Sftpc-KO Mouse

Sftpc, encoding surfactant protein C, is crucial for alveolar homeostasis. It is synthesized by alveolar epithelial type 2 cells (AEC2s) and plays a vital role in surfactant function, which is essential for maintaining normal lung compliance and preventing alveolar collapse. Dysfunction in Sftpc-related processes can lead to various lung diseases [1,2,3,4].

Patient-specific induced pluripotent stem cells (iPSCs) carrying an Sftpc mutation (SFTPCI73T) have been used to model interstitial lung disease (ILD). Mutant iAEC2s show misprocessed and mistrafficked pro-SFTPC protein, diminished AEC2 progenitor capacity, perturbed proteostasis, altered bioenergetic programs, metabolic reprogramming, and NF-κB pathway activation. Treatment with hydroxychloroquine, a pediatric ILD medication, exacerbates these perturbations [1]. In addition, a knockin mouse model expressing a cysteine-to-glycine substitution (C121G) in the Sftpc gene revealed that SftpcC121G expression during fetal development caused fatal postnatal respiratory failure, while induced expression in adult mice led to ER-retained pro-protein, AT2 cell ER stress, polycellular alveolitis, and eventually spontaneous pulmonary fibrosis and restrictive lung impairment [4].

In conclusion, Sftpc is essential for maintaining normal lung function, especially in the context of alveolar homeostasis. The use of genetic models, such as patient-specific iPSCs and knockin mouse models, has provided valuable insights into the role of Sftpc in the pathogenesis of ILD, highlighting its significance in understanding and potentially treating these lung diseases.