Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, United States of America.
Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, United States of America.
Toxicol Appl Pharmacol. 2022 Nov 1;454:116228. doi: 10.1016/j.taap.2022.116228. Epub 2022 Sep 8.
Idiopathic pulmonary fibrosis, a condition with likely genetic and environmental etiology, is relatively more prevalent with poor prognosis in human males. However, the underlying mechanisms for these gender-associated differences in the severity of fibrosis remain unknown. Here, we tested the hypothesis that the transcriptomic repertoire of myeloid cells determines the higher susceptibility of male mice to bleomycin (BLM)-induced lung fibrosis. Adult mice were oropharyngeally challenged with saline or BLM. Lung injury, inflammation, and fibrosis outcomes were assessed, and airspace myeloid-cells were subjected to RNA-sequencing. As compared with the female mice, the male mice manifested significantly increased lung injury, inflammation, proinflammatory cytokines (IL-6, IL-1β, IL-7, and IP-10), and fibrosis in response to BLM challenge. Interestingly, several pro-inflammatory and extracellular matrix-associated genes were significantly up-regulated in male myeloid-cells compared to female myeloid-cells in the saline-control group. Similarly, BLM challenge resulted in greater pro-inflammatory and pro-fibrotic transcriptomic changes in male compared to female myeloid cells. On the other hand, anti-inflammatory and regulatory cytokine, Il10 and Ifng respectively, were uniquely upregulated in BLM-challenged female but not in male myeloid cells when compared to their respective saline-control groups. Further, cross-sex bone marrow transplantation experiments revealed that male hematopoietic progenitor cells (HPCs) increased the granulocytic infiltration in female mice while female HPCs decreased the granulocytic infiltration in male mice post-BLM challenge. These findings suggest that there are inherent transcriptomic differences between the male and female lung myeloid cells and that the pro-inflammatory nature of male myeloid cells is sufficient to increase the susceptibility of female mice to BLM-induced inflammation.
特发性肺纤维化是一种具有遗传和环境病因的疾病，在男性中更为常见，预后较差。然而，纤维化严重程度的这些性别相关差异的潜在机制尚不清楚。在这里，我们检验了这样一个假设，即髓系细胞的转录组谱决定了雄性小鼠对博莱霉素（BLM）诱导的肺纤维化的更高易感性。成年小鼠经口咽给予盐水或 BLM 挑战。评估肺损伤、炎症和纤维化结果，并对气道髓系细胞进行 RNA 测序。与雌性小鼠相比，雄性小鼠在 BLM 挑战后表现出明显增加的肺损伤、炎症、促炎细胞因子（IL-6、IL-1β、IL-7 和 IP-10）和纤维化。有趣的是，与雌性髓系细胞相比，在盐水对照组中，雄性髓系细胞中的几种促炎和细胞外基质相关基因显著上调。同样，BLM 挑战导致雄性髓系细胞中促炎和促纤维化的转录组变化明显大于雌性髓系细胞。另一方面，与 BLM 处理的雄性髓系细胞相比，抗炎和调节性细胞因子 Il10 和 Ifng 分别在 BLM 处理的雌性髓系细胞中特异性上调，而不是在其各自的盐水对照组中上调。此外，交叉性别骨髓移植实验表明，雄性造血祖细胞（HPC）增加了 BLM 后雌性小鼠的粒细胞浸润，而雌性 HPC 则减少了雄性小鼠的粒细胞浸润。这些发现表明，雄性和雌性肺髓系细胞之间存在固有转录组差异，并且雄性髓系细胞的促炎性质足以增加雌性小鼠对 BLM 诱导的炎症的易感性。
