3.1 SKF treatment exhibits poor efficacy on treating PQ
poisoning induced pulmonary fibrosis
We recently identified STIM1 as another molecular target of PQ, which
results in intracellular calcium burden and EMT in AT II cells(Yang et
al., 2022). Hence, we assumed that inhibition of calcium influx mediated
by STIM1 would be a potential strategy for treating PQ toxicity and
pulmonary fibrosis. We therefore examined the efficacy of SKF96365
(SKF), a SOCE inhibitor and a TRP channel blocker, in treating
PQ-poisoned mice. As shown in Fig. 1A, consistent with previous reports,
PQ significantly induces the production of hydroxyprolin, a product of
collagen degradation acting as one of the parameters for reflecting the
severity of pulmonary fibrosis (Spagnolo et al., 2020), which was
impressively reduced with SKF co-treatment (Fig. 1A). However, SKF
treatment did not improve the survival rate of PQ poisoning. All the
mice either in the PQ group or the PQ + SKF group died with a similar
rate (data not shown). Moreover, we further monitored the morphological
change of lungs in the survived mice by H&E staining and Masson
staining, and found severe pulmonary fibrosis in the PQ-poisoned mice
either with or without SKF co-treatment (Fig. 1B). Note, it seemed that
SKF alone would lead to sort of pulmonary fibrosis, indicating that both
intracellular calcium burden or calcium deficiency would be harmful to
lung homeostasis. Consistently, PQ-poisoned mice exhibited gradual
weight loss following the progression of the disease, which was not well
alleviated by SKF, yet SKF treatment showed a temporary remission in day
1 (Fig. 1C). Taken together, these observations suggested that SKF was
not sufficient to reverse PQ toxicity and pulmonary fibrosis, yet with a
reduction in hydroxyproline production.