Primary Graft Dysfunction (PGD) is clinically similar to the acute respiratory distress syndrome (ARDS). Alcohol abuse increases the risk of developing ARDS ∼4- fold in at-risk patients. ∼20% of donors have significant alcohol use, and it was only when instruments such as the Alcohol Use Identification Test (AUDIT) were used in epidemiological studies that the previously unrecognized association between alcohol abuse and ARDS was identified. Therefore, we hypothesized that donor alcohol abuse, defined by this well-validated measure, will correlate with PGD risk.

Purpose. Gastric fundoplication (GF) for gastroesophageal reflux disease (GERD) may protect against the progression of chronic rejection in lung transplant (LT) recipients. However, the association of GERD with acute rejection episodes (ARE) is uncertain. This study sought to identify if ARE were linked to GERD in LT patients.Methods. This single-center retrospective observational study, of patients transplanted from January 11, 2000, to January 31, 2009, correlated results of pH probe testing for GERD with ARE (>= International Society for Heart and Lung Transplantation A1 or B1). We compared the rates of ARE among patients with GERD (DeMeester Score > 14.7) versus without GERD as number of ARE per 1,000 patient-days after LT. Patients undergoing GF prior to LT were excluded.Results. The analysis included 60 LT subjects and 9,249 patient-days: 33 with GERD versus 27 without GERD. We observed 51 ARE among 60 LT recipients. The rate of ARE was highest among patients with GERD: 8.49 versus 2.58, an incidence density ratio (IDR) of 3.29 (P = .00016). Upon multivariate negative binomial regression modeling, only GERD was associated with ARE (IDR 2.15; P = .009). Furthermore, GERD was associated with multiple ARE (36.4% vs 0%; P < .0001) and earlier onset compared with patients without GERD: ARE proportion at 2 months was 0.55 versus 0.26 P = .004).Conclusion. In LT recipients, GERD was associated with a higher rate, multiple events, and earlier onset of ARE. The efficacy of GF to reduce ARE among patients with GERD needs further evaluation.

Development of primary graft dysfunction (PGD) is associated with poor outcomes after transplantation. We hypothesized that Receptor for Advanced Glycation End-products (RAGE) levels in donor lungs is associated with the development of PGD. Furthermore, we hypothesized that RAGE levels would be increased with PGD in recipients after transplantation. We measured RAGE in bronchoalveolar lavage fluid (BALf) from 25 donors and 34 recipients. RAGE was also detected in biopsies (transbronchial biopsy) from recipients with and without PGD. RAGE levels were significantly higher in donor lungs that subsequently developed sustained PGD versus transplanted lungs that did not display PGD. Donor RAGE level was a predictor of recipient PGD (odds ratio = 1.768 per 0.25 ng/mL increase in donor RAGE level). In addition, RAGE levels remained high for 14 days in those recipients that developed severe graft dysfunction. Recipients may be at higher risk for developing PGD if they receive transplanted organs that have higher levels of soluble RAGE prior to explantation. Moreover, the clinical and pathologic abnormalities associated with PGD posttransplantation are associated with increased RAGE expression. These findings also raise the possibility that targeting the RAGE signaling pathway could be a novel strategy for treatment and/or prevention of PGD.

Primary graft dysfunction (PGD) is a severe form of ischemia-reperfusion injury (IRI) and leads to increased mortality. IRI is thought to involve production of reactive oxygen (ROS) and nitrogen species (RNS), leading to redox stress. We hypothesize that redox states will differ between lung transplant recipients (LTR) with and without severe PGD.

