Connective Tissue Growth Factor Is Overexpressed in Explant Lung Tissue and Broncho-Alveolar Lavage in Transplant-Related Pulmonary Fibrosis

Abstract

BackgroundConnective 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).Materials and MethodsCTGF expression was assessed by quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry in end-stage CLAD explant lung tissue (bronchiolitis obliterans syndrome (BOS), n=20; restrictive allograft syndrome (RAS), n=20), pulmonary GHVD (n=9). Unused donor lungs served as control group (n=20). Next, 60 matched lung transplant recipients (BOS, n=20; RAS, n=20; stable lung transplant recipients, n=20) were included for analysis of CTGF protein levels in plasma and broncho-alveolar lavage (BAL) fluid at 3 months post-transplant, 1 year post-transplant, at CLAD diagnosis or 2 years post-transplant in stable patients.ResultsqPCR revealed an overall significant difference in the relative content of CTGF mRNA in BOS, RAS and pulmonary GVHD vs. controls (p=0.014). Immunohistochemistry showed a significant higher percentage and intensity of CTGF-positive respiratory epithelial cells in BOS, RAS and pulmonary GVHD patients vs. controls (p<0.0001). BAL CTGF protein levels were significantly higher at 3 months post-transplant in future RAS vs. stable or BOS (p=0.028). At CLAD diagnosis, BAL protein content was significantly increased in RAS patients vs. stable (p=0.0007) and BOS patients (p=0.042). CTGF plasma values were similar in BOS, RAS, and stable patients (p=0.74).ConclusionsLung CTGF-expression is increased in end-stage CLAD and pulmonary GVHD; and higher CTGF-levels are present in BAL of RAS patients at CLAD diagnosis. Our results suggest a potential role for CTGF in CLAD, especially RAS, and pulmonary GVHD.

Interference with connective tissue growth factor attenuated fibroblast-to-myofibroblast transition and pulmonary fibrosis

“…The roles of CTGF/CCN2 in a variety of fibrotic disorders should be highlighted, as previous studies have reported that it is a pro-fibrotic factor, biomarker, and potential target (25)(26)(27). In carbon tetrachloride-induced liver fibrosis and congenital hepatic fibrosis, CTGF has been shown to be essential for fibrogenesis and could be a new therapeutic target for blocking the progression (28,29).…”

Connective Tissue Growth Factor in Idiopathic Pulmonary Fibrosis: Breaking the Bridge

“…It is characterized by variations in temporospatial heterogeneity fibrosis, the accumulation of fibroblasts (fibroblast foci), and subpleural and paraseptal honeycombing [ 42 ]. Vanstapel et al showed high expression of CTGF in fibrotic regions of restrictive allograft syndrome (RAS) lungs [ 43 ]. Furthermore, CTGF was found to be upregulated in cultured fibroblasts [ 44 ], injured epithelial cells [ 45 ], bronchoalveolar lavage and lung tissue [ 43 ], and plasma [ 46 ].…”

“…Vanstapel et al showed high expression of CTGF in fibrotic regions of restrictive allograft syndrome (RAS) lungs [ 43 ]. Furthermore, CTGF was found to be upregulated in cultured fibroblasts [ 44 ], injured epithelial cells [ 45 ], bronchoalveolar lavage and lung tissue [ 43 ], and plasma [ 46 ]. CTGF is upregulated in patients with IPF as well as in pro-fibrotic mediators and pro-fibrotic environments that contribute to fibrogenesis [ 47 ].…”

Immune processes in the pathogenesis of chronic lung allograft dysfunction: identifying the missing pieces of the puzzle

“…A recent study demonstrated higher levels of tissue CTGF expression in BOS and RAS compared to controls. Interestingly, BAL levels of CTGF were higher in RAS compared to BOS and stable patients, and also elevated at 3 months post-transplant in future RAS patients, perhaps suggesting a more specific role for CTGF in the pathogenesis of RAS [ 124 ].…”