Abstract
Background and Purpose Pulmonary fibrosis (PF) is an irreversible lung
disease with little efficient treatments. Epithelial-mesenchymal
transition (EMT) in alveolar type II (AT II) cells is an initial process
for PF in response to multiple insults. We previously identified
paraquat (PQ), inducing acute lung injury and PF, as an agonist for
STIM1, promoting STIM1-TRPC1 association for intracellular calcium
burden and thus EMT. Here, we investigated the strategy targeting
STIM1-TRPC1 association and excessive calcium influx in treating PF.
Experimental approach Co-immunoprecipitation was for STIM1-TRPC1
association analysis. Western blotting and Real-time quantitative
reverse transcription PCR (QPCR) were for EMT analysis. Calcium imaging,
flow cytometry, and luciferase report assay were for analyzing calcium
signaling. ELISA, histomorphology, and PQ-poisoned mice or cynomolgus
model were for evaluating the efficacy of lysine in treating PF.
Retrospective analysis was for analyzing the correlation between the
severity of PQ poisoning and blood calcium levels. Key Results Lysine
treatment significantly reduces PQ-raised STIM1-TRPC1 association,
excessive calcium influx, and thus EMT in AT II cells. As a result,
lysine treatment strikingly decreases the mortality of PQ-poisoned mice,
with a fully recovery of PQ-induced PF. Immune cells activation, largely
occurred accompanied with epithelial damages and PF, are almost
normalized with lysine treatment in PQ-poisoned cynomolgus model. A
negative correlation between the blood calcium levels and the prognosis
were observed in PQ-poisoned patients. Conclusions and Implications
These results demonstrate lysine as a potential antidote for PQ-induced
PF and provide evidence for maintaining calcium homeostasis as a
potential strategy for treating PF.