Alcohol ingestion by donors amplifies experimental airway disease after heterotopic transplantation.
BACKGROUND
Obliterative bronchiolitis (OB) after lung transplantation is triggered by alloimmunity, but is ultimately mediated by transforming growth factor (TGF)-beta(1)-dependent airway fibrosis.


OBJECTIVE
Chronic alcohol use increases TGF-beta(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.


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-beta(1) and alpha-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-beta(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.
Mitchell
Patrick O
PO
Atlanta Veterans Affairs Medical Center (151-P), 1670 Clairmont Road, Decatur, GA 30033, USA. pmitche@emory.edu
Guidot
David M
DM
D000199:Actins / Q000378:metabolism; D000428:Alcohol Drinking; D000818:Animals; D001989:Bronchiolitis Obliterans / Q000209:etiology* / Q000503:physiopathology*; D003094:Collagen / Q000378:metabolism; D004198:Disease Susceptibility; D006648:Histocompatibility; D008214:Lymphocytes / Q000473:pathology; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D016377:Organ Transplantation / Q000009:adverse effects; D011184:Postoperative Period; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D014019:Tissue Donors; D014022:Tissue Survival; D014132:Trachea / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
D000199:Actins; D053773:Transforming Growth Factor beta1; D003094:Collagen
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