Myeloid- and Epithelial-derived Heparin-Binding Epidermal Growth Factor-like Growth Factor Promotes Pulmonary Fibrosis
Myeloid- and Epithelial-derived Heparin-Binding Epidermal Growth Factor-like Growth Factor Promotes Pulmonary Fibrosis
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DOI：
10.1165/rcmb.2022-0174oc
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发表时间：
2022-12-01
影响因子：
6.4
通讯作者：
Moore, Bethany B.
中科院分区：
文献类型：
--
作者：
Hult, Elissa M.;Gurczynski, Stephen J.;Moore, Bethany B.
特发性肺纤维化（IPF）是一种知之甚少的进行性致死性肺部疾病，目前尚无治愈方法。除了肺泡上皮细胞（AEC）损伤和细胞外基质蛋白过度沉积外，慢性炎症是IPF的标志。文献表明，IPF中观察到的持续性炎症主要由单核细胞和巨噬细胞组成。最近的工作表明，单核细胞衍生的肺泡巨噬细胞（moAM）驱动肺纤维化，但关键moAM细胞属性的进一步表征是必要的。肝素结合表皮生长因子样生长因子（HB-EGF）是一种重要的表皮生长因子受体配体，在血管生成、伤口愈合、角质形成细胞迁移和上皮-间充质转化中具有重要作用。我们过去的工作表明HB-EGF是促纤维化M2巨噬细胞的主要标志物，本研究旨在使用Hbegf（f/f）; Lyz 2Cre（+）小鼠表征髓源性HB-EGF及其在博来霉素诱导的肺纤维化中的主要作用机制。在这里，我们发现IPF患者和肺纤维化小鼠的HB-EGF表达增加，肺纤维化小鼠和人类的肺巨噬细胞和过渡性AEC都表达HB-EGF。我们还表明，HBegf（f/f）; Lyz 2Cre（+）小鼠受到保护，免受博来霉素诱导的纤维化，并且这种保护可能是多因素的，由CCL 2依赖性单核细胞迁移减少、成纤维细胞迁移减少以及当HB-EGF在Lyz 2Cre启动子下去除时，AEC来源的HB-EGF贡献减少引起。
Idiopathic pulmonary fibrosis (IPF) is a poorly understood, progressive lethal lung disease with no known cure. In addition to alveolar epithelial cell (AEC) injury and excessive deposition of extracellular matrix proteins, chronic inflammation is a hallmark of IPF. Literature suggests that the persistent inflammation seen in IPF primarily consists of monocytes and macrophages. Recent work demonstrates that monocyte-derived alveolar macrophages (moAMs) drive lung fibrosis, but further characterization of critical moAM cell attributes is necessary. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an important epidermal growth factor receptor ligand that has essential roles in angiogenesis, wound healing, keratinocyte migration, and epithelial-mesenchymal transition. Our past work has shown HB-EGF is a primary marker of profibrotic M2 macrophages, and this study seeks to characterize myeloid-derived HB-EGF and its primary mechanism of action in bleomycin-induced lung fibrosis using Hbegf(f/f);Lyz2Cre(+) mice. Here, we show that patients with IPF and mice with pulmonary fibrosis have increased expression of HB-EGF and that lung macrophages and transitional AECs of mice with pulmonary fibrosis and humans all express HB-EGF. We also show that Hbegf(f/f);Lyz2Cre(+) mice are protected from bleomycin-induced fibrosis and that this protection is likely multifactorial, caused by decreased CCL2-dependent monocyte migration, decreased fibroblast migration, and decreased contribution of HB-EGF from AEC sources when HB-EGF is removed under the Lyz2Cre promoter.