BACKGROUND:Using an experimental model of airway fibrosis following lung transplantation, we recently showed that chronic alcohol ingestion by donor rats amplifies airway fibrosis in the recipient. Associated with alcohol-mediated amplification of airway fibrosis is increased transforming growth factor beta-1(TGFbeta(1)) and alpha-smooth muscle actin expression. Other studies have shown that interleukin-13 (IL-13) modulates TGFbeta(1) signaling during experimentally-induced airway fibrosis. Therefore, we hypothesized that IL-13 is a component of alcohol-mediated amplification of pro-fibrotic mediators in the alcoholic lung. METHODS:To test this hypothesis, we analyzed tracheal epithelial cells and type II alveolar cells from control- or alcohol-fed rats, alcohol-treated mouse lung fibroblasts, and human bronchial epithelial cells in vitro for expression of various components of the IL-13 signaling pathway. Signaling via the IL-13 pathway was assessed by measuring levels of phosphorylated signal transducers and activators of transcription-6 (STAT6). In addition, we performed heterotopic tracheal transplantation using control-fed and alcohol-fed donor rats and analyzed tracheal allografts for expression of components of the IL-13 signaling pathway by RT-PCR and immunocytochemical analyses. RESULTS:Interleukin-13 expression was detected in type II alveolar epithelial cells and human bronchial epithelial cells, but not in lung fibroblasts. IL-13 expression was decreased in whole lung and type II cells in response to alcohol exposure. In all cell types analyzed, expression of IL-13 signaling receptor (IL-13R alpha(1)) mRNA was markedly increased. In contrast, mRNA and protein expression of the IL-13 decoy receptor (IL-13R alpha(2)) were decreased in all cells analyzed. Exposure to alcohol also increased STAT6 phosphorylation in response to IL-13 and lipopolysaccharide. CONCLUSIONS:Data from multiple cell types in the pulmonary system suggest that IL-13 and its receptors play a role in alcohol-mediated activation of pro-fibrotic pathways. Taken together, these data suggest that alcohol primes the airway for increased IL-13 signaling and subsequent tissue remodeling upon injury such as transplantation.

Evidence of Epithelial to Mesenchymal Transition Associated with Airway Remodeling after Experimental and Clinical Lung Transplantation P.O. Mitchell, P.M. Naik, D.C. Neujahr, S.D. Force, A.M. Ramirez, A.A. Gal, E.C. Lawrence, D.M. Guidot, A. Pelaez, Atlanta Veterans Affairs Medical Center, Decatur, GA; Pulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, GA; McKelvey Center for Lung Transplantation & Pulmonary Vascular Diseases, Emory University, Atlanta, GA; Division of Cardiothoracic Surgery, Emory University, Atlanta, GA; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA

Chronic alcohol exposure in rats induces oxidative stress in the lung via the angiotensin II pathway and elicits an increase in expression of the profibrotic mediator, transforming growth factor β1 (TGF-β1). In addition, fibronectin expression is increased in the lungs of alcohol-fed rats. These data strongly suggest that profibrotic mechanisms are activated in response to chronic alcohol exposure, and if true, this would suggest that alcohol abuse might increase the risk of fibrotic lung diseases. Consistent with this hypothesis, we have recently determined that alcohol ingestion increases TGF-β1 expression and collagen deposition in an experimental model of obliterative bronchiolitis (OB) following tracheal transplantation in rats. Another profibrotic cytokine, interleukin-13 (IL-13), has been shown to be an important mediator of tissue remodeling/fibrosis in the lung and may act upstream of the TGF-β1 pathway. We hypothesized that alterations in the expression of IL-13 or its receptors could contribute to alcohol-mediated amplification of profibrotic mediators in the alcoholic lung. To test this hypothesis, we analyzed whole lungs and type II alveolar epithelial cells isolated from alcohol-fed rats, as well as mouse lung fibroblasts exposed to alcohol in vitro, for various components of the IL-13 signaling pathway. Gene expression of IL-13, along with the α1 and α2 subunits of its receptor (IL-13Rα1 and IL-13Rα2), was examined by assessing mRNA levels by RT-PCR. In parallel, IL-13Rα2 protein expression was determined by immunostaining. We found that IL-13Rα2 protein was expressed in the whole lung, lung fibroblasts, and type II epithelial cells. RT-PCR analyses indicated that whole lung expresses all three components of the IL-13 signaling pathway. Although lungs from alcohol-fed rats displayed decreased IL-13 mRNA expression, IL-13Rα1 expression was increased, and a marked elevation in IL-13Rα1mRNA expression was observed in alcohol-treated primary lung fibroblasts. Associated with the increase in IL-13Rα1 mRNA in lung fibroblasts was an increase in α-smooth muscle actin protein expression, suggesting fibroblast transdifferentiation into myofibroblasts, which is a cardinal feature of fibrotic diseases such as idiopathic pulmonary fibrosis and bronchiolitis obliterans. These data suggest that IL-13 and its receptors play a role in alcohol-mediated activation of profibrotic mechanisms. In particular, we speculate that alcohol abuse increases IL-13Rα1 expression, which could heighten the response of cells in the lung to IL-13, thereby amplifying TGF-β1-induced fibroblast activation and subsequent tissue remodeling.