Gobbo Francesca, Zingariello Maria, Verachi Paola, Falchi Mario, Arciprete Francesca, Martelli Fabrizio, Peli Angelo, Mazzarini Maria, Vierstra Jeff, Mead-Harvey Carolyn, Dueck Amylou C, Sarli Giuseppe, Nava Stefano, Sgalla Giacomo, Richeldi Luca, Migliaccio Anna Rita
Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell'Emilia (Bologna) 40064, Italy.
Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
bioRxiv. 2023 Sep 19:2023.06.20.542249. doi: 10.1101/2023.06.20.542249.
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disorder with limited therapeutic options. Insufficient understanding of driver mutations and poor fidelity of currently available animal models has limited the development of effective therapies. Since GATA1 deficient megakaryocytes sustain myelofibrosis, we hypothesized that they may also induce fibrosis in lungs. We discovered that lungs from IPF patients and mice contain numerous GATA1negative immune-poised megakaryocytes that, in mice, have defective RNA-seq profiling and increased TGF-β1, CXCL1 and P-selectin content. With age, mice develop fibrosis in lungs. Development of lung fibrosis in this model is prevented by deletion and rescued by P-selectin, TGF-β1 or CXCL1 inhibition. Mechanistically, P-selectin inhibition decreases TGF-β1 and CXCL1 content and increases GATA1positive megakaryocytes while TGF-β1 or CXCL1 inhibition decreased CXCL1 only. In conclusion, mice are a novel genetic-driven model for IPF and provide a link between abnormal immune-megakaryocytes and lung fibrosis.
特发性肺纤维化（IPF）是一种进行性纤维化肺部疾病，治疗选择有限。对驱动突变的理解不足以及当前可用动物模型的低忠实度限制了有效疗法的开发。由于GATA1缺陷的巨核细胞会导致骨髓纤维化，我们推测它们也可能诱导肺部纤维化。我们发现，IPF患者和小鼠的肺部含有大量GATA1阴性的免疫平衡巨核细胞，在小鼠中，这些细胞的RNA测序图谱存在缺陷，且转化生长因子-β1（TGF-β1）、CXC趋化因子配体1（CXCL1）和P-选择素含量增加。随着年龄增长，小鼠肺部会出现纤维化。在该模型中，通过基因敲除可预防肺纤维化的发生，而通过抑制P-选择素、TGF-β1或CXCL1可使其得到缓解。从机制上来说，抑制P-选择素会降低TGF-β1和CXCL1的含量，并增加GATA1阳性巨核细胞，而抑制TGF-β1或CXCL1只会降低CXCL1的含量。总之，该小鼠是一种新型的IPF基因驱动模型，为异常免疫巨核细胞与肺纤维化之间建立了联系。
