Fibroblast‐specific perturbation of transforming growth factor β signaling provides insight into potential pathogenic mechanisms of scleroderma‐associated lung fibrosis: Exaggerated response to alveolar epithelial injury in a novel mouse model

Abstract

Objective. To explore increased susceptibility to fibrosis following experimental injury to alveolar epithelial cells (AECs) in a novel transgenic mouse model of scleroderma with fibroblast-specific perturbation of transforming growth factor ␤ (TGF␤) signaling (T␤RII⌬k-fib mice).Methods. Wild-type (WT) and transgenic mice were injured with intratracheally administered saline or bleomycin, and the lungs were harvested for biochemical, histologic, and electron microscopic analysis.Results. Electron microscopy revealed AEC abnormalities in the lungs of untreated transgenic mice and bleomycin-treated WT mice; the lungs of transgenic mice treated with bleomycin showed severe epithelial damage. Compared with lungs from bleomycin-treated WT mice, lungs from bleomycin-treated transgenic mice demonstrated increased fibroproliferation, myofibroblast persistence, and impaired hyperplasia and increased apoptosis of type II AECs. The lungs from saline-treated transgenic mice and those from bleomycin-treated WT mice had phenotypic similarities, suggesting enhanced susceptibility to minor epithelial injury in the transgenic strain. The level of collagen was increased in the lungs from transgenic mice compared with that in the lungs from WT mice after treatment with either bleomycin or saline. Persistent fibrosis in bleomycin-treated transgenic mice was independent of ongoing neutrophil inflammation but was associated with impaired alveolar epithelial repair.Conclusion. These results suggest that in the context of fibroblast-specific perturbation of TGF␤ signaling, even minor epithelial injury induces significant fibrosis. The model supports a central role for TGF␤ in determining fibrosis and demonstrates that lung fibroblasts may regulate the response of AECs to injury. Our findings provide insight into likely pathogenic mechanisms in scleroderma-associated pulmonary fibrosis.

Increased epithelial permeability in pulmonary fibrosis in relation to disease progression

“…Furthermore, epithelial cells are a rich source of a number of profibrotic cytokines, including transforming growth factor (TGF)-b1 [24,25], platelet-derived growth factor [26] and tumour necrosis factor-a [24,27]. More compellingly, in a recent transgenic mouse model of scleroderma [28], even minor epithelial injury was shown to induce significant pulmonary fibrosis, mediated by perturbation of TGF-b signalling, supporting an important pathogenetic role for epithelial injury. Taken together, the current and previous observations suggest that epithelial events are likely to be pathogenetically important in SSc-ILD.…”

Scleroderma pathogenesis: a pivotal role for fibroblasts as effector cells

“…Twenty-five percent of these mice spontaneously develop lung fibrosis, which again recapitulates the disease of SSc. The intratracheal administration of bleomycin to these transgenic mice resulted in an increase in fibroblast proliferation, an increase in myofibro blasts and an increase in type II alveolar epithelial cell apoptosis [41]. In the TβRIIΔk-fib model the transgenic fibroblasts are shown to proliferate more rapidly than wild-type cells, and exhibit an increase in TGF-β markers, including CTGF [42].…”

Interstitial Pneumonia Associated with Connective Tissue Disease: An Overview and an Insight

“…The alveolar epithelial damage and inflammation let resident fibroblasts of pulmonary interstitium to locate to the alveolar wall, and the fibroblasts become activated through a variety of mediators such as TGF-β [145,146]. The activation of resident fibroblasts was shown to be induced by the recruitment of active TGF-β from the lung tissue [147].…”