Silica nanoparticles induce pulmonary damage in rats via VEGFC/D–VEGFR3 signaling-mediated lymphangiogenesis and remodeling

Abstract

Abstract Background Silica nanoparticles (SiNPs) are widely used as drug carriers for improving drug delivery and retention. The lungs are highly sensitive to toxicity of SiNPs entering the respiratory tract. Furthermore, pulmonary lymphangiogenesis, which is the growth of lymphatic vessels observed during multiple pulmonary diseases, plays a vital role in promoting the lymphatic transport of silica in the lungs. However, more research is required on the effects of SiNPs on pulmonary lymphangiogenesis. We investigated the effect of SiNPs-induced pulmonary toxicity on lymphatic vessel formation in rats and evaluated the toxicity and possible molecular mechanisms of 20-nm SiNPs. Female Wistar rats were instilled intratracheally with saline containing 3.0, 6.0, and 12.0 mg/kg of SiNPs once a day for 5 days, then sacrificed on day 7. Lung histopathology, pulmonary permeability, pulmonary lymphatic vessel density changes, and the ultrastructure of the lymph trunk were investigated using light microscopy, spectrophotometry, immunofluorescence, and transmission electron microscopy. CD45 expression in lung tissues was determined using immunohistochemical staining, and protein expression in the lung and lymph trunk was quantified using western blotting. Results We observed increased pulmonary inflammation and permeability, lymphatic endothelial cell damage, pulmonary lymphangiogenesis, and remodeling with increasing SiNPs concentration. Moreover, SiNPs activated the VEGFC/D–VEGFR3 signaling pathway in the lung and lymphatic vessel tissues. Conclusions SiNPs result in inflammation-associated lymphangiogenesis and remodeling, further pulmonary damage, and increased permeability by activating VEGFC/D–VEGFR3 signaling. Our findings provide evidence for SiNPs-induced pulmonary damage and a new perspective for the prevention and treatment of occupational exposure to SiNPs.