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by N Fransén Pettersson, C Carvalho, I Mahmutovic Persson, H Falk-Håkansson, J Liu, L E Olsson, K Von Wachenfeldt

European Respiratory Journal 2022 60: 2542 (conference abstract). doi: 10.1183/13993003.congress-2022.2542

Abstract

Drug-induced interstitial lung disease (DIILD) is underdiagnosed with increasing incidence. To better diagnose and treat DIILD, translational animal models are warranted. Methotrexate (MTX) is commonly used in patients who present with DIILD. Studies indicate that MTX alone does not induce DIILD, rather underlying genetic/environmental factors or combination therapies seem to have an impact on DIILD development. Here, we attempted to develop a translational chronic model of MTX-induced ILD.

MTX was given to mice or rats, by different routes/concentrations/time points (Table). Histological assessment was the main readout in all studies, with additional MRI and lung function measurements, in selected animal groups. Histology showed limited fibrosis and/or inflammation in MTX treated animals, which developed in some of the animals, across various treatment groups. Appeared lung lesions resided from the vasculature. In cases of detected ILD, also systemic effects in other organs were present. However, there was no correlation between disease severity/dose/frequency of MTX administration.

Conclusion: Neither disease incidence nor severity correlated with MTX concentration or exposure route/time. These observations correspond to clinical observations, where MTX treatment alone does not seem to induce DIILD. Therefore, using MTX only as a DIILD-inducing agent in preclinical research poses great challenges.