Pulmonary fibrosis (PF) is the end stage of several interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis. Progressive scarring destroys lung architecture, impairs gas exchange, and leads to respiratory failure. Outcomes are poor: IPF carries a five-year mortality of 30%–50% with median survival of 2–3 years; fibrotic hypersensitivity pneumonitis shows a median survival near 7 years. Current drugs slow decline but do not halt disease. The cell–matrix interface is central to PF biology. Integrins—heterodimeric α/β receptors—govern bidirectional “outside-in” and “inside-out” signaling between cells and the extracellular matrix, shaping proliferation, migration, differentiation, and matrix remodeling. More than 20 integrins are expressed in mammals and multiple members are dysregulated in PF.
Pathogenic Axes: Integrin–TGF-β, Mechanotransduction, and Immunity
Three integrin-dependent pathways coordinate PF progression.
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Integrin–TGF-β axis: αv family members (αvβ1/β3/β5/β6/β8) activate latent TGF-β and amplify Smad signaling in epithelial and mesenchymal cells. Co-regulators such as galectin-3 and periostin facilitate receptor crosstalk that elevates profibrotic gene expression.
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Mechanotransduction: integrins transmit matrix stiffness cues to FAK/Src/Rho pathways, promoting fibroblast migration, invasion, and myofibroblast differentiation.
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Integrin–immunity axis: leukocyte integrins (α4β1, αLβ2, αMβ2, αXβ2, αE) enhance pro-inflammatory and pro-fibrotic programs, including macrophage activation and neutrophil extracellular trap formation.
Cell-Type–Resolved Roles Across the Lung
A synthesis across seven cell types—fibroblasts, myofibroblasts, epithelial cells, fibrocytes, macrophages, CD4+ T cells, and neutrophils—maps distinct integrin functions. Examples: αvβ3 and αvβ5 cooperate with periostin to upregulate SERPINE1, CTGF, IGFBP3, and IL-11 in fibroblasts; α5β1 and α8β1 shift during stromal progenitor differentiation; α4β1 supports alternative macrophage activation; hypoxia-driven αM/αX promotes neutrophil traps. These patterns show spatial and temporal specificity that argues for selective rather than blanket inhibition.
Clinical Translation Status
Four programs illustrate the field’s trajectory:
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GSK3008348 (αvβ6; inhaled): reduced epithelial αvβ6 and TGF-β signaling with good tolerability in early studies but failed Phase II efficacy endpoints; development stopped in 2018.
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BG00011 (anti-αvβ6 antibody): antifibrotic in models, but Phase IIb showed no FVC benefit and more exacerbations and serious adverse events; terminated in 2019.
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IDL-2965 (pan-αv): program halted in 2021 given operational and non-clinical concerns.
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Bexotegrast/PLN-74809 (dual αvβ6/αvβ1; oral): lowered collagen gene expression and TGF-β signaling in IPF precision-cut lung slices; Phase IIa showed modest slowing of FVC decline with dose-dependent biomarker changes and good tolerability; ongoing development.
Preclinical Modalities and Mechanisms
Multiple modalities are advancing: small molecules, antibodies, peptides, natural compounds, and cell-based approaches. Pan-αv inhibitors such as cilengitide and CWHM-12 reduce collagen deposition, α-SMA, fibroblast adhesion to fibronectin, and PI3K-Akt-mTOR activation, consistent with blockade of αv/TGF-β/Smad signaling. Selective agents against αvβ1, αvβ3, αvβ6, and αvβ8 also show antifibrotic effects across in vitro and in vivo models.
Translational Barriers: Model Limits, Redundancy, Safety
Repeated clinical setbacks reflect three obstacles:
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Model fidelity: heavy reliance on acute bleomycin models undervalues chronic human pathology.
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Pathway redundancy: compensatory signaling across integrins can blunt single-target strategies.
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Safety and delivery: systemic integrin inhibition carries risks documented for approved agents in other diseases; targeted pulmonary delivery may mitigate but demands precise aerosol engineering and patient technique.
Biomarkers and Patient Stratification
Elevated αvβ6 may serve as a stratification marker to enrich trials for likely responders. Comparing integrin levels in blood or bronchoalveolar lavage across interstitial lung disease subtypes could guide selection, but standardized sampling and unbiased analysis pipelines are required before routine clinical use. Spatial transcriptomics and single-cell profiling may refine cell-type targeting.
Drug Delivery and Targeted Conjugates
Localized lung delivery aims to increase specificity and reduce systemic exposure. The article notes technical hurdles for inhalers and highlights emerging solutions such as ligand-directed conjugates and biomimetic nanoparticles. Example: αvβ6-targeted peptide–nintedanib conjugates showed selective uptake and enhanced antifibrotic activity in αvβ6-overexpressing cells.
Author Perspective
The authors emphasize the need for integrated strategies: “Effective integrin-based therapies for PF will require a combination of targeted inhibition, precise patient stratification, and advanced delivery technologies,” with balanced, safety-first combinations shaped by spatiotemporal disease biology.
Practical Implications
For translational researchers and trialists:
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Match target and timing to cell context. αv-axis blockade may be most effective when aligned with epithelial TGF-β activation and fibroblast conversion windows.
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Build biomarker-guided protocols. Incorporate αvβ6 and related readouts in blood or lavage with standardized workflows.
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Prioritize delivery science. Evaluate inhaled or ligand-targeted formats to balance on-target efficacy with safety.
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Diversify models. Complement bleomycin with systems that capture chronic remodeling and immune–stromal crosstalk.
