Loss of PKN2 drives fibroblast reprogramming and extracellular matrix remodelling in pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease marked by abnormal fibroblast behavior, extracellular matrix (ECM) remodeling, and impaired tissue repair. Protein kinase N2 (PKN2) has been linked to rapid decline in forced vital capacity in IPF patients, yet the exact role of PKN2 in pulmonary fibrosis is unclear. Researchers proposed that PKN2 regulates fibroblast phenotype and tissue repair.

To investigate the function of PKN2, scientists examined PKN2 expression in human lung tissue, induced sputum, and primary airway and parenchymal fibroblasts taken from non-fibrotic controls and IPF patients. DNA methylation was analyzed using the Illumina HumanMethylationEPIC array. PKN2 function was studied through siRNA-mediated depletion in primary human lung fibroblasts, along with transcriptomic, proteomic, and functional analyses. The impact of PKN2 inhibition on tissue repair was also assessed in zebrafish.

Results indicated that PKN2 expression was lower in IPF lung tissue and primary airway and parenchymal fibroblasts, and was further decreased by TGF-{beta}1. Additionally, differential methylation was found across the PKN2 locus in both fibroblast populations. Integrated transcriptomic and proteomic profiling following PKN2 depletion revealed coordinated remodeling of ECM, cell adhesion, non-canonical WNT, and VEGF pathways.

These changes included dysregulation of COL1A1, WNT, VEGF, and MMP1. PKN2 loss led to increased secretion of VEGF and MMP-1, as well as accelerated fibroblast wound closure. Moreover, PKN inhibition altered epithelial organization and collagen fibre alignment during zebrafish wound repair.

In conclusion, the loss of PKN2 drives fibroblast reprogramming and aberrant ECM remodeling, establishing PKN2 as a crucial regulator of pulmonary fibroblast homeostasis and tissue repair.