James C. Lee

Dietary Curcumin Increases Antioxidant Defenses in Lung, Ameliorates Radiation-Induced Pulmonary Fibrosis, and Improves Survival in Mice

Abstract The effectiveness of lung radiotherapy is limited by radiation tolerance of normal tissues and by the intrinsic radiosensitivity of lung cancer cells. The chemopreventive agent curcumin has known antioxidant and tumor cell radiosensitizing properties. Its usefulness in preventing radiation-induced pneumonopathy has not been tested previously. We evaluated dietary curcumin in radiation-induced pneumonopathy and lung tumor regression in a murine model. Mice were given 1% or 5% (w/w) dietary curcumin or control diet prior to irradiation and for the duration of the experiment. Lungs were evaluated at 3 weeks after irradiation for acute lung injury and inflammation by evaluating bronchoalveolar lavage (BAL) fluid content for proteins, neutrophils and at 4 months for pulmonary fibrosis. In a separate series of experiments, an orthotopic model of lung cancer using intravenously injected Lewis lung carcinoma (LLC) cells was used to exclude possible tumor radioprotection by dietary curcumin. In vitro, curcumin boosted antioxidant defenses by increasing heme oxygenase 1 (HO-1) levels in primary lung endothelial and fibroblast cells and blocked radiation-induced generation of reactive oxygen species (ROS). Dietary curcumin significantly increased HO-1 in lungs as early as after 1 week of feeding, coinciding with a steady-state level of curcumin in plasma. Although both 1% and 5% w/w dietary curcumin exerted physiological changes in lung tissues by significantly decreasing LPS-induced TNF-α production in lungs, only 5% dietary curcumin significantly improved survival of mice after irradiation and decreased radiation-induced lung fibrosis. Importantly, dietary curcumin did not protect LLC pulmonary metastases from radiation killing. Thus dietary curcumin ameliorates radiation-induced pulmonary fibrosis and increases mouse survival while not impairing tumor cell killing by radiation.

Primary Graft Dysfunction

Primary graft dysfunction (PGD) is the most important cause of early morbidity and mortality following lung transplantation. PGD affects up to 25% of all lung transplant procedures and currently has no proven preventive therapy. Lung transplant recipients who recover from PGD may have impaired long-term function and an increased risk of bronchiolitis obliterans syndrome. This article aims to provide a state-of-the-art review of PGD epidemiology, outcomes, and risk factors, and to summarize current efforts at biomarker development and novel strategies for prevention and treatment.

Construct validity of the definition of primary graft dysfunction after lung transplantation

BACKGROUNDnThis study tested the discriminant validity of International Society for Heart and Lung Transplantation (ISHLT) primary graft dysfunction (PGD) grades with lung injury biomarker profiles and survival.nnnMETHODSnThe study samples consisted of a multicenter prospective cohort study for the biomarker analysis and a cohort study of 450 patients for the mortality analyses. PGD was defined according to ISHLT consensus at 24, 48, and 72 hours after transplantation. We compared the changes in plasma markers of acute lung injury between PGD grades using longitudinal data models. To test predictive validity, we compared differences in the 30-day mortality and long-term survival according to PGD grade.nnnRESULTSnPGD Grade 3 demonstrated greater differences between plasma intercellular adhesion molecule 1 (ICAM-1), protein C, and plasminogen activator inhibitor type 1 (PAI-1) levels than did PGD Grades 0 to 2 at 24, 48, and 72 hours after lung transplantation (p < 0.05 for each). Grade 3 had the highest 30-day (test for trend p < 0.001) and overall mortality (log rank p < 0.001), with PGD Grades 1 and 2 demonstrating intermediate risks of mortality. The ability to discriminate both 30-day and overall mortality improved as the time of grading moved away from the time of transplantation (test for trend p < 0.001).nnnCONCLUSIONSnThe ISHLT grading system has good discriminant validity, based on plasma markers of lung injury and mortality. Grade 3 PGD was associated with the most severely altered plasma biomarker profile and the worst outcomes, regardless of the time point of grading. PGD grade at 48 and 72 hours discriminated mortality better than PGD grade at 24 hours.

