Jones Nicole, Rahar Babita, Bernau Ksenija, Schulte Jefree J, Campagnola Paul J, Brasier Allan R
Department of Medicine, School of Medicine and Public Health (SMPH), University of Wisconsin-Madison, Madison, WI 53705, USA.
Institute for Clinical and Translational Research, University of Wisconsin-Madison, Madison, WI 53705, USA.
Int J Mol Sci. 2025 Jun 4;26(11):5393. doi: 10.3390/ijms26115393.
In a susceptible individual, persistent, low-level injury to the airway epithelium initiates an exaggerated wound repair response, ultimately leading to idiopathic pulmonary fibrosis (IPF). The mechanisms driving this fibroproliferative response are not fully understood. Here, we review recent spatially resolved transcriptomics and proteomics studies that provide insight into two distinct matricellular microenvironments important in this pathological fibroproliferation. First, in response to alveolar epithelial injury, alveolar differentiation intermediate (ADI) basal cells arising from Secretoglobin () progenitors re-populate the injured alveolus remodeling the extracellular matrix (ECM). ADI cells exhibit an interconnected cellular stress response involving the unfolded protein response (UPR), epithelial-mesenchymal transition (EMT) and senescence pathways. These pathways reprogram cellular metabolism to support fibrillogenic ECM remodeling. In turn, the remodeled ECM tonically stimulates EMT in the ADI population, perpetuating the transitional cell state. Second, fibroblastic foci (FF) are a distinct microenvironment composed of activated aberrant "basaloid" cells supporting transition of adjacent mesenchyme into hyaluronan synthase (HAS)-expressing fibroblasts and myofibroblasts. Once formed, FF are the major matrix-producing factories that invade and disrupt the alveolar airspace, forming a mature scar. In both microenvironments, the composition and characteristics of the ECM drive persistence of atypical epithelium sustaining matrix production. New approaches to monitor cellular trans-differentiation and matrix characteristics using positron emission tomography (PET)-magnetic resonance imaging (MRI) and optical imaging are described, which hold the potential to monitor the effects of therapeutic interventions to modify the ECM. Greater understanding of the bidirectional interrelationships between matrix and cellular phenotypes will identify new therapeutics and diagnostics to affect the outcomes of this lethal disease.
在易感个体中，气道上皮的持续性低水平损伤引发过度的伤口修复反应，最终导致特发性肺纤维化（IPF）。驱动这种纤维增生反应的机制尚未完全明确。在此，我们综述了近期的空间分辨转录组学和蛋白质组学研究，这些研究为深入了解在这种病理性纤维增生中重要的两种不同的基质细胞微环境提供了线索。首先，为响应肺泡上皮损伤，源自分泌球蛋白（）祖细胞的肺泡分化中间体（ADI）基底细胞重新填充受损肺泡，重塑细胞外基质（ECM）。ADI细胞表现出一种相互关联的细胞应激反应，涉及未折叠蛋白反应（UPR）、上皮 - 间质转化（EMT）和衰老途径。这些途径对细胞代谢进行重新编程，以支持纤维原性ECM重塑。反过来，重塑的ECM持续刺激ADI群体中的EMT，使过渡细胞状态持续存在。其次，成纤维细胞灶（FF）是一个独特的微环境，由活化的异常“基底样”细胞组成，支持相邻间充质向表达透明质酸合酶（HAS）的成纤维细胞和平滑肌成纤维细胞转变。一旦形成，FF就是侵入并破坏肺泡腔的主要基质产生工厂，形成成熟瘢痕。在这两种微环境中，ECM的组成和特性驱动非典型上皮的持续存在，维持基质产生。本文描述了使用正电子发射断层扫描（PET） - 磁共振成像（MRI）和光学成像监测细胞转分化和基质特性的新方法，这些方法有可能监测治疗干预对修饰ECM的效果。对基质与细胞表型之间双向相互关系的更深入理解将有助于识别影响这种致命疾病预后的新疗法和诊断方法。
