Published ahead of print on November 17, 2005, doi:10.1164/rccm.200509-1413OC
Am. J. Respir. Crit. Care Med., Volume 173, Number 5, March 2006, 566-572
A more recent version of this article appeared on March 1, 2006
Submitted on September 9, 2005
Accepted on November 11, 2005
Novel Action of Indoleamine 2,3-Dioxygenase Attenuating Acute Lung Allograft Injury
Hanzhong Liu1, Li Liu2, Bradely S Fletcher3, and Gary A Visner1*
1 Department of Pediatrics, University of Florida, Gainesville, FL, USA,
2 Department of Pharmacology and Therapeutics, University of Florida, Gainseville, FL, USA,
3 Department of Pharmacology and Therapeutics, University of Florida, Gainseville, FL, USA; Medical Research Service, Veteran Affairs Medical Center, Gainesville, FL, USA
* To whom correspondence should be addressed. E-mail: visnerga{at}peds.ufl.edu.
Rationale: Lung allografts are especially prone to reperfusion injury and acute rejection, which in addition to infiltrating lymphocytes, are accompanied by neutrophil infiltration and neutrophil-associated oxidative stress. Indoleamine 2,3-dioxygenase (IDO) is an unique cytosolic enzyme that possess both T-cell-suppressive and anti-oxidant properties.
Objectives: The purpose of this study was to determine if genetic upregulation of IDO could ameliorate acute lung allograft injury.
Methods: Lung orthotopic transplants were performed using Lewis donors and Sprague-Dawley rat recipients (allografts) or the same strain (isografts). Plasmid encoding human IDO was delivered to donor lungs in vivo using a nonviral gene-transfer vector, polyethyleneimine. Transplanted lungs were evaluated at 6 days-post-transplantation, based on pulmonary function, histology, inflammatory responses and its associated oxidative stress. In addition, basic biology of the IDO-overexpressing lung cells was evaluated in vitro in response to external oxidant.
Measurements and Main Results: This gene delivery method led to uniform transgene expression in lung tissue distributed in airway, alveolar epithelial and endothelial cells. IDO overexpression in lung allografts resulted in a significant protective effect with improvement in both functional properties (peak airway pressure and oxygenation) and histological appearance. While IDO was able to block local T-cell responses, it failed to abrogate neutrophilic infiltration and the inflammation-associated oxidative stress. However, IDO enhanced lung cells were resistance to oxidant-induced necrosis and apoptosis by limiting intracellular reactive oxygen species formation.
Conclusions: These results demonstrate that IDO prevents acute lung allograft injury through augmenting local antioxidant defense system in addition to inhibite alloreactive T-cell responses.
Key words: lung transplantation, gene therapy, T-cells, oxidative stress
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