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Doyle T.J.,Harvard University | Hunninghake G.M.,Harvard University | Rosas I.O.,Harvard University | Rosas I.O.,Lovelace Respiratory Research Institute
American Journal of Respiratory and Critical Care Medicine | Year: 2012

The widespread use of high-resolution computed tomography in clinical and research settings has increased the detection of interstitial lung abnormalities (ILA) in asymptomatic and undiagnosed individuals. We reported that in smokers, ILA were present in about 1 of every 12 high-resolution computed tomographic scans; however, the long-term significance of these subclinical changes remains unclear. Studies in families affected with pulmonary fibrosis, smokers with chronic obstructive pulmonary disease, and patients with inflammatory lung disease have shown that asymptomatic and undiagnosed individuals with ILA have reductions in lung volume, functional limitations, increased pulmonary symptoms, histopathologic changes, and molecular profiles similar to those observed in patients with clinically significant interstitial lung disease (ILD). These findings suggest that, in select at-risk populations, ILA may represent early stages of pulmonary fibrosis or subclinical ILD. The growing interest surrounding this topic is motivated by our poor understanding of the inciting events and natural history of ILD, coupled with a lack of effective therapies. In this perspective, we outline past and current research focused on validating radiologic, physiological, and molecular methods to detect subclinical ILD. We discuss the limitationsof the available cross-sectional studies andthe need for future longitudinal studies to determine the prognostic and therapeutic implications of subclinical ILD in populations at risk of developing clinically significant ILD. Copyright © 2012 by the American Thoracic Society.

Scott B.R.,Lovelace Respiratory Research Institute
Dose-Response | Year: 2011

Residential radon has been found to be associated with lung cancer in epidemiologi-cal/ecological studies and the researchers have inappropriately concluded that residential radon causes lung cancer. Their conclusion relates to the linear-no-threshold (LNT) hypothesis-based, risk-assessment paradigm; however, the LNT hypothesis has been invalidated in numerous studies. It is shown in this paper that our hormetic relative risk (HRR) model is consistent with lung cancer data where detailed measurements of radon in each home were carried out. Based on the HRR model, low-level radon radioactive progeny is credited for activated natural protection (ANP) against lung cancer including smoking-related lung cancer. The proportion B(x) (benefit function) of ANP beneficiaries increases as the average radon level x increases to near the Environmental Protection Agency's action level of 4 picocuries/L (approximately 150 Bq m- 3). As the average level of radon increases to somewhat above the action level, ANP beneficiaries progressively decrease to zero (B(x) decreases to 0), facilitating the occurrence of smoking-related lung cancers as well as those related to other less important risk factors. Thus, residential radon does not appear to cause lung cancer but rather to protect, in an exposure-level-dependent manner, from its induction by other agents (e.g., cigarette-smoke-related carcinogens). © 2011 University of Massachusetts.

Belinsky S.A.,Lovelace Respiratory Research Institute
Annual Review of Physiology | Year: 2015

The reprogramming of the epigenome through silencing of genes and microRNAs by cytosine DNA methylation and chromatin remodeling is critical for the initiation and progression of lung cancer through affecting all major cell regulatory pathways. Importantly, the fact that epigenetic reprogramming is reversible by pharmacological agents has opened new avenues for clinical intervention. This review focuses on the tremendous progress made in elucidating genes and microRNAs that are epigenetically silenced in lung cancer and highlights how loss of function impacts cell phenotype and major signaling pathways. The article describes the utility of (a) an in vitro model using hTERT/Cdk4 immortalized human bronchial epithelial cell lines to identify genes and microRNAs silenced during premalignancy and (b) an in vivo orthotopic nude rat lung cancer model to evaluate response to epigenetic therapy. New insights regarding the advantage of aerosol delivery of demethylating agents and the concept of priming tumors for subsequent therapy are presented and discussed. Copyright © 2015 by Annual Reviews. All rights reserved.

Morse D.,Harvard University | Rosas I.O.,Harvard University | Rosas I.O.,Lovelace Respiratory Research Institute
Annual Review of Physiology | Year: 2014

Despite public health campaigns discouraging smoking, 1,000 American children every day become smokers, ensuring that tobacco-related health complications will be with us for decades to come. Smoking is the greatest risk factor for both chronic obstructive lung disease and interstitial lung disease. The facts that not every smoker develops chronic lung disease and that lung pathology differs markedly among smokers indicate that individual susceptibility must be a central determinant of lung injury responses to cigarette smoke. Comparative examination of pathogenic mechanisms of smoke-induced lung disease can shed light on the homeostatic pathways critical to maintaining lung health. In this review, we explore common and divergent biological forces tilting the lung homeostatic balance away from health and toward emphysema or pulmonary fibrosis. We emphasize recent insights that highlight the greatest contrasts or similarities in the pathogenesis of these two chronic lung disease phenotypes. © Copyright ©2014 by Annual Reviews. All rights reserved.

Scott B.R.,Lovelace Respiratory Research Institute
Journal of Cell Communication and Signaling | Year: 2014

Humans are continuously exposed to ionizing radiation throughout life from natural sources that include cosmic, solar, and terrestrial. Much harsher natural radiation and chemical environments existed during our planet’s early years. Mammals survived the harsher environments via evolutionarily-conserved gifts ̶ a continuously evolving system of stress-induced natural protective measures (i.e., activated natural protection [ANP]). The current protective system is differentially activated by stochastic (i.e., variable) low-radiation-dose thresholds and when optimally activated in mammals includes antioxidants, DNA damage repair, p53-related apoptosis of severely-damaged cells, reactive-oxygen-species (ROS)/reactive-nitrogen-species (RNS)- and cytokine-regulated auxiliary apoptosis that selectively removes aberrant cells (e.g., precancerous cells), suppression of disease promoting inflammation, and immunity against cancer cells. The intercellular-signaling-based protective system is regulated at least in part via epigenetic reprogramming of adaptive-response genes. When the system is optimally activated, it protects against cancer and some other diseases, thereby leading to hormetic phenotypes (e.g., reduced disease incidence to below the baseline level; reduced pain from inflammation-related problems). Here, some expressed radiation hormesis phenotypes and related mechanisms are discussed along with their implications for disease prevention and therapy. © 2014, The International CCN Society.

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