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J Thorac Cardiovasc Surg 2006;131:209-217
© 2006 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Chronic aspiration of gastric fluid accelerates pulmonary allograft dysfunction in a rat model of lung transplantation

Matthew G. Hartwig, MD a , James Z. Appel, MD a , Bin Li, MD, PhD a , Chong-Chao Hsieh, MD a , Yong Han Yoon, MD a , Shu S. Lin, MD, PhD a , William Irish, PhD b , William Parker, PhD a , R. Duane Davis, MD a , *

a Department of Surgery, Duke University, Durham, NC
b RTI Health Solutions Research Triangle Park, NC

Received for publication April 8, 2005; revisions received June 20, 2005; accepted for publication June 30, 2005.

* Address for reprints: R. Duane Davis, MD, Department of Surgery, Duke University Medical Center, Box 2605, DUMC, Durham, NC 27710 (Email: davis053{at}mc.duke.edu).

OBJECTIVE: Emerging clinical evidence suggests that gastroesophageal reflux disease is associated with pulmonary allograft dysfunction. In this study, we used a model of rat lung transplantation to test the hypothesis that chronic aspiration of gastric contents accelerates pulmonary allograft dysfunction.

METHODS: We evaluated the effects of chronic aspiration on pulmonary isografts (strain F344) and pulmonary allografts (strain WKY to strain F344). Chronic aspiration consisted of 0.5 mL/kg of filtered gastric contents injected weekly into the left lung for 4 to 8 weeks beginning 1 week after transplantation. Seven days after the last aspiration, animals were killed, and grafts were evaluated grossly and by histologic and immunochemical analyses, including Masson trichrome staining for collagen and immunostaining for CD68+ and CD8+ cells. Serum cytokine concentrations were determined by bead-based immunoassays or enzyme-linked immunosorbent assay.

RESULTS: Allografts without aspiration (n = 12) demonstrated a relatively normal architecture with diffuse International Society for Heart and Lung Transplantation grade 3 acute rejection; occasional grade 4 rejection was noted. In contrast, allografts with chronic aspiration (n = 7) demonstrated severe grade 4 acute rejection with significant monocyte infiltration, fibrosis, and loss of normal alveolar anatomy. Grossly, 8 (67%) of 12 allografts without aspiration seemed to inflate and perfuse normally, whereas all allografts exposed to chronic aspiration were firm and shrunken, without the ability to ventilate (P = .013; Fisher exact test). Aspiration was associated with increases in graft-infiltrating macrophages and CD8+ T cells and higher levels of serum transforming growth factor ß.

CONCLUSIONS: Chronic aspiration of gastric contents promotes accelerated allograft failure and may promote a profibrotic environment.

Abbreviations and Acronyms APC = antigen-presenting cell; BOS = bronchiolitis obliterans syndrome; F344 = Fischer F344; GERD = gastroesophageal reflux disease; IL = interleukin; OB = bronchiolitis obliterans; PA = pulmonary artery; PV = pulmonary vein; TGF = transforming growth factor; WKY = Wistar-Kyoto




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