Neutrophil elastase in the development of nephrogenic systemic fibrosis (NSF)-like skin lesion in renal failure mouse model

by A. Adhipatria P. Kartamihardja, Syahla Nisaa Amalia, Akiko Sekiguchi, Anu Bhattarai, Ayako Taketomi-Takahashi, Sei-ichiro Motegi, Hiroshi Koyama, Yoshito Tsushima

Although neutrophil elastase (NE) may play a role in lung fibrosis and liver fibrosis, NE involvement in the development of nephrogenic systemic fibrosis has been unclear. We investigated the involvement of NE in the development of nephrogenic systemic fibrosis-like skin lesions post-injections of linear gadolinium-based contrast agents in renal failure mouse models. Renal failure mouse models were randomly divided into three groups: control group (saline), gadodiamide group, and gadopentetate group. Each solution was intravenously administered three times per week for three weeks. The mice were observed daily for skin lesions. Quantification of skin lesions, infiltrating inflammatory cells, and profibrotic cytokines in the affected skin was performed by immunostaining and reverse-transcription polymerase chain reaction (RT-PCR). Blood samples were collected from the facial vein to quantify NE enzymatic activity. The ¹⁵⁸Gd concentrations in each sample were quantified using inductively coupled plasma mass spectrometry (ICP-MS). In the gadodiamide group, the mRNA expression of fibrotic markers was increased in the skin lesions compared to the control group. In the gadopentetate group, only collagen 1α and TGF-β mRNA expression were higher than in the control group. The expression of CD3+, CD68+, NE cells and the NE activity in the blood serum were significantly higher in the gadodiamide and gadopentetate groups compared to the control group. Gadolinium concentration in the skin of the gadodiamide group was significantly higher than the gadopentetate group, while almost no traces of gadolinium were found in the control group. Although gadopentetate and gadodiamide affected the fibrotic markers in the skin differently, NE may be involved in the development of fibrosis linked to the GBCAs injections in renal failure mouse models.