Russo Remo Castro, Ryffel Bernhard
Laboratory of Pulmonary Immunology and Mechanics, Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais-UFMG, Belo Horizonte 31270-901, MG, Brazil.
Laboratory of Immuno-Neuro Modulation (INEM), UMR7355 Centre National de la Recherche Scientifique (CNRS), University of Orleans, 45071 Orleans, France.
Cells. 2024 Dec 12;13(24):2058. doi: 10.3390/cells13242058.
Idiopathic pulmonary fibrosis (IPF) is a chronic and lethal interstitial lung disease (ILD) of unknown origin, characterized by limited treatment efficacy and a fibroproliferative nature. It is marked by excessive extracellular matrix deposition in the pulmonary parenchyma, leading to progressive lung volume decline and impaired gas exchange. The chemokine system, a network of proteins involved in cellular communication with diverse biological functions, plays a crucial role in various respiratory diseases. Chemokine receptors trigger the activation, proliferation, and migration of lung-resident cells, including pneumocytes, endothelial cells, alveolar macrophages, and fibroblasts. Around 50 chemokines can potentially interact with 20 receptors, expressed by both leukocytes and non-leukocytes such as tissue parenchyma cells, contributing to processes such as leukocyte mobilization from the bone marrow, recirculation through lymphoid organs, and tissue influx during inflammation or immune response. This narrative review explores the complexity of the chemokine system in the context of IPF and the bleomycin-induced lung fibrosis mouse model. The goal is to identify specific chemokines and receptors as potential therapeutic targets. Recent progress in understanding the role of the chemokine system during IPF, using experimental models and molecular diagnosis, underscores the complex nature of this system in the context of the disease. Despite advances in experimental models and molecular diagnostics, discovering an effective therapy for IPF remains a significant challenge in both medicine and pharmacology. This work delves into microarray results from lung samples of IPF patients and murine samples at different stages of bleomycin-induced pulmonary fibrosis. By discussing common pathways identified in both IPF and the experimental model, we aim to shed light on potential targets for therapeutic intervention. Dysregulation caused by abnormal chemokine levels observed in IPF lungs may activate multiple targets, suggesting that chemokine signaling plays a central role in maintaining or perpetuating lung fibrogenesis. The highlighted chemokine axes (CCL8-CCR2, CCL19/CCL21-CCR7, CXCL9-CXCR3, CCL3/CCL4/CCL5-CCR5, and CCL20-CCR6) present promising opportunities for advancing IPF treatment research and uncovering new pharmacological targets within the chemokine system.
特发性肺纤维化（IPF）是一种病因不明的慢性致死性间质性肺疾病（ILD），其特征为治疗效果有限且具有纤维增殖性质。它的特点是肺实质中细胞外基质过度沉积，导致肺容积进行性下降和气体交换受损。趋化因子系统是一个由参与细胞通讯且具有多种生物学功能的蛋白质组成的网络，在各种呼吸系统疾病中起关键作用。趋化因子受体可触发肺驻留细胞（包括肺细胞、内皮细胞、肺泡巨噬细胞和成纤维细胞）的激活、增殖和迁移。大约50种趋化因子可能与20种受体相互作用，这些受体由白细胞和非白细胞（如组织实质细胞）表达，参与诸如白细胞从骨髓动员、通过淋巴器官再循环以及在炎症或免疫反应期间进入组织等过程。这篇叙述性综述探讨了IPF背景下以及博来霉素诱导的肺纤维化小鼠模型中趋化因子系统的复杂性。目的是确定特定的趋化因子和受体作为潜在的治疗靶点。利用实验模型和分子诊断来理解趋化因子系统在IPF期间作用的最新进展，凸显了该系统在疾病背景下的复杂性质。尽管在实验模型和分子诊断方面取得了进展，但为IPF发现一种有效的治疗方法在医学和药理学上仍然是一项重大挑战。这项工作深入研究了IPF患者肺样本以及博来霉素诱导的肺纤维化不同阶段小鼠样本的微阵列结果。通过讨论在IPF和实验模型中确定的共同途径，我们旨在阐明治疗干预的潜在靶点。IPF肺中观察到的趋化因子水平异常导致的失调可能会激活多个靶点，这表明趋化因子信号传导在维持或延续肺纤维化过程中起核心作用。所强调的趋化因子轴（CCL8 - CCR2、CCL19/CCL21 - CCR7、CXCL9 - CXCR3、CCL3/CCL4/CCL5 - CCR5和CCL20 - CCR6）为推进IPF治疗研究以及在趋化因子系统中发现新的药理学靶点提供了有前景的机会。
