JAK-STAT信号通路参与细胞因子风暴和抗MDA5抗体的产生在皮肌炎合并急进型肺间质病变中的机制研究

皮肌炎（DM）/临床无肌病性皮肌炎（CADM）合并急进型/亚急型肺间质病变（A/SIP）表现为溃疡性Gottron丘疹/征、肌痛、气促和呼衰，对糖皮质激素治疗抵抗，短期内死于呼吸衰竭。目前认为DM/CADM-A/SIP的血清标记物为抗黑素瘤分化相关基因5（MDA5）抗体，发生机制即细胞因子风暴导致急性肺损伤。如何早期预测、尽早干预DM/CADM-A/SIP发生细胞因子风暴？通过本研究：1、建立DM/CADM-A/SIP发生细胞因子风暴的早期预测和病情监测手段，根据血清抗MDA5抗体、细胞因子和生化指标建立血清学诊断公式。2、明确JAK-STAT信号通路参与DM/CADM-A/SIP中细胞因子风暴的发生和抗MDA5抗体的产生机制。3、建立急性肺损伤鼠模型，观察干预JAK-STAT信号通路改善急性肺损伤鼠模型的症状和病程，为JAK/STAT抑制剂靶向治疗DM/CADM-A/SIP提供理论依据。

Acute/subacute interstitial pneumonia (A/SIP), characterized by shortness of breath or even respiratory failure, high fever and myalgia, which is the common severe crisis with high case fatality in dermatomyositis (DM)/clinical amyopathic dermatomyositis (CADM), besides ulcerative Gottron’s papules/sign. Serum anti-Melanoma differentiation-associated gene 5 (MDA5) antibody is now known to be the biomarker of the occurrence of A/SIP in DM/CADM (DM/CADM-A/SIP) patients. The ultimate reason of DM/CADM-A/SIP is acute lung injury caused by cytokine release syndrome (CRS). Some patients who are resistant to glucocorticoid combined with cyclophosphamide often died of respiratory failure in a short term. In this study we aimed first to establish early prediction and disease monitoring tools of CRS in DM/CADM-A/SIP, that is the establishment of serological diagnosis formula according to serum level of anti-MDA5 antibody, cytokines and inflammatory mediator. Second, the participation mechanism of JAK-STAT signaling pathway are needed to be clarified the occurrence of CRS and production of anti-MDA5 antibody. Finally, acute lung injury mouse model is established to observe the symptoms of the mouse model after intervention the JAK-STAT signaling pathway, and provide a reliable theory for DM/CADM-A/SIP targeting therapy. The target therapy instead of using glucocorticoid shock therapy combined with immunosuppressants, not only improves the survival rate of patients, but also provides new research ideas and treatment strategies for the disease.