Connective Tissue Growth Factor in Chronic Lung Allograft Dysfunction: An Explorative Study

Abstract

Purpose Connective tissue growth factor (CTGF) is an important mediator in several fibrotic diseases, including lung fibrosis. We investigated CTGF expression in chronic lung allograft dysfunction (CLAD) and pulmonary graft-versus-host disease (GVHD) by analyzing CTGF expression in broncho-alveolar lavage (BAL) fluid, plasma and lung tissue. Methods Sixty matched lung transplant patients were included (stable, n=20; bronchiolitis obliterans syndrome (BOS), n=20, restrictive allograft syndrome (RAS), n=20). CTGF expression was analyzed in BAL 3m post-transplant, 1y post-transplant, and at CLAD diagnosis or 2y post-transplant for stable patients. Explant lung tissue of CLAD (BOS, n=20; RAS, n=20), pulmonary GHVD (n=9), and discarded donor lungs (n=20) was immunohistochemically stained for CTGF. Results BAL CTGF protein expression was significantly higher at 3m post-transplant in patients who later developed RAS compared to stable or BOS patients (ANOVA p=0.028); while CTGF expression was similar at 1y post-transplant (ANOVA p=0.20). At CLAD diagnosis, CTGF expression was significantly increased in RAS compared to stable (p=0.0007) and BOS (p=0.042). Serial analysis revealed no difference in CTGF values between time points for stable and BOS patients (ANOVA p=0.84, p=0.92), whereas CTGF levels were significantly higher in RAS at CLAD diagnosis compared to 1y post-transplant (ANOVA p=0.029). CTGF plasma values were similar between BOS, RAS, and stable (ANOVA p=0.74). Immunohistochemistry revealed a higher percentage and intensity of CTGF positive respiratory epithelial cells in BOS and RAS lungs compared to controls (ANOVA p Conclusion Higher CTGF expression is present in BAL from RAS patients at CLAD diagnosis. Lung tissue CTGF expression is increased in end-stage RAS, BOS and pulmonary GVHD. Our results suggest a potential role for CTGF in CLAD, especially RAS, and pulmonary GVHD, which warrants further investigation of CTGF and its potential therapeutic modulation in these conditions.