Elevated Pulmonary Artery Pressure Is a Risk Factor for Primary Graft Dysfunction Following Lung Transplantation for Idiopathic Pulmonary Fibrosis

BACKGROUNDnIdiopathic pulmonary fibrosis (IPF) is often associated with elevations in pulmonary artery pressures. Although primary pulmonary arterial hypertension (PAH) has been associated with primary graft dysfunction (PGD), the role of secondary PAH in mediating PGD risk in patients with IPF is incompletely understood. The purpose of this study was to evaluate the relationship between mean pulmonary artery pressure (mPAP) and PGD among patients with IPF.nnnMETHODSnWe performed a multicenter prospective cohort study of 126 lung transplant procedures performed for IPF between March 2002 and August 2007. The primary outcome was grade 3 PGD at 72 h after lung transplant. The mPAP was measured as the initial reading following insertion of the right-sided heart catheter during lung transplant. Multivariable logistic regression was used to adjust for confounding variables.nnnRESULTSnThe mPAP for patients with PGD was 38.5 ± 16.3 mm Hg vs 29.6 ± 11.5 mm Hg for patients without PGD (mean difference, 8.9 mm Hg [95% CI, 3.6-14.2]; P = .001). The increase in odds of PGD associated with each 10-mm Hg increase in mPAP was 1.64 (95% CI, 1.18-2.26; P = .003). In multivariable models, this relationship was independent of confounding by other clinical variables, although the use of cardiopulmonary bypass partially attenuated the relationship.nnnCONCLUSIONSnHigher mPAP in patients with IPF is associated with the development of PGD.

Elevated Plasma Long Pentraxin‐3 Levels and Primary Graft Dysfunction After Lung Transplantation for Idiopathic Pulmonary Fibrosis

Primary graft dysfunction (PGD) after lung transplantation may result from ischemia reperfusion injury (IRI). The innate immune response to IRI may be mediated by Toll‐like receptor and IL‐1‐induced long pentraxin‐3 (PTX3) release. We hypothesized that elevated PTX3 levels were associated with PGD. We performed a nested case control study of lung transplant recipients with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) from the Lung Transplant Outcomes Group cohort. PTX3 levels were measured pretransplant, and 6 and 24 h postreperfusion. Cases were subjects with grade 3 PGD within 72 h of transplantation and controls were those without grade 3 PGD. Generalized estimating equations and multivariable logistic regression were used for analysis. We selected 40 PGD cases and 79 non‐PGD controls. Plasma PTX3 level was associated with PGD in IPF but not COPD recipients (p for interaction < 0.03). Among patients with IPF, PTX3 levels at 6 and 24 h were associated with PGD (OR = 1.6, p = 0.02 at 6 h; OR = 1.4, p = 0.008 at 24 h). Elevated PTX3 levels were associated with the development of PGD after lung transplantation in IPF patients. Future studies evaluating the role of innate immune activation in IPF and PGD are warranted.

A panel of lung injury biomarkers enhances the definition of primary graft dysfunction (PGD) after lung transplantation

BACKGROUNDnWe aimed to identify combinations of biomarkers to enhance the definition of primary graft dysfunction (PGD) for translational research.nnnMETHODSnBiomarkers reflecting lung epithelial injury (soluble receptor for advance glycation end products [sRAGE] and surfactant protein-D [SP-D]), coagulation cascade (plasminogen activator inhibitor-1 [PAI-1] and protein C), and cell adhesion (intracellular adhesion molecule-1 [ICAM-1]) were measured in the plasma of 315 individuals derived from the Lung Transplant Outcomes Group cohort at 6 and 24 hours after transplantation. We assessed biomarker utility in 2 ways: first, we tested the discrimination of grade 3 PGD within 72 hours; second, we tested the predictive utility of plasma biomarkers for 90-day mortality.nnnRESULTSnPGD developed in 86 of 315 individuals (27%). Twenty-patients (8%) died within 90 days of transplantation, of which 16 (70%) had PGD. Biomarkers measured at 24 hours had greater discrimination than at 6 hours. Individually, sRAGE (area under the curve [AUC], 0.71) and PAI-1 (AUC, 0.73) had the best discrimination of PGD. The combinations of sRAGE with PAI-1 (AUC, 0.75), PAI-1 with ICAM-1 (AUC, 0.75), and PAI-1 with SP-D (AUC, 0.76) had the best discrimination. Combinations of greater than 2 biomarkers did not significantly enhance discrimination of PGD. ICAM-1 with PAI-1 (AUC, 0.72) and ICAM-1 with sRAGE (AUC, 0.72) had the best prediction for 90-day mortality. The addition of ICAM-1, PAI-1, or sRAGE to the concurrent clinical PGD grade significantly improved the prediction of 90-day mortality (p < 0.001 each).nnnCONCLUSIONSnMeasurement of the combination of a marker of impaired fibrinolysis with an epithelial injury or cell adhesion marker had the best discrimination for PGD and prediction for early death and may provide an alternative outcome useful in future research.

