Lung volume reduction surgery (LVRS) is an effective adjunct to medical treatment for end stage emphysema. Clinical results suggest that LVRS works by eliminating areas of severely diseased and dysfunctional lung. We previously hypothesized that effective volume reduction might be possible using a non-surgical approach to cause permanent atelectasis of specific target regions. By collapsing these regions and applying a fibrin-based sealant, we have shown that it is possible to achieve lung volume reduction without surgery in a sheep model of emphysema. While these studies confirmed our initial hypothesis, they have also demonstrated several important shortcomings. BVR achieved solely by mechanical collapse and application of fibrin sealant is frequently incomplete. Only 1/2 to 1/3 of the target regions remained collapsed at 2month follow-up. Furthermore, several target regions developed tissue necrosis. To address these limitations, we have modified our approach to BVR. A new generation of reagents has been developed which modulates local cellular responses, and promotes fibroblast in-growth and scar formation without necrosis. Preliminary studies indicate that these modifications address the limitations identified in our original study. We now hypothesize that: improved BVR can be achieved using washout solution + glue reagents which cause site-specific collapse, and modulation of fibroblast and epithelial cell biology to generate controlled, efficient scar formation. The objectives of this proposal are to: 1) characterize physiological and biological responses using these improved reagents in a sheep model of emphysema, and 2) compare results to those obtained using conventional surgical therapy. We believe that by accomplishing these objectives, we can help advance this technology into the clinical arena.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory and Applied Physiology Study Section (RAP)
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Croxton, Thomas
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Brigham and Women's Hospital
United States
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Bedenice, D; Rozanski, E; Bach, J et al. (2006) Canine awake head-out plethysmography (HOP): characterization of external resistive loading and spontaneous laryngeal paralysis. Respir Physiol Neurobiol 151:61-73
Ingenito, Edward P; Tsai, Larry W; Mentzer, Steven J et al. (2005) Respiratory impedance following bronchoscopic or surgical lung volume reduction for emphysema. Respiration 72:406-17
Suki, Bela; Ito, Satoru; Stamenovic, Dimitrije et al. (2005) Biomechanics of the lung parenchyma: critical roles of collagen and mechanical forces. J Appl Physiol 98:1892-9
Mazan, Melissa R; Ingenito, Edward P; Tsai, Larry et al. (2005) Pulmonary function tests fail to predict exercise intolerance in sheep with emphysema. Med Sci Sports Exerc 37:550-6
Ingenito, Edward P; Tsai, Larry W; Majumdar, Arnab et al. (2005) On the role of surface tension in the pathophysiology of emphysema. Am J Respir Crit Care Med 171:300-4
Hoffman, Andrew; Tsai, Larry; Mazan, Melissa et al. (2005) Pulmonary function tests versus computed tomography in sheep with experimental emphysema. Exp Lung Res 31:497-512
Bedenice, Daniela; Bar-Yishay, Ephraim; Ingenito, Edward P et al. (2004) Evaluation of head-out constant volume body plethysmography for measurement of specific airway resistance in conscious, sedated sheep. Am J Vet Res 65:1259-64
Ingenito, Edward P; Berger, Robert L; Henderson, A Cortney et al. (2003) Bronchoscopic lung volume reduction using tissue engineering principles. Am J Respir Crit Care Med 167:771-8
Ingenito, E P; Reilly, J J; Mentzer, S J et al. (2001) Bronchoscopic volume reduction: a safe and effective alternative to surgical therapy for emphysema. Am J Respir Crit Care Med 164:295-301