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Stat-6 signaling pathway and not Interleukin-1 mediates multi-walled carbon nanotube-induced lung fibrosis in mice: insights from an adverse outcome pathway framework [IL1-R1_KO]

ABSTRACT: Five-to-seven week old female wild type C57BL/6 mice (WT) and C57BL/6 mice deficient in IL1-R1 (IL1-R1 KO) were exposed to Mitsui-7, a type of multiwalled nanotube at a dose of 162 µg/mouse by intratracheal administration. Inflammation was assessed 24 h and 28 days following treatment and fibrotic leison was assessed 28 days following treatment. Inflammation was lower in IL1-RI KO mice compared to that observed in the wild type mice at 24h post exposure. This diffrence was no longer observed at 28 days post-exposure. In contrast, STAT6 KO mice showed suppressed inflammation and fibrotic leison at 28 days post-exposure compared to the wild type mice. The results from this study suggest that STAT 6 signaling pathway is essential for multiwalled nanotube induced fibrotic desease.

ORGANISM(S): Mus musculus

PROVIDER: GSE290818 | GEO | 2025/03/03

REPOSITORIES: GEO

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Project description:Recent in vivo studies reported that inhaled carbon nanotube distribute in the alveolar region resulting in an acute inflammation, progressive fibrotic response and particle accumulation at the bronchoalveolar junction with low clearance. With similar biopersistence and shape as asbestos, a known lung carcinogen, growing concern has arisen for elevated risk of carbon nanotube-induced lung carcinogenesis; however few studies have evaluated long-term human health risks associated with chronic pulmonary carbon nanotube exposures compared to asbestos. To address this knowledge gap, we conducted subchronic in vitro exposures of dispersed single walled carbon nanotube, multi-walled carbon nanotube and crocidolite asbestos to human small airway epithelial cells to assess their neoplastic transformation potential. Subchronic single-, multi-walled carbon nanotube and asbestos exposures caused human lung cell neoplastic transformation exhibited by increased proliferation, anchorage-independent growth, invasion and angiogenesis. Whole genome profiling and protein expression analyses showed that carbon nanotube-induced transformation mechanism(s) was largely different from asbestos-related inflammatory signaling, suggesting specific carbon nanotube-induced carcinogenic potential. This study provides novel carbon nanotube and asbestos toxicogenomic information for risk assessment and an in vitro model to evaluate transformation potential of carbon nanotubes and other nanoparticles. Whole genome expression profiling was conducted on human immortalized small airway epithelial cells (SAEC-hTERT) following 6 month in vitro chronic exposure to six separate treatments to assess differences in carbon nanotube (CNT) vs. asbestos potential tumorigenesis signaling. Dispersed single wall CNT (D-SWCNT), multi-wall CNT (D-MWCNT), ultrafine carbon black (D-UFCB), crocidolite asbestos (ASB) and saline (SAL) exposed cells were compared to SurvantaM-BM-. dispersant (DISP) passage control cells. Each treatment possessed 3 biological cDNA replicates. One technical replicate was performed per biological sample.