Respiratory failure is a major cause of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). However, the mechanical determinants of ventilatory pump function are still not well understood. Our goal is to use an engineering approach to investigate the mechanical factors that mediate pump failure in COPD. Hyperinflation of the lungs and extreme diaphragm shortening can distort the sheet of the diaphragm, cause loss of its membrane curvature, and reduce its muscle force. This will severely limit the function of the ventilatory pump. Our objective is to build a general model of diaphragm mechanics that can be utilized to evaluate the effect of lung volume reduction surgery on respiratory pump function in patients with severe emphysema. We will extend our knowledge of diaphragm and chest wall mechanics in dogs, and will begin to apply the same principles and approaches to the study of ventilatory mechanics in normal human subjects and patients with severe emphysema before and after lung volume reduction surgery (LVRS). Finally, we will develop a comprehensive theory of diaphragm mechanics that can eventually be used to predict diaphragm muscle function in both healthy and diseased states. We will achieve this objective with in vivo studies of diaphragm mechanics in dogs and humans complemented with mathematical modeling techniques.
Our specific aims are:
Specific Aim #1 : To determine how hyperinflation of the lungs alters the pressure generating ability of the diaphragm during simultaneous sub-maximal and maximal activation of both hemi-diaphragms. Hypothesis 1: Extreme muscle contraction of both hemi-diaphragms at high frequencies of stimulation and at lower lung volumes causes flattening and distortion of the membrane of the diaphragm, and therefore its generating ability of pressure is severely compromised.
Specific Aim #2 : To develop a comprehensive mechanical model of the diaphragm. Hypothesis 3: A comprehensive mechanical model of the diaphragm that utilizes both structure and constitutive relationships of the diaphragm should provide sufficient quantitative information on the evaluation of the pressure generating ability of the ventilatory pump.
Specific Aim #3 : To evaluate diaphragm function in patients with end-stage emphysema before and after LVRS, and in normal humans. Hypothesis 2a: In normal individuals, muscle fibers are oriented along the direction of maximum principal curvature, Hypothesis 2b: In severe emphysema patients, the diaphragm is comparatively flattened, and after LVRS, there is a gain in diaphragm muscle fiber curvature. Therefore, membrane tension is transmitted into trans-diaphragmatic pressure more effectively than before the surgery. Once we obtained the distribution of principal curvatures we will use our model of diaphragm mechanics developed in Aim 2 to predict diaphragm function in normal individuals and patients with severe emphysema before and after LVRS. The completion of these aims will significantly enhance our fundamental understanding of the ventilatory pump function in health and disease. ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Smith, Robert A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Greybeck, Brooke; Lu, Raymond; Ramanujam, Arvind et al. (2017) Regional diaphragm volume displacement is heterogeneous in dogs. Am J Physiol Regul Integr Comp Physiol 312:R443-R450
Greybeck, Brad J; Wettergreen, Matthew; Hubmayr, Rolf D et al. (2011) Diaphragm curvature modulates the relationship between muscle shortening and volume displacement. Am J Physiol Regul Integr Comp Physiol 301:R76-82
Mohamed, Junaith S; Lopez, Michael A; Boriek, Aladin M (2010) Mechanical stretch up-regulates microRNA-26a and induces human airway smooth muscle hypertrophy by suppressing glycogen synthase kinase-3?. J Biol Chem 285:29336-47
Mohamed, Junaith Shaik; Boriek, Aladin M (2010) Stretch augments TGF-beta1 expression through RhoA/ROCK1/2, PTK, and PI3K in airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 299:L413-24
Chu, Iris; Fernandez, Cristina; Rodowicz, Kathleen Allen et al. (2010) Diaphragm muscle shortening modulates kinematics of lower rib cage in dogs. Am J Physiol Regul Integr Comp Physiol 299:R1456-62
Sharafkhaneh, Amir; Babb, Tony G; Officer, Todd M et al. (2007) The confounding effects of thoracic gas compression on measurement of acute bronchodilator response. Am J Respir Crit Care Med 175:330-5
Boriek, Aladin M; Black, Ben; Hubmayr, Rolf et al. (2006) Length and curvature of the dog diaphragm. J Appl Physiol 101:794-8
Hwang, Willy; Kelly, Neil G; Boriek, Aladin M (2005) Passive mechanics of muscle tendinous junction of canine diaphragm. J Appl Physiol 98:1328-33
Boriek, Aladin M; Hwang, Willy; Trinh, Linda et al. (2005) Shape and tension distribution of the active canine diaphragm. Am J Physiol Regul Integr Comp Physiol 288:R1021-7
Hwang, Willy; Carvalho, Jason C; Tarlovsky, Isaac et al. (2005) Passive mechanics of canine internal abdominal muscles. J Appl Physiol 98:1829-35

Showing the most recent 10 out of 12 publications