The fibroblast activation protein alpha as a biomarker of pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a rare, chronic, and progressive interstitial lung disease with an average survival of approximately 3 years. The evolution of IPF is unpredictable, with some patients presenting a relatively stable condition with limited progression over time, whereas others deteriorate rapidly. In addition to IPF, other interstitial lung diseases can lead to pulmonary fibrosis, and up to a third have a progressive phenotype with the same prognosis as IPF. Clinical, biological, and radiological risk factors of progression were identified, but no specific biomarkers of fibrogenesis are currently available. A recent interest in the fibroblast activation protein alpha (FAPα) has emerged. FAPα is a transmembrane serine protease with extracellular activity. It can also be found in a soluble form, also named anti-plasmin cleaving enzyme (APCE). FAPα is specifically expressed by activated fibroblasts, and quinoline-based specific inhibitors (FAPI) were developed, allowing us to visualize its distribution in vivo by imaging techniques. In this review, we discuss the use of FAPα as a useful biomarker for the progression of lung fibrosis, by both its assessment in human fluids and/or its detection by imaging techniques and immunohistochemistry.

Keywords: FAP; FAPI; IPF; PPF; biomarker; fibroblast activation protein; fibrosis; progression.

Figure 1

Summary of the pathophysiology of the fibroblast activation protein α (FAPα) in lung fibrosis. The expression of FAPα by fibroblasts is stimulated by transforming growth factor β (TGF-β) with a synergistic effect of interleukin 1β (IL-1β). FAPα is not able to cleave directly collagens I and III but complements matrix metalloproteinases (MMP) by cleaving partially digested collagen fragments. In the absence of FAPα, these partially digested collagen fragments accumulate in the lungs and more extensive fibrosis is observed. Created with Biorender.com.

Figure 2

Assessment of FAPα levels in bronchoalveolar lavage fluid (BALF) from control subjects (CTRL) and patients with idiopathic pulmonary fibrosis (IPF) with either a stable or a progressive phenotype according to the 2022 ATS/ERS/JRS/ALAT Clinical Practice Guidelines (10). Data are reproduced from Lavis et al. (51).

Figure 3

⁶⁸Ga-FAPI uptake assessed by PET/CT in a patient with idiopathic pulmonary fibrosis and the corresponding high-resolution CT. An intense uptake of the radiotracer is observed in some subpleural lesions (blue arrows), whereas some present a weak uptake (green arrow), suggesting a lower fibrogenesis activity kindly provided by the Department of Nuclear Medicine of the Hôpital Universitaire de Bruxelles (HUB), Brussels, Belgium.

Figure 4

Fibroblast activation protein α (FAPα) immunostaining in a fibroblast foci from a lung explant of a patient with idiopathic pulmonary fibrosis with the corresponding hematoxylin-eosin staining. The use of FAPα immunostaining enables rapid identification of fibroblast foci and a more accurate assessment of their number. Magnification fold 200×. The images come from the Biobank of Pneumology—HUB. The protocol for FAPα immunostaining was detailed in Lavis et al. (51).

Figure 5

Perspectives on the use of the fibroblast activation protein α (FAPα) as a future biomarker of fibrogenesis in idiopathic pulmonary fibrosis (IPF) and other fibrosing interstitial lung diseases (ILD). BALF, bronchoalveolar lavage fluid; FAPI, FAPα inhibitor; PET/CT, positron emission tomography/computed tomography; SPECT, single-photon emission computed tomography.