Background Interstitial lung diseases (ILDs) include a large number of diseases associated with progressive pulmonary fibrosis (PPF), including idiopathic pulmonary fibrosis (IPF). Despite the rarity of each of the fibrotic ILDs individually, they cumulatively affect a considerable number of patients. PPF is characterised by an excessive collagen deposition leading to functional decline. Objectives Therapeutic options are limited to nintedanib and pirfenidone which are only able to reduce fibrosis progression. CD206-expressing M2 macrophages are involved in fibrosis progression, and whether they may be relevant therapeutic targets or biomarkers remains an open question. Results In our study, CD206+ lung macrophages were monitored in bleomycin-induced lung fibrosis in mice by combining flow cytometry, scRNAseq and in vivo molecular imaging using a single photon emission computed tomography (SPECT) radiopharmaceutical, 99mTc-tilmanocept. The antifibrotic effect of the inhibition of M2 macrophage polarisation with a JAK inhibitor, tofacitinib, was assessed in vivo. We demonstrate that CD206-targeted in vivo SPECT imaging with 99mTc-tilmanocept was able to accurately detect and quantify the increase in CD206+ macrophages from early to advanced stages of experimental fibrosis and ex vivo in lung biopsies from patients with IPF. CD206-targeted imaging also specifically detected a decrease in CD206+ lung macrophages on nintedanib and tofacitinib treatment. Importantly, early in vivo imaging of CD206+ macrophages allowed the prediction of experimental lung fibrosis progression as well as nintedanib and tofacitinib efficacy. Conclusions These findings indicate that M2 macrophages may be relevant theranostic targets for personalised medicine for patients with PPF. Data are available upon reasonable request.

中文翻译：

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CD206+巨噬细胞是实验性肺纤维化的相关非侵入性成像生物标志物和治疗靶点


背景间质性肺疾病（ILD）包括大量与进行性肺纤维化（PPF）相关的疾病，包括特发性肺纤维化（IPF）。尽管每种纤维化 ILD 都很罕见，但它们累积起来会影响相当多的患者。 PPF 的特点是胶原蛋白过度沉积，导致功能下降。目标 治疗选择仅限于尼达尼布和吡非尼酮，它们只能减缓纤维化进展。表达 CD206 的 M2 巨噬细胞参与纤维化进展，它们是否可能是相关的治疗靶点或生物标志物仍然是一个悬而未决的问题。结果在我们的研究中，通过结合流式细胞术、scRNAseq 和使用单光子发射计算机断层扫描 (SPECT) 放射性药物 99mTc-tilmanocept 的体内分子成像，监测博来霉素诱导的小鼠肺纤维化中的 CD206+ 肺巨噬细胞。在体内评估了 JAK 抑制剂托法替尼抑制 M2 巨噬细胞极化的抗纤维化作用。我们证明，使用 99mTc-tilmanocept 进行的 CD206 靶向体内 SPECT 成像能够准确检测和量化实验性纤维化早期到晚期阶段以及 IPF 患者肺活检中 CD206+ 巨噬细胞的增加。 CD206 靶向成像还专门检测到尼达尼布和托法替布治疗后 CD206+ 肺巨噬细胞的减少。重要的是，CD206+巨噬细胞的早期体内成像可以预测实验性肺纤维化进展以及尼达尼布和托法替布的疗效。结论 这些研究结果表明，M2 巨噬细胞可能是 PPF 患者个性化医疗的相关治疗诊断靶点。 数据可根据合理要求提供。