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Risk Anal. 2011 Jan;31(1):38-62. doi: 10.1111/j.1539-6924.2010.01487.x. Epub 2010 Sep 15.

A causal model of chronic obstructive pulmonary disease (COPD) risk.

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Cox Associates and University of Colorado, 503 Franklin Street, Denver, CO 80218, USA.


Research on the etiology of chronic pulmonary disease (COPD), an irreversible degenerative lung disease affecting 15% to 20% of smokers, has blossomed over the past half-century. Profound new insights have emerged from a combination of in vitro and -omics studies on affected lung cell populations (including cytotoxic CD8(+) T lymphocytes, regulatory CD4(+) helper T cells, dendritic cells, alveolar macrophages and neutrophils, alveolar and bronchiolar epithelial cells, goblet cells, and fibroblasts) and extracellular matrix components (especially, elastin and collagen fibers); in vivo studies on wild-type and genetically engineered mice and other rodents; clinical investigation of cell- and molecular-level changes in asymptomatic smokers and COPD patients; genetic studies of susceptible and rapidly-progressing phenotypes (both human and animal); biomarker studies of enzyme and protein degradation products in induced sputum, bronchiolar lavage, urine, and blood; and epidemiological and clinical investigations of the time course of disease progression. To this rich mix of data, we add a relatively simple in silico computational model that incorporates recent insights into COPD disease causation and progression. Our model explains irreversible degeneration of lung tissue as resulting from a cascade of positive feedback loops: a macrophage inflammation loop, a neutrophil inflammation loop, and an alveolar epithelial cell apoptosis loop. Unrepaired damage results in clinical symptoms. The resulting model illustrates how to simplify and make more understandable the main aspects of the very complex dynamics of COPD initiation and progression, as well as how to predict the effects on risk of interventions that affect specific biological responses.

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