Oxidative Stress Correleates with Survival in Lung Transplantation.

Abstract

Introduction: Oxidative stress plays a key role in balancing of innate and adaptive immunity in pulmonary inflammation. The roles of two major endogenous thiols and antioxidants, Cys (Cysteine) and GSH (Glutathione), in HIV infections and other diseases have been associated with wasting and immunological dysfunction. We hypothesized that increased levels of oxidative stress as measured directly in lung lavage, and assessed by lung macrophage transcriptional profiling would correlate with poorer outcomes in lung transplant patients. Methods:. During 2007 to 2012 cohort of 86 lung transplant patients were followed to identify predictors using death and graft function as primary outcome. 23 (27%) patients died and 96% lung transplant patients manifest at least one decline in spirometry. BAL from these patients (344 total samples, mean 4 samples per patient) was analyzed by HPLC. The oxidative stress markers GSH, GSSG, CyS, CySS, GSH/CySS, GSSG/CyS and GSH/CyS were measured from each BAL sample. Macrophage expression profiling was performed by RT-PCR on BAL macrophages recovered during BAL after brief adherence to plastic. Our preliminary work had shown a strong correlation of the oxidative stress induced gene prostaglandin-endoperoxide synthase 1 (PTGS1) to levels of oxidized cysteine and glutathione. Hence PTGS1 expression was chosen as a measure for this study. Results: Our analysis identified Glutathione disulfide (GssG) (p=0.0489; HR=1.133) as a predictor of death in this cohort. The other markers of oxidative stress showed weak non-statistically significant correlation with survival. In support of the finding that oxidative stress correlates to outcome we found PTGS1 gene expression in lung macrophages was also associated with death (p=0.0463; HR=2.217). Despite these survival associations, neither PTGS1 of GssG longitudinal measures correleated with lung spirometry. Conculsion: We found that oxidative stress as measured by GssG levels significantly correlated with a risk of death in our cohort. That PTGS 1 gene expression was also increased raises the possibility that oxidative stress results in skewing of lung macrophage polarity. Based on these findings we are assessing the relationship between oxidative stress and macrophage function in a prospective study.