antibodies in blood

Pulmonary fibrosis is characterized by progressive lung scarring, with abnormal extracellular matrix production by activated fibroblasts or myofibroblasts (1.). In idiopathic pulmonary fibrosis (IPF), 2 the cause of fibroblast activation and matrix deposition is unknown, although it is suggested that it is the result of aberrant scarring of a lesion of unknown origin (2.). IPF affects approximately 50,000 patients per year in the United States, and the median survival is three to five years after diagnosis (1.).

The recently approved novel antifibrotic agents Nintedanib (Ofev) and Pirfenidone (Esbriet) decrease the rate of decline in lung function and improve survival in IPF (3., 4.); however, the overall results remain poor.

Fibroblast growth factors (FGF) are involved in the pathogenesis of pulmonary fibrosis. FGF receptor tyrosine kinase (FGFR) activity is inhibited by Nintedanib (5., 6.), which decreases bleomycin-induced fibrosis in mice (7., 8.). Inhibition of FGF signaling using a soluble FGFR2c ectodomain decreased the proliferation and differentiation of TGF-β1-induced primary lung fibroblasts in vitro, as well as bleomycin-induced fibrosis in vivo (9.). This ectodomain inhibits multiple FGFs known to bind to the IIIc splice variant of FGFR2, including FGFs 1, 2, 4, 6, 8, 9, 17, and 18 (10.).

A recent study demonstrated altered expression of FGFR1 and FGF1 in the lungs of IPF and suggested that FGF signaling is critical for fibroblast migration in pulmonary fibrosis (11.). Furthermore, the administration of a specific FGFR1 inhibitor (NP603) inhibits carbon tetrachloride-induced liver fibrosis in rats (12.). Although these studies have demonstrated the importance of FGF signaling in the pathogenesis of pulmonary fibrosis, the cellular mechanisms involved remain elusive. In particular, it is not known which cell type (s) are critical targets for FGFs in the pathogenesis of pulmonary fibrosis in vivo.

In primary human lung fibroblasts, the administration of TGF-β1 induced the expression of the FGF receptor (13.) and the expression and secretion of FGF2 in culture media (14, 15.). Primary pulmonary fibroblasts isolated from rats exposed to peplomycin, a bleomycin-related compound, have increased FGF2 production (16.). TGF-β1-induced phosphorylation of ERK, JNK and AP-1 (14., 15.), differentiation of fibroblasts into myofibroblasts, proliferation (17.) and production of FGF2 (18.) are inhibited by neutralizing antibodies of FGF2, suggesting a cooperative mechanism between FGF2 and TGF-β1. These data suggest that FGF signaling in fibroblasts is critical in the pathogenesis of pulmonary fibrosis.

To test whether FGF signaling in lung mesenchyme and fibroblasts is necessary for the pathogenesis of pulmonary fibrosis in vivo, we have generated mice with a specific inducible knockout of the mesenchyme of FGF receptors 1, 2 and 3 using mice. with Tamoxifen-inducible Cre. Recombinase driven by the procollagen Iα2 promoter (Col1α2-CreER) (19., 20.21.). Simultaneous deletion of multiple FGF receptors was performed due to overlapping receptor specificity of many FGFs, including FGF1, FGF2, and FGF9 (22.), as well as simultaneous expression of multiple FGFRs in the lung mesenchyme in vivo.

In this report we demonstrate that the Col1α2 + lineage is enriched in fibrotic tissue after bleomycin treatment, and that cell-autonomous FGFR signaling is required for this lineage enrichment. Deletion of FGFR in the lung mesenchyme decreases collagen expression and the development of pulmonary fibrosis in response to bleomycin. Our data suggest that inhibition of FGFR signaling pathways in fibroblasts slows the enrichment of lung mesenchyme in injured areas, providing a mechanical justification for the use of FGF inhibitors to slow the progression of pulmonary fibrosis.