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一种用于成像支气管肺发育不良所致代谢变化的多模态成像方法。

A multimodal imaging approach for imaging the metabolic changes resulting from bronchopulmonary dysplasia.

作者信息

Gorman Brittney L, Li Zhi, Deutsch Gail, Huyck Heidi L, Beishembieva Niana, Olson Heather, Villazon Jorge, Yu Ping, Pryhuber Gloria S, Clair Geremy, Shi Lingyan, Anderton Christopher R

机构信息

Environmental and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA, 99354, United States.

Shu Chien-Gene Lay Department of Bioengineering, University of California San Diego, La Jolla, California 92093, United States.

出版信息

bioRxiv. 2025 Jun 22:2025.06.16.660017. doi: 10.1101/2025.06.16.660017.

Abstract

Lung tissue is composed of various functional units, each essential for maintaining the intricate functions of the lung. Disruptions in the molecular and cellular mechanisms in the lung can cause tissue fibrosis, inflammation, and severe breathing difficulties, which are common in conditions such as bronchopulmonary dysplasia (BPD). BPD's molecular changes are not well understood, which hinders effective diagnosis and treatment. Here, we present a new multimodal imaging workflow for detailed molecular and metabolic characterization of tissues at multiple spatial scales. We applied a combined imaging approach using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) and ultrafast focused light-based imaging & photonics platform (U-FLIP) that included two-photon fluorescence (TPF), second harmonic generation (SHG), and stimulated Raman scattering (SRS). We also developed a hierarchical multimodal registration network (HiMReg) for the precise co-registration of each modality. This approach revealed previously unknown metabolic changes in distinct functional tissue units affected by BPD, including altered lipid distributions, reduced optical redox states, and specific collagen remodeling in bronchioles. Our findings evidenced alterations in lipid composition and metabolism of BPD-affected alveoli compared to healthy tissue, providing novel insights into disease pathophysiology. Our findings elucidate the intricate spatial and molecular complexity of BPD, building on prior research that did not provide the spatial resolution necessary to capture the nuances of metabolic alterations. This multimodal approach offers exceptional insights into disease exploration and could transform the way we study spatially heterogeneous conditions. By providing detailed maps of the metabolic shifts occurring in distinct tissue microanatomical features, the methods developed here could enable the discovery of new therapeutic avenues, making it highly attractive for the field of biomedical research.

摘要

肺组织由各种功能单元组成,每个单元对于维持肺的复杂功能都至关重要。肺中分子和细胞机制的破坏可导致组织纤维化、炎症和严重呼吸困难,这些在支气管肺发育不良(BPD)等病症中很常见。BPD的分子变化尚未完全了解,这阻碍了有效的诊断和治疗。在此,我们提出了一种新的多模态成像工作流程,用于在多个空间尺度上对组织进行详细的分子和代谢表征。我们应用了一种联合成像方法,使用基质辅助激光解吸/电离质谱成像(MALDI-MSI)和基于超快聚焦光的成像与光子学平台(U-FLIP),该平台包括双光子荧光(TPF)、二次谐波产生(SHG)和受激拉曼散射(SRS)。我们还开发了一种分层多模态配准网络(HiMReg),用于每种模态的精确共配准。这种方法揭示了受BPD影响的不同功能组织单元中以前未知的代谢变化,包括脂质分布改变、光学氧化还原状态降低以及细支气管中特定的胶原重塑。我们的研究结果证明,与健康组织相比,BPD影响的肺泡的脂质组成和代谢发生了改变,为疾病病理生理学提供了新的见解。我们的研究结果阐明了BPD复杂的空间和分子复杂性,基于之前的研究没有提供捕捉代谢改变细微差别所需的空间分辨率。这种多模态方法为疾病探索提供了非凡的见解,并可能改变我们研究空间异质性疾病的方式。通过提供不同组织微解剖特征中发生的代谢变化的详细图谱,这里开发的方法可以发现新的治疗途径,使其在生物医学研究领域极具吸引力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aa0f/12262683/299a6e5fc398/nihpp-2025.06.16.660017v1-f0001.jpg

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