Exposure to silica dust may trigger pulmonary fibrosis (PF) because silica particles block a self-cleansing process used by cells, termed autophagy, which drives cell death in the lungs, a study using both human cells and mice showed.
Researchers say the findings may improve our understanding of how silica-induced PF emerges, and how molecular targets might reverse it.
The study, “Autophagic flux blockage in alveolar epithelial cells is essential in silica nanoparticle-induced pulmonary fibrosis” was published in the journal Cell Death & Disease.
In many cases, patients who develop PF had been exposed to inorganic dusts, including asbestos, silica, coal dust, beryllium, or hard metal dusts.
Inhalation of tiny silica particles freed up during drilling, crushing, loading, and dumping can cause lung disease, including PF. People with occupations including construction, sandblasting, and mining are particularly at risk.
Studies have suggested that silica particles can activate autophagy in alveolar epithelial cells (AECs). Derived from the Greek words meaning “self-eating”, autophagy is a natural mechanism used by cells to deliver malfunctioning or damaged cellular components for destruction in acidic vesicles called lysosomes.
To better understand the role of autophagy in PF triggered by silica, researchers exposed lab-cultured human lung cells, AECs, and mice to very small particles, or nanoparticles, of silica.
They saw that when these tiny particles entered lung cells, the autophagy process was interrupted, causing programmed cell death — a process called apoptosis. The increase in lung cell death is what is thought to lead to PF development.
Researchers found that the entry of silica nanoparticles inside cells stunted the degradation (“trashing”) capacity of the autophagy system, because it prevented the acidification of lysosomes. These vesicles need an acidic pH to activate the enzymes that chew up the unwanted materials.
However, researchers were able to reverse this effect in cells by applying agents (namely cAMP and rapamycin) that promote the reacidification of autophagic vesicles and normalize the autophagy flow, protecting cells from dying.
A similar result was seen in mice. In animals exposed to silica nanoparticles, rapamycin treatment enhanced autophagy and attenuated PF signs. Specifically, it restored lung function and reduced collagen accumulation in the lungs, indicative of less lung scarring.
Overall, the results demonstrated that defective lung cell autophagy is involved in the development of PF induced by silica particles. Researchers showed that this defect can be rescued by using agents that re-establish the acidification of autophagic vesicles and their degradation capacity.
“Altogether, our data demonstrate a repressive effect of silica nanoparticles [SiNPs] on lysosomal acidification, contributing to the decreased autophagic degradation in AECs, thus leading to apoptosis and subsequent PF,” the researchers said, adding that the findings “may provide an improved understanding of SiNPs-induced PF and molecular targets to antagonize it.”