Neurotrophic Tyrosine Kinase Receptor B/Neurotrophin 4 Signaling Axis Is Perturbed in Clinical and Experimental Pulmonary Fibrosis
Neurotrophic Tyrosine Kinase Receptor B/Neurotrophin 4 Signaling Axis Is Perturbed in Clinical and Experimental Pulmonary Fibrosis
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DOI：
10.1165/rcmb.2010-0195oc
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发表时间：
2011-10-01
影响因子：
6.4
通讯作者：
Kwapiszewska, Grazyna
中科院分区：
文献类型：
--
作者：
Avcuoglu, Sibel;Wygrecka, Malgorzata;Kwapiszewska, Grazyna
神经营养因子（NTs）正在成为令人兴奋的新参与者在正常的肺生理，以及在一些病理过程中，在患病的肺。在这项研究中，在特发性肺纤维化（IPF）患者的人肺和博莱霉素诱导的肺纤维化小鼠的肺中观察到NT 4/5及其同源受体2型神经营养酪氨酸激酶受体（TrkB）的表达增加。NT 4/5和TrkB的表达定位于受影响的肺中的增生的肺泡II型细胞（ATII）和成纤维细胞灶。NT 4/5和TrkB的浓度增加在从博来霉素处理的小鼠的肺分离的ATII中是明显的。原代ATII显示将NT 4/5分泌到细胞培养基中。促纤维化细胞因子转化生长因子-β 1刺激TrkB，但不刺激NT 4/5基因表达，表明受影响肺中受干扰的促纤维化生长因子信号传导可能驱动TrkB的表达。NT 4/5通过Trk B/细胞外调节激酶/蛋白激酶B途径促进ATII的增殖，并且还可以通过Trk B依赖性和蛋白激酶B依赖性途径驱动原代人和小鼠肺成纤维细胞的增殖。总之，这些数据表明，TrkB/NT 4/5轴失调可能导致与肺纤维化相关的几种病理学病变，包括ATII增生和成纤维细胞增殖，我们将IPF添加到疾病列表中，如疼痛和癌症，已提出针对其治疗靶向TrkB/神经营养因子轴进行进一步研究。
The neurotrophins (NTs) are emerging as exciting new participants in normal lung physiology, as well as in several pathological processes in diseased lungs. In this study, the increased expression of NT4/5 and of its cognate receptor, the neurotrophic tyrosine kinase receptor Type 2 (TrkB), was observed in human lungs explanted from patients with idiopathic pulmonary fibrosis (IPF), and in lungs from mice with bleomycin-induced pulmonary fibrosis. The expression of NT4/5 and TrkB localized to hyperplastic alveolar Type II cells (ATII) and fibroblastic foci in affected lungs. Increased concentrations of NT4/5 and TrkB were evident in ATII isolated from the lungs of bleomycin-treated mice. Primary ATII were shown to secrete NT4/5 into the cell culture medium. The profibrotic cytokine transforming growth factor-beta 1, stimulated TrkB, but not NT4/5 gene expression, suggesting that perturbed profibrotic growth factor signaling in affected lungs may drive the expression of TrkB. NT4/5 enhanced the proliferation of ATII through a TrkB/extracellular-regulated kinase/protein kinase B pathway, and could also drive the proliferation of primary human and murine lung fibroblasts, through TrkB-dependent and protein kinase B-dependent pathways. Taken together, these data suggest that a dysregulated TrkB/NT4/5 axis may contribute to several of the pathological lesions associated with pulmonary fibrosis, including ATII hyperplasia and the proliferation of fibroblasts, and we would add IPF to the list of disorders, such as pain and cancer, for which therapeutic targeting of the TrkB/neurotrophin axis has been proposed for further investigation.