Use of a pulmosphere model to evaluate drug antifibrotic responses in interstitial lung diseases

Abstract

Background 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. Methods 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. Results 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). Conclusions 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.

The evolution ofin vitromodels of lung fibrosis: promising prospects for drug discovery

“…Interestingly, pulmosphere invasiveness was altered in presence of antifibrotic molecules, such as pirfenidone and nintedanib. In this context, a very recent study [ 59 ] found that pulmospheres derived from transbronchial biopsies of individuals with non-IPF ILDs exhibit a higher degree of invasiveness when compared to control samples. This level of invasiveness was found to correlate with a decline in forced vital capacity within 6–12 months post-biopsy.…”

Alveolar Organoids in Lung Disease Modeling

“…Interstitial lung diseases (ILD) include parenchymal lung diseases with similar clinical properties and impaired repair after injury [22]. They possess divergent physiological mechanisms and are classified based on various phenotypes, such as autoimmune and unclassifiable ILD, exposure-related, sarcoidosis, idiopathic nonspecific interstitial pneumonia, and chronic hypersensitivity [22,23]. Idiopathic pulmonary fibrosis (IPF) belongs to ILD, and the disease's main etiology is not well understood.…”