(1229) Fibroblast Activation Protein Alpha (fapa) in Chronic Lung Allograft Dysfunction

• Published in: The Journal of heart and lung transplantation Vol. 42; no. 4; p. S525
• Main Authors: Moneke, I., Burkle, J., Pfaffendorf, E., Bronsert, P., Zissel, G., Faendrich, S., Passlick, B., Diederichs, S., Jungraithmayr, W.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-04-2023
• ISSN: 1053-2498; 1557-3117
• DOI: 10.1016/j.healun.2023.02.1439

Chronic lung allograft dysfunction (CLAD) limits survival after lung transplantation (Tx). CLAD is characterized by a progressive fibrosis within small airways and lung parenchyma. Up to now, there is no effective therapy to reverse or prevent the fibrotic changes. Fibroblast activation protein alpha (FAPa) is a molecule, closely related to CD26, with enzymatic activity that also plays a key role in fibrotic processes. Here, we hypothesize that FAPa contributes to the development of CLAD in lung transplant patients.
We analyzed the medical records of all patients who underwent lung transplantation at our institution between 2004 and 2021. Lung biopsies of patients who underwent lung transplantation were analyzed by immunohistochemistry for FAPa. We employed the human lung cell lines Wi-38 (fibroblast) and A549 (alveolar epithelial cells) for the analysis of pro-fibrotic genes and proteins by RT-qPCR and Western blot in vitro. For testing the migration and proliferation of fibroblasts, Incucyte® and Celltiter-Glo® were used, respectively.
Representative immunohistochemical analyses of patient lung biopsies after lung transplantation revealed the expression of FAPa positive fibroblasts in CLAD lesions compared to lung biopsies from patients without CLAD. We found in vitro, that treatment with Vildagliptin, a CD26 inhibitor with antifibrotic activity, reduced the relative RNA expression of e.g. aSMA (87%, p=0,007) but also FAPa (46%, p=0.048) in TGF-β-activated lung fibroblasts. Moreover, inhibition of epithelial to mesenchymal transition (EMT) in A549 cells by vildagliptin showed reduced expression of FAPa.
FAPa is expressed in CLAD lesions of lung transplant patients. In vitro data show that CD26-inhibition downregulates key pro-fibrotic driver genes, such as FAPa, and reduces migration and proliferation of fibroblasts, as well as EMT in A549. FAPa seems to play a role in the development of fibrotic changes in CLAD. Whether it is essential for the process is currently being investigated. Since there is almost no expression in heathy tissue, FAPa might be a good candidate for a marker or potential target for fibrosis related changes as they occur in CLAD.