Department of Internal Medicine, University of Michigan, 109 Zina Pitcher Place, 2063 BSRB, Box 2200, Ann Arbor, MI, 48109, USA.
Department of Pediatric Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA.
Sci Rep. 2021 Feb 19;11(1):4268. doi: 10.1038/s41598-021-83531-3.
Ataxia-telangiectasia (A-T) is an autosomal recessive, multisystem disorder characterized by cerebellar degeneration, cancer predisposition, and immune system defects. A major cause of mortality in A-T patients is severe pulmonary disease; however, the underlying causes of the lung complications are poorly understood, and there are currently no curative therapeutic interventions. In this study, we examined the lung phenotypes caused by ATM-deficient immune cells using a mouse model of A-T pulmonary disease. In response to acute lung injury, ATM-deficiency causes decreased survival, reduced blood oxygen saturation, elevated neutrophil recruitment, exaggerated and prolonged inflammatory responses and excessive lung injury compared to controls. We found that ATM null bone marrow adoptively transferred to WT recipients induces similar phenotypes that culminate in impaired lung function. Moreover, we demonstrated that activated ATM-deficient macrophages exhibit significantly elevated production of harmful reactive oxygen and nitrogen species and pro-inflammatory cytokines. These findings indicate that ATM-deficient immune cells play major roles in causing the lung pathologies in A-T. Based on these results, we examined the impact of inhibiting the aberrant inflammatory responses caused by ATM-deficiency with reparixin, a CXCR1/CXCR2 chemokine receptor antagonist. We demonstrated that reparixin treatment reduces neutrophil recruitment, edema and tissue damage in ATM mutant lungs. Thus, our findings indicate that targeted inhibition of CXCR1/CXCR2 attenuates pulmonary phenotypes caused by ATM-deficiency and suggest that this treatment approach represents a viable therapeutic strategy for A-T lung disease.
共济失调毛细血管扩张症（A-T）是一种常染色体隐性、多系统疾病，其特征为小脑退行性变、癌症易感性和免疫系统缺陷。A-T 患者死亡的主要原因是严重的肺部疾病；然而，肺部并发症的根本原因尚不清楚，目前也没有治愈性的治疗干预措施。在这项研究中，我们使用 A-T 肺部疾病的小鼠模型研究了由 ATM 缺陷免疫细胞引起的肺部表型。在急性肺损伤反应中，与对照组相比，ATM 缺陷会导致生存率降低、血氧饱和度降低、中性粒细胞募集增加、炎症反应加剧和延长以及肺损伤过度。我们发现，ATM 缺失的骨髓通过过继转移到 WT 受体中，会引起类似的表型，最终导致肺功能受损。此外，我们还证明了激活的 ATM 缺陷巨噬细胞会显著增加有害的活性氧和氮物种以及促炎细胞因子的产生。这些发现表明 ATM 缺陷免疫细胞在 A-T 的肺部病变中起着重要作用。基于这些结果，我们用 reparixin 检查了抑制 ATM 缺陷引起的异常炎症反应对 A-T 肺部疾病的影响，reparixin 是一种 CXCR1/CXCR2 趋化因子受体拮抗剂。我们证明了 reparixin 治疗可减少 ATM 突变肺中的中性粒细胞募集、水肿和组织损伤。因此，我们的研究结果表明，靶向抑制 CXCR1/CXCR2 可减轻 ATM 缺陷引起的肺部表型，并提示这种治疗方法是 A-T 肺部疾病的一种可行治疗策略。
