MSC-Secreted KGF Repairs Lung Injury Through a Novel Gab1/ERK/NF-κB Signaling Chain

Acute lung injury (ALI) and its severe form ARDS carry high mortality and are characterized by alveolar epithelial damage, inflammatory fluid accumulation, and impaired alveolar fluid clearance (AFC). The epithelial sodium channel (ENaC) on alveolar type 2 (AT2) cells governs this fluid reabsorption, and its dysfunction is central to pulmonary edema. Mesenchymal stem cells (MSCs) have shown promise in treating ALI, but the precise paracrine mechanisms driving their benefit have remained incompletely understood.

This study systematically investigated how KGF secreted by bone marrow-derived MSCs protects against LPS-induced ALI. In primary mouse AT2 cells, LPS reduced levels of the scaffolding protein Gab1 and ENaC (α and γ subunits) while activating ERK and NF-κB signaling. KGF treatment reversed all these effects. Using the ERK inhibitor PD98059, the team showed that ERK acts downstream of Gab1 and upstream of NF-κB, with Gab1 serving as a critical node linking KGF receptor activation to downstream inflammatory suppression.

Mechanistically, LPS weakened the binding of NF-κB p65 to its inhibitor IκB, promoting p65 nuclear translocation and suppressing ENaC transcription. KGF — and the NF-κB inhibitor QNZ — each independently restored the p65/IκB interaction, blocked nuclear translocation of p65, and rescued ENaC protein and mRNA expression. ENaC functional activity was confirmed using amiloride-sensitive currents in Ussing chambers and airway surface liquid height measurements, both of which were reduced by LPS and restored by KGF.

In co-culture experiments, MSCs suppressed ERK/NF-κB activation and restored Gab1 and ENaC levels in LPS-treated AT2 cells. MSCs with KGF knocked down (MSC-siKGF) lost most of this benefit, confirming KGF as the dominant paracrine effector. In the mouse ALI model, tail-vein-injected MSCs significantly improved lung histology, reduced wet/dry weight ratios, and enhanced AFC. MSC-siKGF was markedly less effective, but combining MSC-siKGF with QNZ partially rescued the therapeutic effect, indicating that the KGF/Gab1/ERK/NF-κB axis is the primary but not sole mechanism.

These findings establish a detailed molecular roadmap — KGF → Gab1 → ERK inhibition → NF-κB suppression → ENaC upregulation — by which MSC-secreted KGF combats pulmonary edema, offering both mechanistic clarity and potential therapeutic targets for ALI/ARDS.