Transduction of pulmonary fibrosis-associated mutant surfactant protein C (SFPTC<sup>Δexon4</sup>) into AEC2 revealed characteristic transcriptional traits similar to those of patients with idiopathic pulmonary fibrosis.
We have previously shown that targeting the type II alveolar epithelium for injury by repetitively administering diphtheria toxin to transgenic mice expressing the diphtheria toxin receptor off of the surfactant protein C promoter (SPC-DTR) develop lung fibrosis, confirming that AEC injury is sufficient to cause fibrosis.
These data provide proof of principle that mutant SP-C expression in vivo causes spontaneous lung fibrosis, strengthening the role of AT2 cell dysfunction as a key upstream driver of IPF pathogenesis.
Although mutant forms of the gene encoding surfactant protein C (SFTPC) have been linked to interstitial lung disease, the mechanisms by which the most common of these mutations, SFTPCI73T, results in lung fibrosis are uncertain.In this issue of the JCI, Nureki et al. developed a knockin mouse model and showed that SFTPCI73T is expressed by alveolar type II (AT2) epithelial cells in the lungs.
Here we show in humans that MUC5B, a mucin thought to be restricted to conducting airways, is co-expressed with surfactant protein C (SFTPC) in type 2 alveolar epithelia and in epithelial cells lining honeycomb cysts, indicating that cell types involved in lung fibrosis in distal airspace express MUC5B.
Surfactant protein C mutations are dominant or sporadic disorders leading to a broad spectrum of manifestations from neonatal respiratory distress syndrome to adult pulmonary fibrosis.
The mutation increases endoplasmic reticulum stress and induces apoptotic cell death compared with wild-type SP-C in alveolar type II cells, supporting the significance of this mutation in the pathogenesis of pulmonary fibrosis.
Genetic studies in familial lung fibrosis have demonstrated an association with surfactant protein C genes: two mutations have been found resulting in protein misfolding and causing type-II epithelial cell injury.
The genomic DNA of the affected brothers was sequenced for the reported surfactant protein C (SP-C) gene mutations in patients with familial pulmonary fibrosis, but none was documented.
Recent reports have linked genetic mutations in surfactant protein C (SFTPC) with familial forms of pulmonary fibrosis, including one large family in which a number of family members were diagnosed with usual interstitial pneumonitis (UIP), the pathological correlate to IPF.
Transgenic mice expressing transforming growth factor alpha (TGF-alpha) in type II cells under control of the lung-specific surfactant protein-C (SP-C) promoter develop pulmonary fibrosis and marked airspace hypoplasia.