Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Superfund Research Center at The University of Alabama at Birmingham, 901 19Th St S, BMR2, Rm 404, Birmingham, AL, 35294, USA.
Respir Res. 2023 Mar 28;24(1):96. doi: 10.1186/s12931-023-02404-7.
Interstitial lung diseases (ILD) encompass a heterogenous group of diffuse parenchymal lung disorders characterized by variable degrees of inflammation and fibrosis. Pretherapeutic clinical testing models for such diseases can serve as a platform to test and develop effective therapeutic strategies. In this study, we developed patient derived 3D organoid model to recapitulate the disease process of ILDs. We characterized the inherent property of invasiveness in this model and tested for antifibrotic responses with an aim to develop a potential platform for personalized medicine in ILDs.
In this prospective study, 23 patients with ILD were recruited and underwent lung biopsy. 3D organoid-based models (pulmospheres) were developed from the lung biopsy tissues. Pulmonary functioning testing and other relevant clinical parameters were collected at the time of enrollment and follow up visits. The patient derived pulmospheres were compared to normal control pulmospheres obtained from 9 explant lung donor samples. These pulmospheres were characterized by their invasive capabilities and responsiveness to the antifibrotic drugs, pirfenidone and nintedanib.
Invasiveness of the pulmospheres was measured by the zone of invasiveness percentage (ZOI%). The ILD pulmospheres (n = 23) had a higher ZOI% as compared to control pulmospheres (n = 9) (516.2 ± 115.6 versus 54.63 ± 19.6 respectively. ILD pulmospheres were responsive to pirfenidone in 12 of the 23 patients (52%) and responsive to nintedanib in all 23 patients (100%). Pirfenidone was noted to be selectively responsive in patients with connective tissue disease related ILD (CTD-ILD) at low doses. There was no correlation between the basal pulmosphere invasiveness, response to antifibrotics, and FVC change (Δ FVC).
The 3D pulmosphere model demonstrates invasiveness which is unique to each individual subject and is greater in ILD pulmospheres as compared to controls. This property can be utilized to test responses to drugs such as antifibrotics. The 3D pulmosphere model could serve as a platform for the development of personalized approaches to therapeutics and drug development in ILDs and potentially other chronic lung diseases.
间质性肺疾病（ILD）包含一组异质性弥漫性实质肺疾病，其特征为炎症和纤维化程度不同。此类疾病的治疗前临床检测模型可以作为测试和开发有效治疗策略的平台。在这项研究中，我们开发了患者来源的 3D 类器官模型，以重现ILD 的疾病过程。我们对该模型的固有侵袭性进行了特征描述，并测试了抗纤维化反应，旨在为 ILD 中的个体化医学开发提供一个潜在的平台。
在这项前瞻性研究中，招募了 23 名 ILD 患者进行肺活检。从肺活检组织中开发 3D 类器官模型（肺球体）。在入组时和随访时收集了肺功能检测和其他相关临床参数。将患者来源的肺球体与从 9 个供体肺样本中获得的正常对照肺球体进行比较。通过侵袭性百分比（ZOI%）测量肺球体的侵袭性。ILD 肺球体（n=23）的 ZOI%高于对照肺球体（n=9）（516.2±115.6 对 54.63±19.6）。ILD 肺球体对吡非尼酮（n=23 中的 12 例，52%）和尼达尼布（n=23 中的 23 例，100%）均有反应。在结缔组织疾病相关 ILD（CTD-ILD）患者中，低剂量的吡非尼酮被发现具有选择性反应。基底肺球体侵袭性、对抗纤维化药物的反应与 FVC 变化（ΔFVC）之间无相关性。
3D 肺球体模型显示出侵袭性，这是每个个体特有的，ILD 肺球体比对照肺球体更具侵袭性。该特性可用于测试抗纤维化药物等药物的反应。3D 肺球体模型可作为个体化治疗和 ILD 及潜在其他慢性肺部疾病药物开发的平台。
