3.6 Blood calcium levels are negatively correlated with the
severity of PQ poisoning in patients
As lysine suppresses PQ-induced pulmonary fibrosis by reducing
STIM1-TRPC1 axis increased intracellular calcium levels and EMT process,
we considered intracellular calcium homeostasis was critical for
maintaining normal pulmonary functions. To further confirmed the
importance of calcium signal during PQ-raised pulmonary fibrosis, we
turned our sights into the clinical records. By carefully analyzing the
laboratory blood tests, we found that the blood calcium levels of
PQ-poisoned patients were significantly decreased compared to healthy
volunteers. Further analysis revealed a negative correlation between the
calcium levels and the PQ concentrations in blood (Fig. 5A&B).
Importantly, no significant correlation was observed in potassium,
sodium, or chlorine (Fig. 5C-E). We further tracked the records of each
patient with little poisoning. These patients exhibited continuous
reduction of blood calcium levels during the malignant progression
indicated by the increased blood creatinine levels. Intriguingly, the
blood calcium levels were restored, yet not fully, when patients were
recovered from PQ poisoning indicated by the reduction of blood
creatinine levels into normal range (Fig. 5F). Whereas, patients
suffering high amount of PQ poisoning died accompanied with extremely
high creatinine levels and low blood calcium levels (Fig. 5G). The
reduction of blood calcium levels in PQ-poisoned patients could be due
to multiple reasons, from which one of the possibilities could be due to
the large usage of extracellular calcium pools by STIM1-mediated calcium
entry as we previously reported (Yang et al., 2022). To address this
possibility, we analyzed the blood calcium levels in two PQ-poisoned
animal models with or without lysine treatment, and found that
PQ-poisoned mice exhibited a significant reduction of blood calcium
levels, which was dramatically restored by lysine treatment (Fig. 5H).
Consistent with the observations in PQ-poisoned mice model, lysine
treatment impressively alleviated the reduction of blood calcium levels
in the PQ-poisoned cynomolgus model (Fig. 5I). Interestingly,
PQ-poisoned group exhibited a recovery of blood calcium levels during
daytime in the second and third days, which might be ascribed to a
feedback regulation of blood calcium levels due to calcium absorption in
the gut and calcium reabsorption in the kidney. Nevertheless, these
results indicated the potential functions of calcium signaling in
modulation of the pathogenesis in PQ-raised toxicity and pulmonary
fibrosis.