Pulmonary emphysema is a prevalent lung disease defined by permanent enlargement of airspaces, but also associated with systemic effects on organs that include the bone marrow and the cardiovascular system. Little is known about the mechanisms of systemic illness in emphysema and their impact, if any, on the lung disease. The lung destruction, clinically apparent after years of cigarette smoking has been attributed to protease-antiprotease imbalance, chronic inflammation, oxidative stress, and excessive alveolar cell death with loss of pulmonary capillaries that support the alveolar unit. We demonstrated that pluripotent cells contained in adipose stroma, called adipose stem or stromal cells promote capillary growth and limit ischemic tissue damage in models of acute skeletal muscle, myocardial, and cerebral ischemia and these salutary effects are mediated by angiogenic and anti-apoptotic paracrine factors. Given the feasibility of obtaining these stem cells, requiring no or limited ex vivo expansion, we tested the effect of adipose stem cells on cigarette smoke-induced murine emphysema. This form of regenerative treatment resulted in preservation of alveolar surface area and marked protection of the bone marrow from the suppressive effects of smoke on the number and cycling of multiple lineages of progenitor cells. We therefore generated the novel hypothesis that treatment with adipose stem cells will ameliorate the alveolar structural loss induced by cigarette smoking by decreasing lung structural cell death and reducing the loss of bone marrow-derived progenitor cells. To test this novel promising therapy for emphysema and to advance understanding of the crosstalk between the lung and bone marrow in emphysema development, we focused on 3 specific aims: 1. to determine the efficacy of adipose stem cells to limit cigarette smoke-induced murine emphysema;2. to determine the effect of adipose stem cell treatment on the cigarette smoke-induced bone marrow-derived progenitor cell loss and to establish its importance to the development of emphysema;3. to establish the role of adipose stem cell-secreted paracrine factors VEGF, HGF, and TSG-6 in the inhibition of lung destruction and of bone marrow hypoplasia induced by adipose stem cell exposure. We have assembled a multidisciplinary team with expertise in emphysema pathobiology, adipose stem cell-, vascular-, and bone marrow stem cell-biology to investigate the proposed comprehensive research plan. If completed, this work will determine the effectiveness, optimal approach, and mechanisms of adult, thus generally ethically accepted, adipose stem cell therapy in a relevant emphysema model, and will accelerate its implementation as a potential therapeutic approach in COPD.

Public Health Relevance

Here we propose a new investigation of the efficacy of and mechanisms underlying the treatment with adipose stromal or stem cells to ameliorate emphysema induced by cigarette smoke in mice. We are uniquely qualified to conduct this study, since we have a combined experience in the research of cigarette smoke-induced lung injury, and basic and translational applications of adult adipose stem cells to other diseases that involve apoptosis of capillary vascular beds. In addition, by studying how adipose stem cells rescue the bone marrow from the deleterious effects of cigarette smoking, this work will study a potentially novel mechanism of cigarette-induced injury, involving the loss of bone marrow-derived progenitor cells. Our work is therefore expected to provide the rationale for a therapeutic strategy that involves the use of ethically acceptable and easily obtainable stem cells in patients with COPD, which may be extended to other diseases in which bone marrow progenitor cell participation is key.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL105772-01A1
Application #
8239228
Study Section
Special Emphasis Panel (ZRG1-CVRS-G (03))
Program Officer
Punturieri, Antonello
Project Start
2011-12-15
Project End
2015-11-30
Budget Start
2011-12-15
Budget End
2012-11-30
Support Year
1
Fiscal Year
2012
Total Cost
$380,140
Indirect Cost
$130,140
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
McCaslin, Charles A; Petrusca, Daniela N; Poirier, Christophe et al. (2015) Impact of alginate-producing Pseudomonas aeruginosa on alveolar macrophage apoptotic cell clearance. J Cyst Fibros 14:70-7
Lockett, Angelia D; Brown, Mary Beth; Santos-Falcon, Nieves et al. (2014) Active trafficking of alpha 1 antitrypsin across the lung endothelium. PLoS One 9:e93979
Voiles, Larry; Lewis, David E; Han, Ling et al. (2014) Overexpression of type VI collagen in neoplastic lung tissues. Oncol Rep 32:1897-904
Hong, Soon Jun; Hou, Dongming; Brinton, Todd J et al. (2014) Intracoronary and retrograde coronary venous myocardial delivery of adipose-derived stem cells in swine infarction lead to transient myocardial trapping with predominant pulmonary redistribution. Catheter Cardiovasc Interv 83:E17-25
Toney, Brent M; Fisher, Amanda J; Albrecht, Marjorie et al. (2014) Selective endothelin-A receptor blockade attenuates endotoxin-induced pulmonary hypertension and pulmonary vascular dysfunction. Pulm Circ 4:300-10
Brown, Mary Beth; Hunt, William R; Noe, Julie E et al. (2014) Loss of cystic fibrosis transmembrane conductance regulator impairs lung endothelial cell barrier function and increases susceptibility to microvascular damage from cigarette smoke. Pulm Circ 4:260-8
Cruickshank-Quinn, Charmion I; Mahaffey, Spencer; Justice, Matthew J et al. (2014) Transient and persistent metabolomic changes in plasma following chronic cigarette smoke exposure in a mouse model. PLoS One 9:e101855
Bourin, Philippe; Bunnell, Bruce A; Casteilla, Louis et al. (2013) Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International So Cytotherapy 15:641-8