The translation of the preceding English text in Chinese:
肺纤维化（PF）是多种间质性肺疾病的终末阶段，包括特发性肺纤维化（IPF）和纤维化性过敏性肺炎。进行性瘢痕形成破坏肺结构，损害气体交换，并导致呼吸衰竭。预后不良：IPF 的 5 年死亡率为 30%–50%，中位生存期 2–3 年；纤维化性过敏性肺炎的中位生存期约为 7 年。现有药物可延缓病程，但无法阻止疾病进展。细胞–基质界面是 PF 生物学的核心。整合素是异二聚体 α/β 受体，调控细胞与细胞外基质之间的双向 “外向–内” 与 “内向–外” 信号，影响增殖、迁移、分化和基质重塑。哺乳动物中表达超过 20 种整合素，PF 中多种成员失调。
致病轴：整合素–TGF-β、机械转导和免疫
三条依赖整合素的通路协调 PF 的进展：
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整合素–TGF-β 轴：αv 家族成员（αvβ1/β3/β5/β6/β8）可激活潜在 TGF-β，并在上皮和间质细胞中增强 Smad 信号。伴侣分子如半乳糖凝集素-3 和骨桥蛋白促进受体串话，提高促纤维化基因表达。
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机械转导：整合素将基质硬度信号传递至 FAK/Src/Rho 通路，促进成纤维细胞迁移、侵袭及肌成纤维细胞分化。
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整合素–免疫轴：白细胞整合素（α4β1、αLβ2、αMβ2、αXβ2、αE）增强促炎与促纤维化程序，包括巨噬细胞活化和中性粒细胞胞外陷阱形成。
跨细胞类型的作用
整合来自七类细胞——成纤维细胞、肌成纤维细胞、上皮细胞、成纤维细胞、巨噬细胞、CD4+ T 细胞和中性粒细胞——可绘制整合素的特异功能图谱。
示例：αvβ3 与 αvβ5 在成纤维细胞中协同骨桥蛋白上调 SERPINE1、CTGF、IGFBP3 和 IL-11；α5β1 与 α8β1 在基质前体分化过程中发生转换；α4β1 支持巨噬细胞的替代激活；缺氧驱动的 αM/αX 促进中性粒细胞陷阱形成。这些模式具有时空特异性，提示选择性抑制优于全局阻断。
临床转化现状
四个项目体现该领域走向：
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GSK3008348（αvβ6；吸入）：降低上皮 αvβ6 和 TGF-β 信号，早期耐受性良好，但 II 期疗效终点失败，2018 年停止开发。
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BG00011（抗 αvβ6 抗体）：动物模型抗纤维化，但 IIb 期未显示 FVC 改善，且急性加重和严重不良事件增加，2019 年终止。
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IDL-2965（泛 αv 抑制）：2021 年因运营和非临床问题终止。
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Bexotegrast/PLN-74809（双靶 αvβ6/αvβ1；口服）：在 IPF 精准切片中降低胶原基因和 TGF-β 信号；IIa 期显示 FVC 下降减缓，生物标志物剂量依赖性变化，耐受性良好，研发持续。
临床前策略与机制
多种形式正在推进：小分子、抗体、肽类、天然化合物和细胞疗法。泛 αv 抑制剂（如 cilengitide、CWHM-12）可减少胶原沉积、α-SMA、成纤维细胞黏附及 PI3K-Akt-mTOR 激活，符合 αv/TGF-β/Smad 阻断效应。针对 αvβ1、αvβ3、αvβ6 和 αvβ8 的选择性药物在体内外均显示抗纤维化作用。
转化障碍：模型局限、通路冗余、安全性
临床反复失败的三大原因：
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模型问题：过度依赖急性博来霉素模型，低估慢性病理。
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通路冗余：整合素之间的补偿信号削弱单靶治疗效果。
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安全性与递送：系统性整合素抑制存在已知风险，肺部局部递送可能改善，但需精确气溶胶工程与患者操作配合。
生物标志物与患者分层
升高的 αvβ6 可作为分层标志，筛选潜在应答者。比较血液或支气管肺泡灌洗液中不同间质性肺疾病亚型的整合素水平或可指导选择，但需标准化采样与无偏分析。空间转录组与单细胞测序可能进一步优化细胞类型靶向。
药物递送与靶向偶联物
局部肺部递送可提高特异性并减少全身暴露。技术障碍包括吸入器设计。新方案包括配体导向偶联物与仿生纳米颗粒。示例：αvβ6 靶向肽–尼达尼布偶联物在 αvβ6 过表达细胞中显示选择性摄取和增强抗纤维化活性。
作者观点
作者强调综合策略：“有效的 PF 整合素靶向治疗需要靶向抑制、精准患者分层和先进递送技术的结合”，并以安全为首要前提，依据时空病理生物学制定联合方案。
实践启示
对转化研究者与临床试验人员：
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将靶点与时机匹配至细胞环境。αv 轴阻断在上皮 TGF-β 激活和成纤维细胞转化期可能最有效。
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构建生物标志物引导的方案。在血液或灌洗液中纳入 αvβ6 等读数并标准化。
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优先推进递送科学。评估吸入或配体靶向形式，在靶效应与安全性间取得平衡。
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模型多样化。补充急性模型以捕捉慢性重塑与免疫–基质互作。
Reference:
Zhangyang Bi, Guodong Zang, Xiaodong Wang, Li Tian, Wei Zhang
Integrins and pulmonary fibrosis: Pathogenic roles and therapeutic opportunities.
Biomol Biomed [Internet]. 2025 Jun. 19 [cited 2025 Oct. 2];26(2):200–214.
Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/12545
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