Mechanisms of Increased Lung Fibrosis in Males

描述（由申请方提供）：系统性硬化症相关间质性肺病（SSc-ILD）是一种慢性炎症性疾病，特征为包括肺在内的多个器官严重纤维化。SSc在女性中比男性更常见;然而，男性经历了加速的疾病，生存率降低。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易感性或损伤的性别差异的潜在机制仍知之甚少。该提议是由我们的动物模型观察结果指导的，即与XY性染色体补体的小鼠相比，具有XX性染色体补体的小鼠表现出对全身性炎症性疾病发展的易感性增加，无论性别如何。有趣的是，具有XY性染色体补体的雄性和雌性小鼠都比具有XX性染色体补体的小鼠发生更严重的纤维化。XY小鼠中增加的纤维化与IL-13增加和IL-13 RA 2（IL-13的诱饵受体）表达减少相关。IL-13 RA 2基因位于X染色体上。因此，与XX小鼠相比，免疫的XY小鼠具有降低的IL-13 RA 2表达，导致与纤维化有关的IL-13增加。这些数据表明，X染色体基因剂量在调节炎症性疾病的易感性和损伤中可能发挥作用。 使用上述小鼠模型，我们将检验以下假设：无论性腺性别如何，XY性染色体补体均赋予肺纤维化和SSc-ILD更大的风险。具体而言，我们将测试博来霉素诱导的肺纤维化在具有XY性染色体基因型的小鼠中是否比在具有XX性染色体基因型的小鼠中更严重（Aim 1）。在本提案的目标2中，我们将开始将这一发现转化到人类身上。具体而言，我们将确定X染色体编码基因的表达，并寻求它们与SSc患者纤维化的相关性。使用血液和支气管肺泡灌洗（BAL），我们将检验以下假设：这些样本中X染色体编码基因IL 13 RA 2的表达水平与SSc-ILD的严重程度呈负相关。基本原理是男性具有一个IL-13 RA 2拷贝，因此可能具有比女性更低的IL-13 RA 2水平。由于IL-13 RA 2作为2型细胞因子的诱饵受体，男性在炎症部位可能比女性具有更高水平的2型细胞因子。2型细胞因子可诱导可诱导纤维化的TGFb的产生。因此，虽然2型细胞因子和TGFb都可以诱导免疫调节并降低自身免疫和炎症的初始易感性，但过量的这些细胞因子可能导致男性组织修复失调，纤维化和器官损伤。获得的结果将为进一步研究奠定基础，以建立男性加速SSc进展的生物标志物，并确定SSc-ILD和其他以过度纤维化为特征的疾病的新治疗靶点。(End摘要）

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)