Mechanisms of Increased Lung Fibrosis in Males

描述(申请人提供)：系统性硬化症相关性间质性肺疾病(SSC-ILD)是一种慢性炎症性疾病，以包括肺在内的多个器官的严重纤维化为特征。SSc在女性中比在男性中更常见；然而，男性经历了一种加速的疾病，存活率降低。博莱霉素诱导的肺纤维化在雄性小鼠中也比雌性小鼠更严重。SSc易感性或损害的性别差异背后的机制仍然知之甚少。这一建议是由我们的动物模型观察到的，与具有XY性染色体补充的小鼠相比，无论性别如何，具有XX性染色体补充的小鼠比具有XY性染色体补充的小鼠表现出更高的系统性炎症疾病的易感性。有趣的是，具有XY性染色体互补的雄性和雌性小鼠都比具有XX性染色体互补的小鼠发展出更严重的纤维化。XY小鼠纤维化的增加与IL-13增加和IL-13RA2表达减少有关，IL-13RA2是IL-13的诱饵受体。IL-13RA2基因位于X染色体上。因此，与XX小鼠相比，免疫的XY小鼠降低了IL-13RA2的表达，导致与纤维化有关的IL-13的增加。这些数据表明，X染色体基因剂量可能在调节炎症性疾病的易感性和损害方面发挥作用。利用上述小鼠模型，我们将检验这样的假设，即无论性腺性别如何，XY性染色体互补都会增加肺纤维化和SSC-ILD的风险。具体地说，我们将测试携带XY性染色体基因的小鼠的博莱霉素诱导的肺纤维化是否比携带XX性染色体基因的小鼠更严重(目标1)。在这项提案的目标2中，我们将开始将这一发现转化为人类。具体地说，我们将确定X染色体编码基因的表达，并寻找它们与SSC患者纤维化的相关性。利用血液和支气管肺泡灌洗(BAL)，我们将检验X染色体编码基因IL13RA2在这些样本中的表达水平将与SSC-ILD的严重程度负相关的假设。潜在的理论基础是，男性只有一份IL13RA2拷贝，因此，IL-13RA2的水平可能低于女性。由于IL-13RA2作为2型细胞因子的诱饵受体，男性在炎症部位的2型细胞因子水平可能高于女性。2型细胞因子可以诱导TGFb的产生，从而诱导纤维化。因此，虽然2型细胞因子和TGFb都可以诱导免疫调节，降低自身免疫和炎症的初始易感性，但这些细胞因子过量会导致男性失调的组织修复、纤维化和器官损伤。所获得的发现将为进一步的研究奠定基础，以建立男性SSc进展加速的生物标记物，并确定SSc-ILD和其他以过度纤维化为特征的疾病的治疗新靶点。(摘要结束)

DESCRIPTION (provided by applicant): Systemic sclerosis associated interstitial lung disease (SSc-ILD) is a chronic inflammatory condition characterized by severe fibrosis in multiple organs including lungs. SSc is more common in women than in men; however men experience an accelerated disease with reduced survival. Bleomycin-induced lung fibrosis is also more severe in male mice than in females. Mechanisms underlying such sex differences in susceptibility to or damage from SSc remain poorly understood. This proposal is guided by our animal model observations that mice with XX sex chromosome complement exhibit increased susceptibility to the development of systemic inflammatory disease as compared to mice with XY sex chromosome complement, regardless of the gender. Intriguingly, both male and female mice with XY sex chromosome complement develop a more severe fibrosis than mice with XX sex chromosome complement. The increased fibrosis in XY mice is associated with increased IL-13 and reduced expression of IL-13RA2, a decoy receptor for IL-13. The gene for IL-13RA2 is located on X chromosome. Thus, compared to XX mice, the immunized XY mice have reduced expression of IL-13RA2, leading to increased IL-13 that has been implicated in fibrosis. These data suggest a possible role of X chromosome gene dosage in modulating susceptibility to and damage from inflammatory diseases. Using the above mouse model, we will test the hypothesis that regardless of the gonadal sex, XY sex chromosome complement confers a greater risk for lung fibrosis and SSc-ILD. Specifically, we will test whether bleomycin induced lung fibrosis is more severe in mice with XY sex chromosome genotype than in mice with XX sex chromosome genotype (Aim 1). In Aim 2 of this proposal, we will begin to translate the finding onto humans. Specifically, we will determine the expression of X chromosome encoded genes and seek their correlation with fibrosis in patients with SSc. Using blood and bronchoalveolar lavage (BAL), we will test the hypothesis that expression levels of an X chromosome-encoded gene, IL13RA2, in these samples will negatively correlate with the severity of SSc-ILD. The underlying rationale is that men have one copy of IL13RA2 and thus, may have lower levels of IL-13RA2 than women. Since IL-13RA2 serves as a decoy receptor for type 2 cytokines, men are likely to have higher levels of type 2 cytokines than women at the site of inflammation. Type 2 cytokines can induce the production of TGFb that can induce fibrosis. Thus, while both type 2 cytokines and TGFb can induce immune regulation and reduce the initial susceptibility for autoimmunity and inflammation, excess of these cytokines can cause dysregulated tissue repair, fibrosis and organ damage in men. The findings obtained will form the basis for further studies to establish biomarkers of accelerated SSc progression in men and to identify new targets of treatment for SSc-ILD and other diseases that are characterized by excessive fibrosis. (End of Abstract)