Yan Ninghui, Shao Chenyi, Zhen Yan, Zhang Xueliang, Xia Nana, Guo Qiang
Department of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Ren Ji Hospital, Jiading Branch, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Vet Sci. 2024 Aug 12;11:1431738. doi: 10.3389/fvets.2024.1431738. eCollection 2024.
Diffuse alveolar hemorrhage (DAH) is a catastrophic clinical syndrome and one of the manifestations of pulmonary involvement in systemic lupus erythematosus (SLE), which is characterized by hemoptysis, diffuse pulmonary infiltrates, and respiratory failure. However, the treatment options for DAH remain limited, and DAH-related studies are needed to explore more effective therapeutic directions for better disease management and improved prognosis.
This study utilized the pristane-induced DAH murine model to mimic the pathological process of DAH in patients with SLE. Proteomic analysis was conducted to detect differentially expressed proteins (DEPs) in the plasma of surviving and non-surviving mice, followed by an analysis of biological functions and pathways. The most significant DEP was then confirmed in the plasma of SLE patients with or without DAH and DAH murine model with or without fatal outcomes. Finally, the therapeutic value of haptoglobin (Hp) replacement was validated in a DAH murine model through lung histopathology, RT-qPCR, and survival analysis.
This study identified 178 DEPs, with 118 upregulated and 60 downregulated DEPs in the non-survival group. Within a set of notable Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, complement and coagulation cascades emerged as the most prominent pathway associated with the process of DAH. Later, the most significant DEP, haptoglobin (Hp), was confirmed to exhibit a significant decrease in the plasma of individuals with SLE-DAH and DAH murine model with poor outcomes by the ELISA test. Finally, compared with the control group, the severity of DAH in the Hp treatment group was alleviated significantly, as manifested by the decreased levels of pro-inflammatory cytokines (IL-6 and TNF-α), increased levels of anti-inflammatory cytokines (IL-10 and TGF-β), and decreased mortality.
A reduction in plasma Hp levels was observed in SLE-DAH, and the replacement therapy with Hp could alleviate pulmonary hemorrhage and reduce mortality in DAH mice. This study identified Hp as a potential biomarker for its clinical diagnosis and a direction for treatment.
弥漫性肺泡出血（DAH）是一种灾难性的临床综合征，是系统性红斑狼疮（SLE）肺部受累的表现之一，其特征为咯血、弥漫性肺部浸润和呼吸衰竭。然而，DAH的治疗选择仍然有限，需要开展与DAH相关的研究，以探索更有效的治疗方向，从而更好地管理疾病并改善预后。
本研究利用 pristane 诱导的 DAH 小鼠模型来模拟 SLE 患者 DAH 的病理过程。进行蛋白质组学分析以检测存活和非存活小鼠血浆中的差异表达蛋白（DEP），随后分析其生物学功能和通路。然后在有或无 DAH 的 SLE 患者血浆以及有或无致命结局的 DAH 小鼠模型中对最显著的 DEP 进行验证。最后，通过肺组织病理学、RT-qPCR 和生存分析在 DAH 小鼠模型中验证触珠蛋白（Hp）替代疗法的治疗价值。
本研究鉴定出 178 个 DEP，其中非存活组中有 118 个上调的 DEP 和 60 个下调的 DEP。在一组显著的京都基因与基因组百科全书（KEGG）通路中，补体和凝血级联反应是与 DAH 过程相关的最突出通路。随后，通过 ELISA 试验证实，最显著的 DEP 触珠蛋白（Hp）在患有 SLE-DAH 的个体以及预后不良的 DAH 小鼠模型血浆中显著降低。最后，与对照组相比，Hp 治疗组的 DAH 严重程度显著减轻，表现为促炎细胞因子（IL-6 和 TNF-α）水平降低、抗炎细胞因子（IL-10 和 TGF-β）水平升高以及死亡率降低。
在 SLE-DAH 中观察到血浆 Hp 水平降低，并且 Hp 替代疗法可减轻 DAH 小鼠的肺出血并降低死亡率。本研究确定 Hp 作为其临床诊断的潜在生物标志物和治疗方向。
