Computational modeling helps uncover mechanisms related to the progression of emphysema.

Emphysema is a progressive disease characterized by deterioration of alveolar structure and decline in lung function. While morphometric and molecular biology studies have not fully uncovered the underlying mechanisms, they have produced data to advance computational modeling. In this review, we discuss examples in which modeling has led to novel insight into mechanisms related to disease progression. Finally, we propose a general scheme of multiscale modeling approach that could help unravel the progressive nature of emphysema and provide patient specific mechanisms perhaps suitable for use in treatment therapies.

[1]  Y C Fung,et al.  A model of the lung structure and its validation. , 1988, Journal of applied physiology.

[2]  Andres Kriete,et al.  Micro-CT of the human lung: imaging of alveoli and virtual endoscopy of an alveolar duct in a normal lung and in a lung with centrilobular emphysema--initial observations. , 2005, Radiology.

[3]  J. Butler,et al.  Dihedral angles of septal "bend" structures in lung parenchyma. , 1996, Journal of applied physiology.

[4]  Laimute Taraseviciene-Stewart,et al.  Molecular pathogenesis of emphysema. , 2008, The Journal of clinical investigation.

[5]  S. Redner,et al.  Introduction To Percolation Theory , 2018 .

[6]  S. Arab,et al.  The design of a new truncated and engineered alpha1-antitrypsin based on theoretical studies: an antiprotease therapeutics for pulmonary diseases , 2013, Theoretical Biology and Medical Modelling.

[7]  J. Butler,et al.  Lengths and topology of alveolar septal borders. , 1989, Journal of applied physiology.

[8]  Takeshi Kubo,et al.  Longitudinal Study of Spatially Heterogeneous Emphysema Progression in Current Smokers with Chronic Obstructive Pulmonary Disease , 2012, PloS one.

[9]  G. Joos,et al.  Role of apoptosis in the pathogenesis of COPD and pulmonary emphysema , 2006, Respiratory research.

[10]  B Suki,et al.  Roles of mechanical forces and collagen failure in the development of elastase-induced emphysema. , 2001, American journal of respiratory and critical care medicine.

[11]  Arnab Majumdar,et al.  Linking Microscopic Spatial Patterns of Tissue Destruction in Emphysema to Macroscopic Decline in Stiffness Using a 3D Computational Model , 2011, PLoS Comput. Biol..

[12]  D. Mannino,et al.  Burden and pathogenesis of chronic obstructive pulmonary disease. , 2009, Proceedings of the American Thoracic Society.

[13]  Ji‐Hyun Lee,et al.  Imbalance of Apoptosis and Cell Proliferation Contributes to the Development and Persistence of Emphysema , 2012, Lung.

[14]  B Suki,et al.  Lung volumes and respiratory mechanics in elastase-induced emphysema in mice. , 2008, Journal of applied physiology.

[15]  A. Majumdar,et al.  Mechanical forces regulate elastase activity and binding site availability in lung elastin. , 2010, Biophysical journal.

[16]  Peter D Sly,et al.  In Vivo Measurements of Changes in Respiratory Mechanics with Age in Mice Deficient in Surfactant Protein D , 2003, Pediatric Research.

[17]  K. Lutchen,et al.  Tissue heterogeneity in the mouse lung: effects of elastase treatment. , 2004, Journal of applied physiology.

[18]  Arnab Majumdar,et al.  Three-dimensional measurement of alveolar airspace volumes in normal and emphysematous lungs using micro-CT. , 2009, Journal of applied physiology.

[19]  E. Kimmel,et al.  Surface tension and the dodecahedron model for lung elasticity. , 1990, Journal of biomechanical engineering.

[20]  G. McLennan,et al.  Stress distribution in a three dimensional, geometric alveolar sac under normal and emphysematous conditions , 2007, International Journal of COPD.

[21]  R. Tuder,et al.  The pathobiological mechanisms of emphysema models: what do they have in common? , 2003, Pulmonary pharmacology & therapeutics.

[22]  R C Schroter,et al.  The mechanical behavior of a mammalian lung alveolar duct model. , 1995, Journal of biomechanical engineering.

[23]  J. Bates,et al.  Tumor Necrosis Factor–α Overexpression in Lung Disease , 2005 .

[24]  Arnab Majumdar,et al.  Linking parenchymal disease progression to changes in lung mechanical function by percolation. , 2007, American journal of respiratory and critical care medicine.

[25]  A. Majumdar,et al.  On the role of surface tension in the pathophysiology of emphysema. , 2005, American journal of respiratory and critical care medicine.

[26]  Arnab Majumdar,et al.  In silico modeling of interstitial lung mechanics: implications for disease development and repair. , 2007, Drug discovery today. Disease models.

[27]  T A Wilson,et al.  A model for mechanical structure of the alveolar duct. , 1982, Journal of applied physiology: respiratory, environmental and exercise physiology.

[28]  D Stamenović,et al.  Micromechanical foundations of pulmonary elasticity. , 1990, Physiological reviews.

[29]  A. Churg,et al.  Proteases and emphysema , 2005, Current opinion in pulmonary medicine.

[30]  E. Ingenito,et al.  Physiological Modeling of Responses to Upper Versus Lower Lobe Lung Volume Reduction in Homogeneous Emphysema , 2012, Front. Physio..

[31]  Takeshi Kubo,et al.  Emphysema distribution and annual changes in pulmonary function in male patients with chronic obstructive pulmonary disease , 2012, Respiratory Research.

[32]  K. Lutchen,et al.  Respiratory Impedance following Bronchoscopic or Surgical Lung Volume Reduction for Emphysema , 2005, Respiration.

[33]  A. Majumdar,et al.  Structure-function relations in an elastase-induced mouse model of emphysema. , 2011, American Journal of Respiratory Cell and Molecular Biology.

[34]  B Suki,et al.  Complexity of terminal airspace geometry assessed by lung computed tomography in normal subjects and patients with chronic obstructive pulmonary disease. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Christopher B. Massa,et al.  Reliability of Estimating Stochastic Lung Tissue Heterogeneity from Pulmonary Impedance Spectra: A Forward-Inverse Modeling Study , 2007, Annals of Biomedical Engineering.

[36]  Arnab Majumdar,et al.  Lung and alveolar wall elastic and hysteretic behavior in rats: effects of in vivo elastase treatment. , 2003, Journal of applied physiology.

[37]  A Gefen,et al.  Analysis of stress distribution in the alveolar septa of normal and simulated emphysematic lungs. , 1999, Journal of biomechanics.

[38]  Béla Suki,et al.  On the progressive nature of emphysema: roles of proteases, inflammation, and mechanical forces. , 2003, American journal of respiratory and critical care medicine.

[39]  S. Muro,et al.  Impact of exacerbations on emphysema progression in chronic obstructive pulmonary disease. , 2011, American journal of respiratory and critical care medicine.

[40]  Leilei Yin,et al.  Stereological assessment of mouse lung parenchyma via nondestructive, multiscale micro-CT imaging validated by light microscopic histology. , 2013, Journal of applied physiology.

[41]  A. Majumdar,et al.  Dynamics of enzymatic digestion of elastic fibers and networks under tension , 2011, Proceedings of the National Academy of Sciences.