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

Abstract

Silica nanoparticles (SiNPs) are widely used as drug carriers for improving drug delivery and retention. The lungs are highly sensitive to the 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 SiNP-induced pulmonary toxicity on lymphatic vessel formation in rats and evaluated the toxicity and possible molecular mechanisms of 20-nm SiNPs. Saline containing 3.0, 6.0, and 12.0 mg/kg of SiNPs was instilled intrathecally into female Wistar rats once a day for five days, then sacrificed on day seven. 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. We observed increased pulmonary inflammation and permeability, lymphatic endothelial cell damage, pulmonary lymphangiogenesis, and remodeling with increasing SiNP concentration. Moreover, SiNPs activated the VEGFC/D-VEGFR3 signaling pathway in the lung and lymphatic vessel tissues. SiNPs caused pulmonary damage, increased permeability and resulted in inflammation-associated lymphangiogenesis and remodeling by activating VEGFC/D-VEGFR3 signaling. Our findings provide evidence for SiNP-induced pulmonary damage and a new perspective for the prevention and treatment of occupational exposure to SiNPs.

Keywords: Inflammation-associated lymphangiogenesis; Lymphatic endothelial cell damage; Lymphatic vessel remodelling; Nano-silica; Pulmonary permeability.