Donor transmission of malignant melanoma in a lung transplant recipient 32 years after curative resection

In the current era of organ shortages and long wait times for life‐saving transplants, marginal or extended donors are increasingly being considered; one such category of marginal organs is from donors with a previous history of malignancy. Melanoma in particular has been associated with increased risk of developing late recurrence. In this report, we describe a case of fatal donor melanoma transmission to a 64‐year‐old lung transplant recipient 32u2003years after surgical excision of the melanoma. Based on this report and review of the available literature, we conclude that a history of donor melanoma, regardless of the stage and time interval from ‘curative’ surgical resection, should remain a strong relative contraindication to transplantation.

Lung Transplant Outcomes in White and African American Recipients: Special Focus on Acute and Chronic Rejection

BACKGROUNDnThe effects of lung transplant recipient race on post-transplant outcomes have not been adequately evaluated. This cohort study seeks to determine the characteristics of African American lung transplant recipients and the effects of African American race on post-transplant outcomes, particularly acute and chronic rejection, compared with white recipients, at a single center.nnnMETHODSnThere were 485 first-time lung transplantations (431 white, 47 African American, 5 Hispanic and 2 Asian recipients) performed at the University of Pennsylvania between 1991 and 2006. All white and African American recipients were compared based on pre-transplant diagnoses and post-transplant survival. The cohort from 1998 to 2006 (239 white and 25 African American recipients) was also compared based on acute rejection score (ARS) and development of bronchiolitis obliterans syndrome (BOS).nnnRESULTSnChronic obstructive pulmonary disease was the most common diagnosis leading to lung transplantation in both groups, but sarcoidosis was a much more common indication in African American recipients (white, 1%; African American, 28%; p < 0.001). Survival was similar in the two groups (white vs African American groups: 1 month, 90.0% vs 87.2%; 1 year, 74.9% vs 74.5%; 5 years, 52.3% vs 50.5%, respectively; p = 0.84). Freedom from BOS at 3 years (white, 60.3%; African American, 62.8%; p = 0.30) and ARS per biopsy (white, 0.83 +/- 0.82; African American, 0.63 +/- 0.77; p = 0.31) were similar in both groups.nnnCONCLUSIONSnWhite and African American patients seek lung transplantation for different diseases, but post-transplant outcomes were found to be similar. Larger, multi-center studies are needed to confirm these results.

Gene expression profiling of flaxseed in mouse lung tissues-modulation of toxicologically relevant genes

BackgroundFlaxseed (FS), a nutritional supplement consisting mainly of omega-3 fatty acids and lignan phenolics has potent anti-inflammatory, anti-fibrotic and antioxidant properties. The usefulness of flaxseed as an alternative and complimentary treatment option has been known since ancient times. We have shown that dietary FS supplementation ameliorates oxidative stress and inflammation in experimental models of acute and chronic lung injury in mice resulting from diverse toxicants. The development of lung tissue damage in response to direct or indirect oxidant stress is a complex process, associated with changes in expression levels of a number of genes. We therefore postulated that flaxseed might modulate gene expression of vital signaling pathways, thus interfering with the development of tissue injury.MethodsWe evaluated gene expression in lungs of flaxseed-fed (10%FS) mice under unchallenged, control conditions. We reasoned that array technology would provide a powerful tool for studying the mechanisms behind this response and aid the evaluation of dietary flaxseed intervention with a focus on toxicologically relevant molecular gene targets. Gene expression levels in lung tissues were analyzed using a large-scale array whereby 28,800 genes were evaluated.Results3,713 genes (12.8 %) were significantly (pu2009<u20090.05) differentially expressed, of which 2,088 had a >1.5-fold change. Genes affected by FS include those in protective pathways such as Phase I and Phase II.ConclusionsThe array studies have provided information on how FS modulates gene expression in lung and how they might be related to protective mechanisms. In addition, our study has confirmed that flaxseed is a nutritional supplement with potentially useful therapeutic applications in complementary and alternative (CAM) medicine especially in relation to treatment of lung disease.

Primary Graft Dysfunction After Lung Transplantation

Primary graft dysfunction is a form of acute injury after lung transplantation that is associated with significant short- and long-term morbidity and mortality. Multiple mechanisms contribute to the pathogenesis of primary graft dysfunction, including ischemia reperfusion injury, epithelial cell death, endothelial cell dysfunction, innate immune activation, oxidative stress, and release of inflammatory cytokines and chemokines. This article reviews the epidemiology, pathogenesis, risk factors, prevention, and treatment of primary graft dysfunction.