Alveolar macrophages drive lung fibroblast function in cocultures of IPF and normal patient samples.
Alveolar macrophages drive lung fibroblast function in cocultures of IPF and normal patient samples.
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在 IPF 和正常患者样本的共培养物中，肺泡巨噬细胞驱动肺成纤维细胞功能。
DOI：
10.1152/ajplung.00263.2022
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Ballinger,MeganN
中科院分区：
文献类型：
--
作者：
Novak,CaymenM;Sethuraman,Shruthi;Luikart,KristinaL;Reader,BrendaF;Wheat,JanaS;Whitson,Bryan;Ghadiali,SamirN;Ballinger,MeganN
特发性肺纤维化（IPF）的特征是胶原蛋白积聚增加，并且是进行性和非消退性的。虽然纤维化的进展可能是由成纤维细胞和肺泡巨噬细胞（AM）的相互作用，这种细胞的相互作用尚未完全阐明。为了研究AM-成纤维细胞相互作用，从IPF和正常人肺组织中分离细胞，并在直接2-D共培养、直接3-D共培养、间接transwell和3-D水凝胶中单独或一起培养。通过基因表达、细胞因子/趋化因子分泌和水凝胶收缩性评估AM对成纤维细胞功能的影响。与成纤维细胞直接接触培养的正常AM下调细胞外基质（ECM）基因表达，而IPF AM几乎没有影响。通过将共培养物包封在3-D胶原水凝胶中并随时间监测凝胶直径来评估成纤维细胞收缩性。正常和IPF AM均降低正常成纤维细胞的基线收缩性，但对IPF成纤维细胞几乎没有影响。与正常AM相比，当用Toll样受体（TLR）激动剂刺激时，IPF AM的促炎细胞因子TNFα和IL-1β的产生增加。TLR配体刺激不改变成纤维细胞收缩，但外源性TNFα和TGFβ刺激确实改变了收缩。为了确定观察到的变化是否需要细胞间接触，使用AM条件培养基和transwell系统。与直接共培养相比，Transwell培养显示ECM基因表达变化减少，AM的条件培养基不改变成纤维细胞收缩，无论疾病状态如何。总之，这些数据表明，正常的成纤维细胞更响应于AM串扰，AM对成纤维细胞行为的影响取决于细胞的接近度。
Idiopathic pulmonary fibrosis (IPF) is characterized by increased collagen accumulation that is progressive and nonresolving. Although fibrosis progression may be regulated by fibroblasts and alveolar macrophage (AM) interactions, this cellular interplay has not been fully elucidated. To study AM-fibroblast interactions, cells were isolated from IPF and normal human lung tissue and cultured independently or together in direct 2-D coculture, direct 3-D coculture, indirect transwell, and in 3-D hydrogels. AM influence on fibroblast function was assessed by gene expression, cytokine/chemokine secretion, and hydrogel contractility. Normal AMs cultured in direct contact with fibroblasts downregulated extracellular matrix (ECM) gene expression whereas IPF AMs had little to no effect. Fibroblast contractility was assessed by encapsulating cocultures in 3-D collagen hydrogels and monitoring gel diameter over time. Both normal and IPF AMs reduced baseline contractility of normal fibroblasts but had little to no effect on IPF fibroblasts. When stimulated with Toll-like receptor (TLR) agonists, IPF AMs increased production of pro-inflammatory cytokines TNFα and IL-1β, compared with normal AMs. TLR ligand stimulation did not alter fibroblast contraction, but stimulation with exogenous TNFα and TGFβ did alter contraction. To determine if the observed changes required cell-to-cell contact, AM-conditioned media and transwell systems were utilized. Transwell culture showed decreased ECM gene expression changes compared with direct coculture and conditioned media from AMs did not alter fibroblast contraction regardless of disease state. Taken together, these data indicate that normal fibroblasts are more responsive to AM crosstalk, and that AM influence on fibroblast behavior depends on cell proximity.
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