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1 University of Colorado at Denver and Health Sciences Center, Denver, Colorado; 2 University of Tokyo, Tokyo, Japan; 3 Medical College of Virginia, Richmond, Virginia; 4 National Jewish Medical and Research Center, Denver, Colorado; and 5 VA Palo Alto Health Care System, Stanford University, Palo Alto, California
Correspondence and requests for reprints should be addressed to Mark Nicolls, M.D., Stanford University, 3801 Miranda Ave., Medical Service (111P), Palo Alto, CA 94304. E-mail: mnicolls{at}stanford.edu
Airway fibrosis is the major cause of long-term morbidity/mortality following lung transplantation. To study the role of the microcirculation in airway fibrosis, BALB/c or B6 tracheas were transplanted orthotopically into B6 recipients for 2, 4, 6, 8, 10, 12, and 28 days (n = 3–4/group) (1). Before killing, fluorescein isothiocyanate–conjugated tomato lectin was injected intravenously to identify perfused blood vessels. Treatment groups were: syngeneic, untreated allogeneic, and allogeneic recipients treated with anti–LFA-1/ anti-CD40L mAb therapy. To assess the interaction of donor and recipient vasculature, BALB/c or FVB tracheas were transplanted into FVB Tie2/β-gal mice that express β-gal on vascular endothelium and injected with red India Ink before killing. Allogeneic and syngeneic grafts connected with recipient vessels by Day 4. By Day 10, untreated allografts had lost vascular perfusion, whereas syngeneic and immunosuppressed allografts maintained perfusion. Relative graft hypoxia began was noted at Day 6 and was progressive. Tracheas transplanted into Tie2/β-gal mice demonstrated that perfused grafts have a chimeric vascular supply at the graft anastamosis. Subepithelial fibrosis developed 12 days after transplantation. Late reperfusion was noted at 28 days in fibrotic airways.
In summary, all airway grafts reperfuse soon after transplantation with a chimeric connection of blood vessels. This study represents the first demonstration in transplantation that the functional microcirculation is lost during rejection. This vascular loss occurs just before the development of subepithelial fibrosis. Late perfusion again occurs in established fibrosis. The study highlights how inflamed airways can become hypoxic and ischemic before the development of fibrosis.
FOOTNOTES
Research Funding: 1R01HL0862662 (to M.R.N.).
Conflict of Interest Statement: A.N.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. N.F.V. received lectures fees and grant support from Pfizer. M.R.Z. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.M.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.R.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form January 2, 2008; accepted in final form January 4, 2008)
REFERENCES
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