Fowler Kenneth A, Jania Corey M, Tilley Stephen L, Panoskaltsis-Mortari Angela, Baldwin Albert S, Serody Jonathan S, Coghill James M
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Biol Blood Marrow Transplant. 2017 Apr;23(4):569-580. doi: 10.1016/j.bbmt.2017.01.083. Epub 2017 Feb 1.
Idiopathic pneumonia syndrome (IPS) is a noninfectious inflammatory disorder of the lungs that occurs most often after fully myeloablative allogeneic hematopoietic stem cell transplantation (HSCT). IPS can be severe and is associated with high 1-year mortality rates despite existing therapies. The canonical nuclear factor-(NF) κB signaling pathway has previously been linked to several inflammatory disorders of the lung, including asthma and lung allograft rejection. It has never been specifically targeted as a novel IPS treatment approach, however. Here, we report that the IκB kinase 2 (IKK2) antagonist BAY 65-5811 or "compound A," a highly potent and specific inhibitor of the NF-κB pathway, was able to improve median survival times and recipient oxygenation in a well-described mouse model of IPS. Compound A impaired the production of the proinflammatory chemokines CCL2 and CCL5 within the host lung after transplantation. This resulted in significantly lower numbers of donor lung infiltrating CD4 and CD8 T cells and reduced pulmonary inflammatory cytokine production after allograft. Compound A's beneficial effects appeared to be specific for limiting pulmonary injury, as the drug was unable to improve outcomes in a B6 into B6D2 haplotype-matched murine HSCT model in which recipient mice succumb to lethal acute graft-versus-host disease of the gastrointestinal tract. Collectively, our data suggest that the targeting of the canonical NF-κB pathway with a small molecule IKK2 antagonist may represent an effective and novel therapy for the specific management of acute lung injury that can occur after allogeneic HSCT.
特发性肺炎综合征（IPS）是一种肺部非感染性炎症性疾病，最常发生在清髓性同种异体造血干细胞移植（HSCT）后。尽管现有治疗方法，IPS仍可能很严重，且与1年高死亡率相关。经典的核因子-（NF）κB信号通路此前已与多种肺部炎症性疾病相关，包括哮喘和肺移植排斥反应。然而，它从未被专门作为一种新型的IPS治疗方法。在此，我们报告IκB激酶2（IKK2）拮抗剂BAY 65-5811或“化合物A”（一种高效且特异性的NF-κB通路抑制剂）能够在一个已充分描述的IPS小鼠模型中提高中位生存时间和受体氧合。化合物A在移植后损害了宿主肺内促炎趋化因子CCL2和CCL5的产生。这导致供体肺浸润的CD4和CD8 T细胞数量显著减少，并降低了同种异体移植后的肺部炎性细胞因子产生。化合物A的有益作用似乎对限制肺部损伤具有特异性，因为该药物在B6到B6D2单倍型匹配的小鼠HSCT模型中无法改善结果，在该模型中受体小鼠死于致命的胃肠道急性移植物抗宿主病。总体而言，我们的数据表明，用小分子IKK2拮抗剂靶向经典的NF-κB通路可能代表一种有效且新颖的疗法，用于特异性治疗同种异体HSCT后可能发生的急性肺损伤。
