The endocrine FGFs axis: A systemic anti-fibrotic response that could prevent pulmonary fibrogenesis?

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease for which therapeutic options are limited, with an unmet need to identify new therapeutic targets. IPF is thought to be the consequence of repeated microlesions of the alveolar epithelium, leading to aberrant epithelial-mesenchymal communication and the accumulation of extracellular matrix proteins. The reactivation of developmental pathways, such as Fibroblast Growth Factors (FGFs), is a well-described mechanism during lung fibrogenesis. Secreted FGFs with local paracrine effects can either exert an anti-fibrotic or a pro-fibrotic action during this pathological process through their FGF receptors (FGFRs) and heparan sulfate residues as co-receptors. Among FGFs, endocrine FGFs (FGF29, FGF21, and FGF23) play a central role in the control of metabolism and tissue homeostasis. They are characterized by a low affinity for heparan sulfate, present in the cell vicinity, allowing them to have endocrine activity. Nevertheless, their interaction with FGFRs requires the presence of mandatory co-receptors, alpha and beta Klotho proteins (KLA and KLB). Endocrine FGFs are of growing interest for their anti-fibrotic action during liver, kidney, or myocardial fibrosis. Innovative therapies based on FGF19 or FGF21 analogs are currently being studied in humans during liver fibrosis. Recent data report a similar anti-fibrotic action of endocrine FGFs in the lung, suggesting a systemic regulation of the pulmonary fibrotic process. In this review, we summarize the current knowledge on the protective effect of endocrine FGFs during the fibrotic processes, with a focus on pulmonary fibrosis.

Interstitial lung diseases after hematopoietic stem cell transplantation: New pattern of lung chronic graft-versus-host disease?

Bronchiolitis obliterans syndrome (BOS) after allogeneic HSCT is the only formally recognized manifestation of lung chronic graft-versus-host disease (GVHD). Other lung complications were reported, including interstitial lung diseases (ILDs). Whether ILDs belong to the spectrum of lung cGVHD remains unknown. We compared characteristics and specific risk factors for both ILD and BOS. Data collected from consecutive patients diagnosed with ILD or BOS from 1981-2019 were analyzed. The strength of the association between patient characteristics and ILD occurrence was measured via odds ratios estimated from univariable logistic models. Multivariable models allowed us to handle potential confounding variables. Overall survival (OS) was estimated using the Kaplan-Meier method. 238 patients were included: 79 with ILD and 159 with BOS. At diagnosis, FEV1 was lower in patients with BOS compared to patients with ILD, while DLCO was lower in ILD. 84% of ILD patients received systemic corticosteroids, leading to improved CT scans and pulmonary function, whereas most BOS patients were treated by inhaled corticosteroids, with lung-function stabilization. In the multivariable analysis, prior thoracic irradiation and absence of prior treatment with prednisone were associated with ILD. OS was similar, even if hematological relapse was more frequent in the ILD group. Both complications occurred mainly in patients with GVHD history.