Abstract
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. While the primary risk factor for COPD is cigarette smoke exposure, vitamin D deficiency has been epidemiologically implicated as a factor in the progressive development of COPD-associated emphysema. Because of difficulties inherent to studies involving multiple risk factors in the progression of COPD in humans, we developed a murine model in which to study the separate and combined effects of vitamin D deficiency and cigarette smoke exposure. During a 16-week period, mice were exposed to one of four conditions, control diet breathing room air (CD-NS), control diet with cigarette smoke exposure (CD-CSE), vitamin D deficient diet breathing room air (VDD-NS) or vitamin D deficient diet with cigarette smoke exposure (VDD-CSE). At the end of the exposure period, the lungs were examined by a pathologist and separately by morphometric analysis. In parallel experiments, mice were anesthetized for pulmonary function testing followed by sacrifice and analysis. Emphysema (determined by an increase in alveolar mean linear intercept length) was more severe in the VDD-CSE mice compared to control animals and animals exposed to VDD or CSE alone. The VDD-CSE and the CD-CSE mice had increased total lung capacity and increased static lung compliance. There was also a significant increase in the matrix metalloproteinase-9: tissue inhibitor of metalloproteinases-1 (TIMP-1) ratio in VDD-CSE mice compared with all controls. Alpha-1 antitrypsin (A1AT) expression was reduced in VDD-CSE mice as well. In summary, vitamin D deficiency, when combined with cigarette smoke exposure, seemed to accelerate the appearance of emphysemas, perhaps by virtue of an increased protease-antiprotease ratio in the combined VDD-CSE animals. These results support the value of our mouse model in the study of COPD.
Highlights
Chronic obstructive pulmonary disease (COPD) is the third leading cause of chronic morbidity and mortality in the United States and is projected to rank fifth in 2020 in burden of disease worldwide (Rabe et al, 2007)
While we found a non-significant trend toward increased expression of matrix metalloproteinases (MMPs)-9 when comparing control diet-non smoke exposed (CD-NS) to vitamin D deficient diet (VDD)-CSE (Figure 5B), analyses revealed a significant drop in expression of its cognate inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1) (Mercer et al, 2005) only in the VDD-CSE group (Figure 5C)
Lifespan, period of exposure required to develop disease, as well as heterogeneity of lifestyle and co-morbid factors preclude straightforward examination of the contribution of vitamin D deficiency to development of emphysema in humans. For this reason we developed a new, pragmatic model for the study of emphysema by combining Vitamin D deficiency and cigarette smoke exposure in mice
Summary
Chronic obstructive pulmonary disease (COPD) is the third leading cause of chronic morbidity and mortality in the United States and is projected to rank fifth in 2020 in burden of disease worldwide (Rabe et al, 2007). The increased activity of proteases is important given that protease-antiprotease imbalance plays a key pathogenic role in the development of emphysema in COPD. In this regard, alpha-1-antitrypsin (A1AT) is the prototypical member of the serine protease inhibitor (serpin) superfamily of proteins, which have a major role in inactivating neutrophil elastase and other proteases to maintain protease-antiprotease balance (Lomas and Mahadeva, 2002). Alpha-1 antitrypsin deficiency (AATD), a genetic disease resulting in low levels of antiproteases, is a risk factor for emphysema, which supports the importance of protease-antiprotease balance in the pathogenesis of emphysema (Sandhaus, 2010). Another family of proteolytic enzymes, the matrix metalloproteinases (MMPs), and their inhibitors, tissue inhibitor of metalloproteinases (TIMPs), are involved in remodeling the extracellular matrix and in host defense (Elkington and Friedland, 2006) and are associated with tissue destruction in emphysema (Abboud and Vimalanathan, 2008)
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