The impact of time intervals on drug efficacy and phenotypic outcomes in acute respiratory distress syndrome (ARDS) in mice.
Acute respiratory distress syndrome (ARDS) is a serious lung condition resulting from a variety of causes, with potentially fatal consequences requiring intensive care. This phenomenon can be modeled in preclinical models, notably by instilling lipopolysaccharide (LPS) in mice. The induced phenotype closely recapitulates the human syndrome, including pulmonary edema, leukocyte infiltration, acute inflammation, impaired lung function and histological damage. However, experimental designs using LPS instillations are extremely diverse in the literature. This greatly complicates the interpretation of the timing of the induced phenotype for the design of future studies, and hinders the proper identification of the optimal time frame for assessing different endpoints. Consequently, defining the treatment window in relation to the onset of disease also presents a significant challenge for addressing questions or testing the efficacy of compounds. In this context, the temporality of the different endpoints typically measured in the model was assessed in normal and neutrophil-depleted male C57bl/6 mice using LPS induction, in order to evaluate the best window for appropriate assessment of endpoints with optimal dynamic response range. Ventilation parameters were assessed by whole-body plethysmography, and neutrophil recruitment was evaluated in bronchoalveolar lavage fluids and directly in lung tissue. Myeloperoxidase imaging and activity in lysates and lung fluids were compared, as were inflammatory cytokines and pulmonary extravasation by enzyme-linked immunosorbent assays. In addition, dexamethasone, the reference positive control in this model, was also administered at different times before and after phenotype induction to assess how kinetics affected each parameter. Overall, our data demonstrate that each endpoint assessed in this study has singular kinetics, and highlight the crucial importance of the timing between ARDS phenotype and treatment administration and/or analysis. These results also strongly suggest that analyses, both in vivo and post-mortem, should be conducted at multiple time points to properly capture the dynamic phenotype of the LPS-induced ARDS model and its response to treatment.
Read the article here: https: //www.nature.com/articles/s41598-024-71659-x
TransBioTech researchers associated with the publication: Sarah Paris-Robidas, Carole-Ann Huppé, Frédéric Couture
