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Iron-induced oxidative stress alters the transcriptome of bronchoalveolar lavage cells in silicosis

ABSTRACT: Elevated iron levels are observed in silicosis patients, leading alveolar macrophages to increase ferritin production in response to this cellular stress. Our study employed a multi-omic approach to investigate how excess iron/ferritin influences the molecular profile of bronchoalveolar lavage (BAL) cells. Thirty-one participants were included, with RNA sequencing conducted on BAL cells from stone benchtop industry workers diagnosed with simple or complicated silicosis, compared to a cohort with no disease. BAL fluid (BALF) was analysed using gas chromatography-mass spectrometry (GC-MS) to screen for 498 volatile organic compounds (VOCs). Compared to no disease, simple silicosis showed 172 differentially expressed genes (DEGs), while complicated silicosis displayed 531 DEGs. Spearman correlation analysis revealed 1072 genes significantly positively association with BALF ferritin. Gene set variation analysis revealed upregulation in glutathione metabolism pathways in BAL cells, including ferroptosis repressor genes (GCLC/GCLM, GSR, SLC7A11, TXNRD1, and AIFM2). In the BALF, 116 VOCs were detected, with 4 showing reduced levels in silicosis patients, independent of smoking status. Notably, the abundance of these VOCs exhibited an inverse association with ferritin levels. In summary, antioxidant defence pathways, incorporating genes that encode proteins to prevent ferroptosis, an iron-dependent non-apoptotic form of cell death, are upregulated in BAL from silicosis patients. Excess iron/ferritin was also associated with a reduction in multiple VOCs present in BALF, which may reflect their oxidative metabolism. We propose that BAL macrophages loaded with iron experience oxidative stress, leading to the activation of an anti-ferroptotic gene network that prolongs the survival of this dysfunctional BAL cell population.

ORGANISM(S): Homo sapiens

PROVIDER: GSE264182 | GEO | 2024/12/31

REPOSITORIES: GEO

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Project description:Sepsis-associated acute kidney injury (SA-AKI) is a key contributor to the life threatening sequalae attributed to sepsis. Mechanistically, SA-AKI is a consequence of unabated myeloid cell activation and oxidative stress that induces tubular injury. Iron mediates inflammatory pathways directly and through regulating the expression of myeloid-derived ferritin, an iron storage protein comprised of ferritin light (FtL) and ferritin heavy chain (FtH) subunits. Previous work revealed myeloid FtH deletion leads to a compensatory increase in intracellular and circulating FtL and is associated with amelioration of SA-AKI. We designed this study to test the hypothesis that loss of myeloid FtL and subsequently, circulating FtL will exacerbate the sepsis-induced inflammatory response and worsen SA-AKI. We generated a novel myeloid-specific FtL knockout mouse (FtLLysM-/-) and induced sepsis via cecal ligation and puncture or lipopolysaccharide endotoxemia. As expected, serum ferritin levels were significantly lower in the knockout mice, suggesting that myeloid cells dominantly contribute to circulating ferritin. Interestingly, while sepsis induction led to a marked production of pro- and anti-inflammatory cytokines, there was no statistical difference between the genotypes. There was a similar loss of kidney function, as evident by a rise in serum creatinine and cystatin C, and renal injury identified by expression of kidney injury molecule-1 and neutrophil gelatinase associated lipocalin. Finally, RNA sequencing revealed upregulation of pathways for cell cycle arrest and autophagy post-sepsis, but no significant differences were observed between genotypes, including in key genes associated with ferroptosis, an iron-mediated form of cell death. The loss of FtL did not impact sepsis-mediated activation of NFkB or HIF-1a signaling, key inflammatory pathways associated with dysregulated host response. Taken together, while FtL overexpression was shown to be protective against sepsis, loss of FtL did not influence sepsis pathogenesis.

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Iron-induced oxidative stress alters the transcriptome of bronchoalveolar lavage cells in silicosis

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