Limiting the intracellular calcium accumulation alleviates fibroblast senescence and pulmonary fibrosis.

Abstract

Activation of specific calcium regulators, along with their downstream intracellular calcium signaling pathways has been established as a hallmark feature of cellular senescence. Nevertheless, alternations in intracellular free calcium concentration and the functional consequences thereof during cellular senescence and age-related diseases remain incompletely understood, particularly in fibroblasts. In this study, we measured intracellular calcium levels during senescence and observed a significant increase. Subsequently, chelation of intracellular calcium accumulation induced by senescence stimuli effectively delayed not only calcium elevation, but also reactive oxygen species (ROS) accumulation, DNA damage and fibroblast senescence. In vivo experiments demonstrated that intraperitoneal administration of the calcium chelator BAPTA-AM (BAPTA) markedly alleviated the pulmonary fibrosis phenotypes, as evidenced by attenuated loss of body weight, reduced infiltration of inflammatory cells, decreased collagen deposition and diminished expression of both fibrosis and senescence markers. Notably, transcriptomic analysis of fibrotic lung tissues revealed that BAPTA treatment significantly suppressed the senescence associated secretory phenotype (SASP). Collectively, our findings indicate that restriction of the intracellular calcium accumulation upon senescence triggers can mitigate fibroblast senescence and ameliorate pulmonary fibrosis, thereby highlighting the therapeutic potential of calcium chelators in age-associated pathologies.