Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

Abstract

The pathogenesis of pulmonary fibrosis involves lung epithelial injury and aberrant proliferation of fibroblasts, and results in progressive pulmonary scarring and declining lung function. In vitro, fibroblast growth factor (FGF) 2 promotes myofibroblast differentiation and proliferation in cooperation with the profibrotic growth factor, transforming growth factor-b1, but the in vivo requirement for FGF2 in the development of pulmonary fibrosis is not known. The bleomycin model of lung injury and pulmonary fibrosis was applied to Fgf2 knockout (Fgf2 2/2) and littermate control mice. Weight loss, mortality, pulmonary fibrosis, and histology were analyzed after a single intranasal dose of bleomycin. Inflammation was evaluated in bronchoalveolar lavage (BAL) fluid, and epithelial barrier integrity was assessed by measuring BAL protein and Evans Blue dye permeability. Fgf2 is expressed in mouse and human lung epithelial and inflammatory cells, and, in response to bleomycin, Fgf2 2/2 mice have significantly increased mortality and weight loss. Analysis of BAL fluid and histology show that pulmonary fibrosis is unaltered, but Fgf2 2/2 mice fail to efficiently resolve inflammation, have increased BAL cellularity, and, importantly, deficient recovery of epithelial integrity. Fgf2 2/2 mice similarly have deficient recovery of club cell secretory protein 1 bronchial epithelium in response to naphthalene. We conclude that FGF2 is not required for bleomycin-induced pulmonary fibrosis, but rather is essential for epithelial repair and maintaining epithelial integrity after bleomycin-induced lung injury in mice. These data identify that FGF2 acts as a protective growth factor after lung epithelial injury, and call into question the role of FGF2 as a profibrotic growth factor in vivo.Keywords: fibroblast growth factor 2; bleomycin; pulmonary fibrosis; lung injury; alveolar epithelial repair Clinical RelevanceFibroblast growth factors (FGFs) and, in particular, FGF2, are implicated in the pathogenesis of pulmonary fibrosis and recovery from airway epithelial cell (AEC) injury; however, the in vivo requirement for FGF2 in the development of pulmonary fibrosis is not known. In this study, we have found that mice lacking FGF2 do not show altered levels of fibrosis in response to bleomycin, indicating that FGF2 is dispensable for the generation of bleomycin-induced pulmonary fibrosis. In addition, we show that FGF2 knockout mice have increased mortality and weight loss in response to bleomycin, accompanied by deficient recovery of mature alveolar epithelium and epithelial barrier function. These findings suggest that FGF2 is required for lung epithelial recovery, that pharmacological inhibition of FGF signaling could impair the response to lung injury, and that FGF2 administration or augmentation may have therapeutic benefit for lung injury.Lung alveolar epithelial cell (AEC) injury can be caused by a variety of insults, including infection, trauma, aspiration, and sepsis. Chronic AEC injury of unknown origin is central to ...

Lung Regeneration Therapy for Chronic Obstructive Pulmonary Disease

“…In addition, Lee et al25 observed the protective effects of FGF-2 in an interferon-γ–induced emphysema mouse model. Moreover, in addition to the emphysema model, the role of FGF-2 in pulmonary epithelial recovery was also demonstrated in a bleomycin-induced pulmonary fibrosis model using FGF-2 knockout mice26.…”

“…Because considerable evidence indicates that the major action mechanism of cell therapy is based on paracrine effects 1213161718, researchers have attempted to regenerate diseased lung with various molecules2021222324252627. Of these numerous candidates, to date retinoids are the only one that has been widely investigated in the clinical field (Table 4).…”

“…As discussed above, there are a number of candidates with proven disease-modifying effects in animal models, such as retinoids, FGF-2, HGF, and even estrogen 2021222324252627. However, only retinoids have been tried in the clinical field32333435.…”

Pathogenesis of IPF

“…In IPF patients, there are scant data regarding the localization of FGF-2 in the lungs. However, the expression of FGF-2 mRNA has been reported to be upregulated in BLM-treated lungs in mice [57]. Although immunohistochemical staining has been reported to show the expression of FGF-2 in inflammatory cells, the role of the FGF-2/FGFR axis in mouse models of lung fibrosis remains unclear.…”

“…Ju et al reported that the administration of soluble FGFR2c ectodomain significantly reduces the extent of lung fibrosis in TGF-β-induced lung fibrosis mice [58]. However, Guzy et al recently reported that Fgf2 À/À mice show increased mortality due to epithelial injury induced by BLM without any effects on lung fibrosis [57]. At present, it is not possible to draw firm conclusions regarding the role of FGF-2 in the pathogenesis of pulmonary fibrosis in mice or in humans.…”