively, the use of biomarkers as surrogate endpoints. The long latency of asbestos related diseases may offer delayed intervention opportunities. The lack of chemoprevention trials for asbestos exposure highlights the urgent need for research in this field.

PMID: 22399624 [PubMed - in process]

Reactive oxygen and nitrogen species in pulmonary hypertension.

Free Radic Biol Med. 2012 Mar 5;

Authors: Tabima DM, Frizzell S, Gladwin MT

Abstract
Pulmonary vascular disease can be defined as either a disease affecting the pulmonary capillaries and pulmonary arterioles, termed pulmonary arterial hypertension, or as a disease affecting the left ventricle, called pulmonary venous hypertension. Pulmonary arterial hypertension (PAH) is a disorder of the pulmonary circulation characterized by endothelial dysfunction, as well as intimal and smooth muscle proliferation. Progressive increases in pulmonary vascular resistance and pressure impair the performance of the right ventricle, resulting in declining cardiac output, reduced exercise capacity, right heart failure, and ultimately death. While the primary and heritable forms of the disease are thought to affect over 5,000 patients in the U.S., the disease can occur secondary to congenital heart disease, most advanced lung diseases, and many systemic diseases. Multiple studies implicate oxidative stress in the development of PAH. Further, this oxidative stress has been shown to be associated with alterations in reactive oxygen species (ROS), reactive nitrogen species (RNS) and nitric oxide (NO) signaling pathways, whereby bioavailable NO is decreased and ROS and RNS production are increased. Many canonical ROS and NO signaling pathways are simultaneously disrupted in PAH, with increased expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and xanthine oxidoreductase, uncoupling of endothelial NO synthase (eNOS), and reduction in mitochondrial number, as well as impaired mitochondrial function. Upstream dysregulation of ROS/NO redox homeostasis impairs vascular tone and contributes to the pathological activation of anti-apoptotic and mitogenic pathways, leading to cell proliferation and obliteration of the vasculature. This manuscript will review the available data regarding the role of oxidative and nitrosative stress and endothelial dysfunction in the pathophysiology of pulmonary hypertension, and provide a description of targeted therapies for this disease.

PMID: 22401856 [PubMed - as supplied by publisher]

Increased corticosteroid sensitivity by a long acting β(2) agonist formoterol via β(2) adrenoceptor independent protein phosphatase 2A activation.

Pulm Pharmacol Ther. 2012 Mar 2;

Authors: Kobayashi Y, Mercado N, Miller-Larsson A, Barnes PJ, Ito K

Abstract
Long-acting β(2)-adrenoceptor agonists (LABAs) are reported to enhance anti-inflammatory effects of corticosteroids in vitro and in vivo, although the molecular mechanisms have not yet been elucidated. We investigated the role of serine/threonine protein phosphatase 2A (PP2A) on regulation of corticosteroid sensitivity via inhibition of glucocorticoid receptor (GR) phosphorylation as the target of formoterol, an LABA. Corticosteroid sensitivity was determined as IC(50) to dexamethasone (Dex) on TNFα-induced IL-8 release in a U937 monocytic cell line (Dex-IC(50)). Phosphorylation levels of GR-Ser(226) and c-Jun N-terminal kinase (JNK) were determined by western-blotting. Phosphatase activity of immunopurified PP2A was measured by fluorescence-based assay. Exposure to IL-2/IL-4 for 48 h decreased Dex sensitivity with a concomitant increase of GR phosphorylation at Ser(226) with JNK1 activation. Formoterol restored Dex sensitivity by inhibiting phosphorylation of GR-Ser(226) and JNK1. PP2A inhibition by okadaic acid, a phosphatase inhibitor, abrogated formoterol-mediated effects. In addition, formoterol enhanced PP2A activity in intact or IL-2/IL-4 treated U937 cells and human peripheral blood mononuclear cells. In addition, PP2A activation by formoterol was not antagonized by ICI-118551, and formoterol could activate PP2A directly in cell free system. Taken together, formoterol increases corticosteroid sensitivity via activation of PP2A in receptor independent manner, explaining its benefits as add-on therapy for the treatment of corticosteroid-insensitive diseases, such as severe asthma.

PMID: 22401993 [PubMed - as supplied by publisher]