Platelet counts predict prognosis in IPF, but are not the main source of pulmonary TGFß1
Platelet counts predict prognosis in IPF, but are not the main source of pulmonary TGFß1
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血小板计数可预测 IPF 的预后，但不是肺 TGF™1 的主要来源
DOI：
10.1101/2020.03.06.978874
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Chong D
中科院分区：
文献类型：
--
作者：
Chong D
转化生长因子-β1（Transforming growth factor-β1，TGFβ1）是间质性肺疾病（interstitial lung diseases，ILD）包括特发性肺纤维化（idiopathic pulmonary fibrosis，IPF）的关键促纤维化细胞因子，但其主要来源尚不清楚。血小板具有丰富的TGFβ1储备，但其在IPF中的作用尚不明确。我们试图研究血小板或血小板衍生的TGFβ1是否介导IPF疾病进展。招募ILD/IPF和非ILD患者以确定血小板反应性并随访死亡率。为了研究血小板源性TGFβ1是否调节肺纤维化，在博莱霉素诱导的PF模型中使用了巨核细胞和血小板中靶向缺失TGFβ1的小鼠（TGFβ1fl/fl.PF4-Cre）。我们发现，血小板计数升高的IPF患者死亡率显著较高，沿着ILD患者肺和支气管肺泡灌洗液（BAL）中血小板、中性粒细胞、TGFβ1和CCL 5显著升高。尽管博来霉素处理小鼠的肺内容易检测到血小板，但TGFβ1fl/fl. PF 4-Cre和对照小鼠之间的肺部炎症或纤维化程度均无显著差异。我们的结果首次证明血小板衍生的TGFβ1在动物模型中驱动肺纤维化是多余的。然而，血小板可以预测IPF的死亡率，这涉及其他血小板源性介质，如CCL 5，促进人类IPF疾病。
Transforming growth factor-β1 (TGFβ1) is the key pro-fibrotic cytokine implicated in the interstitial lung diseases (ILD), including idiopathic pulmonary fibrosis (IPF), but the primary source of TGFβ1 in these diseases is unknown. Platelets have abundant TGFβ1 stores, however their role in IPF is ill-defined. We sought to investigate whether platelets or platelet-derived TGFβ1 mediate IPF disease progression.ILD/IPF and non-ILD patients were recruited to determine platelet reactivity and followed for mortality. To study whether platelet-derived TGFβ1 modulates pulmonary fibrosis, mice with a targeted deletion of TGFβ1 in megakaryocytes and platelets (TGFβ1fl/fl.PF4-Cre) were used in the bleomycin-induced PF model.We found a significantly higher mortality in IPF patients with elevated platelet counts, along with significantly increased platelets, neutrophils, TGFβ1 and CCL5 in the lung and bronchoalveolar lavage (BAL) of ILD patients. Despite platelets being readily detected within the lungs of bleomycin-treated mice, neither the degree of pulmonary inflammation or fibrosis were significantly different between TGFβ1fl/fl.PF4-Cre and control mice.Our results demonstrate for the first-time that platelet-derived TGFβ1 is redundant in driving pulmonary fibrosis in an animal model. However, platelets can predict mortality in IPF implicating other platelet-derived mediators, such as CCL5, in promoting human IPF disease.