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Alcohol Ingestion by Donors Amplifies Experimental Airway Disease after Heterotopic Transplantation

¹ Atlanta Veterans Affairs Medical Center and ² Division of Pulmonary, Allergy, and Critical Care Medicine, Emory University School of Medicine, Atlanta, Georgia

Correspondence and requests for reprints should be addressed to Patrick O. Mitchell, Ph.D., Atlanta Veterans Affairs Medical Center (151-P), 1670 Clairmont Road, Decatur, GA 30033. E-mail: pmitche{at}emory.edu

Rationale: Obliterative bronchiolitis (OB) after lung transplantation is triggered by alloimmunity, but is ultimately mediated by transforming growth factor (TGF)-₁–dependent airway fibrosis.

Objectives: Chronic alcohol use increases TGF-₁ expression and renders the lung susceptible to injury. Therefore, we hypothesized that donor alcohol abuse could prime the lung allograft for OB, as many organ donors have a history of alcohol abuse.

Methods: Tracheas from control and alcohol-fed rats (8 wk) were heterotopically transplanted into recipients with varying degrees of alloimmune mismatch and analyzed for obliterative airway disease severity on Postoperative Day 21.

Measurements and Main Results: Although donor alcohol ingestion did not increase the number of antigen-presenting cells or infiltrating lymphocytes, it nevertheless increased allograft lumenal collagen content fourfold compared with allografts from control donors. In parallel, alcohol increased TGF-₁ and -smooth muscle actin expression in allografts. Alcohol amplified airway disease even in isografts with minor alloimmune mismatches. In contrast, it did not cause any airway disease in isografts in a pure isogenic background, suggesting that a minimal alloimmune response is necessary to trigger alcohol-induced airway fibrosis.

Conclusions: Although alloimmune inflammation is required to initiate airway disease, alcohol primes the allograft for greater TGF-₁ expression, myofibroblast transdifferentiation, and fibrosis than by alloimmune inflammation alone. This has serious clinical implications, as many lung donors have underlying alcohol abuse that may prime the allograft recipient for subsequent OB.

Key Words: fibrosis • lung transplant • obliterative bronchiolitis • transforming growth factor-1

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Obliterative bronchiolitis (OB) is the main long-term cause of graft dysfunction after lung transplantation. Although some risk factors have been implicated in the development of OB, predicting which graft recipients develop OB has been as yet unreliable. What This Study Adds to the Field Donor alcohol abuse amplifies the severity of OB in the recipient.

 

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