In adult dogs after pneumonectomy (PNX), mechanical forces on the remaining lung are thought to stimulate compensatory lung growth. Following moderate (42% of total) resection, lobar growth is non-uniform. As resection increases (58-70%), alveolar growth is stimulated in all remaining lobes probably due to mechanical forces exceeding a threshold for cellular stimulation. Supplementation with all trans-retinoic acid (RA), a promoter of cell growth and differentiation, enhanced some aspects of alveolar-capillary response following 58% but not 42% resection, suggesting a relationship between the intensity of endogenous stimuli and the capacity for pharmacological growth enhancement. Lobar expansion explains ~40-70% of post-PNX compensation, presumably via increased septal strain/shear;residual compensation might be explained by elevated lobar perfusion via increased strain/shear on alveolar capillaries. Lobar expansion may also alter and interact with regional perfusion. Relationship of in vivo tissue mechanical stress to cellular response has not been established, but the hypoxia-inducible factor-erythropoietin-vascular endothelial growth factor (HIF-EPO- VEGF) axis is implicated. Our hypotheses are: 1) Regional compensatory lung growth varies directly with the intensity of regional mechanical stimuli, and 2) Growth factor supplementation amplifies natural response to post-PNX mechanical stimuli, but cannot initiate de novo compensatory lung growth in the absence of sufficient endogenous stimuli.
In Aim 1, we will quantify post-PNX regional lung strain and shear using bronchovascular landmarks imaged at different transpulmonary pressures by high resolution computed tomography (HRCT) and correlate strain/shear with regional cellular response in HIF-EPO-VEGF axis.
In Aim 2, we will test the effects of altering lobar perfusion on post-PNX compensation by banding one lobar pulmonary artery, which restrict its perfusion while exaggerating post-PNX perfusion to unbanded lobes. Regional perfusion will be measured by fluorescent microspheres. The remaining lobes will be assessed for cell signaling and for alveolar ultrastructure by morphometry.
In Aim 3, we will establish cause-effect mechanisms of mechanical stresses on growth- related signaling in vitro using cultured lung epithelial cells subjected to mechanical strain and endothelial cells subjected to strain and fluid shear. Mechano-stress response of HIF-EPO-VEGF axis will be compared to its O2-sensitive response. In vitro signaling events will be related to parallel in vivo stress response. Epithelial- endothelial co-cultures will test for diffusible mediators of mechanotransduction.
In Aim 4, we will amplify EPO/EPO-R signaling post-PNX by nebulization of recombinant human erythropoietin (rhEPO) to determine its local effect on angiogenesis, growth and function in relation to in vivo regional mechanical stresses. These studies define fundamental mechanical stimuli-response relationships in a robust model of compensatory lung growth, and explore a potential intervention for augmenting the endogenous response. Results have important basic and clinical implications for the re-initiation of lung growth in human chronic lung disease.

Public Health Relevance

When one lung is surgically removed, the remaining lung undergoes compensatory growth where more lung tissue is generated to improve lung function. Our goal is to understand the stimuli and regulatory pathways responsible for re-initiating growth in the adult lung, specifically those pathways related to mechanical forces that stretch and distort the remaining tissue and blood vessels. We will study the intact lung as well as lung cells grown in culture subjected to mechanical distortion. These studies will advance fundamental knowledge of lung regeneration, and explore a potential intervention for augmenting the natural response. The results have important implications for the stimulation of lung re-growth in the treatment of human lung disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL040070-23
Application #
8204937
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Freemer, Michelle M,
Project Start
1988-07-01
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
23
Fiscal Year
2012
Total Cost
$422,313
Indirect Cost
$156,080
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Yilmaz, C; Ravikumar, P; Gyawali, D et al. (2015) Alveolar-capillary adaptation to chronic hypoxia in the fatty lung. Acta Physiol (Oxf) 213:933-46
Ravikumar, Priya; Ye, Jianfeng; Zhang, Jianning et al. (2014) ?-Klotho protects against oxidative damage in pulmonary epithelia. Am J Physiol Lung Cell Mol Physiol 307:L566-75
Menon, Jyothi U; Ravikumar, Priya; Pise, Amruta et al. (2014) Polymeric nanoparticles for pulmonary protein and DNA delivery. Acta Biomater 10:2643-52
Ravikumar, Priya; Yilmaz, Cuneyt; Dane, D Merrill et al. (2014) Defining a stimuli-response relationship in compensatory lung growth following major resection. J Appl Physiol (1985) 116:816-24
Yilmaz, Cuneyt; Dane, Dan M; Ravikumar, Priya et al. (2014) Noninvasive assessment of alveolar microvascular recruitment in conscious non-sedated rats. Respir Physiol Neurobiol 190:105-12
Dane, D Merrill; Yilmaz, Cuneyt; Estrera, Aaron S et al. (2013) Separating in vivo mechanical stimuli for postpneumonectomy compensation: physiological assessment. J Appl Physiol (1985) 114:99-106
Hsia, Connie C W; Schmitz, Anke; Lambertz, Markus et al. (2013) Evolution of air breathing: oxygen homeostasis and the transitions from water to land and sky. Compr Physiol 3:849-915
Ravikumar, Priya; Yilmaz, Cuneyt; Bellotto, Dennis J et al. (2013) Separating in vivo mechanical stimuli for postpneumonectomy compensation: imaging and ultrastructural assessment. J Appl Physiol (1985) 114:961-70
Ravikumar, Priya; Dane, D Merrill; McDonough, Paul et al. (2011) Long-term post-pneumonectomy pulmonary adaptation following all-trans-retinoic acid supplementation. J Appl Physiol 110:764-73
Borland, Colin D R; Dunningham, Helen; Bottrill, Fiona et al. (2010) Significant blood resistance to nitric oxide transfer in the lung. J Appl Physiol 108:1052-60

Showing the most recent 10 out of 62 publications