Abstract Pulmonary fibrosis is a progressive disease, characterized by the emergence of aberrant cell type and molecular signaling activation. The treatment option for this disease is very limited, and these options are only for halting disease progression with no cure. Therefore, there’s a critical need for new and effective therapies. Our recent study identifies the novel role of Serine peptidase inhibitor Kazal type 1 (SPINK1), a small, secreted protein known as pancreatic secretory trypsin inhibitor, in the pathogenesis of pulmonary fibrosis. From large-scale single-cell RNA sequencing study, we observed selective upregulation of SPINK1 in the pathological cell types, including aberrant basaloid cells (ABCs) and monocyte-derived macrophages (MoMs). In addition to its activation in aberrant cell types, our spatial transcriptomes demonstrated that SPINK1 is co-localized with myofibroblasts within the fibrotic foci of affected lungs, indicating its physical interaction of collagen-production cell types toward the profibrotic development. In our in vivo model, we administered recombinant SPINK1 intra-tracheally in murine models, which resulted in marked collagen deposition and histopathological remodeling. Our investigation further revealed that SPINK1 promotes fibrosis by reprogramming the gene signature within stromal cells. Ex vivo human precision-cut lung slice (PCLS) validated our bioinformatics discovery and in vivo mouse findings. We observed that the treatment of SPINK1 triggered profibrotic progression, with increased collagen accumulation and fibroblast activation. Finally, our in vitro studies revealed the activated molecular signaling activation mediated by SPINK1. We found that SPINK1 can promote fibroblast-to-myofibroblast differentiation and induces EGFR-dependent signaling cascades, which further contributes to the fibrogenic remodeling. Our research findings uncover SPINK1, as an important molecular contributor to pulmonary fibrosis, and by targeting SPINK1-EGFR signaling may offer promising therapeutic target for the treatment of fibrotic lung disease. This abstract is funded by: NIH
Hossain et al. (Fri,) studied this question.