Anti-inflammatory therapies from bedside to bench: Frameworks to support preclinical development

The discovery of anti-inflammatory therapies is a top priority for people suffering from respiratory diseases. However, the limited clinical efficacy of new drugs-often not predicted in preclinical studies-underscores the need for improved evaluation criteria. This study retrospectively evaluates marketed anti-inflammatory therapies with different mechanisms of action (azithromycin, ibuprofen, and dexamethasone) to identify suitable preclinical models and biomarkers for efficacy testing. Lipopolysaccharide (LPS) exposure and both acute and chronic Pseudomonas aeruginosa lung infection models, using different treatment regimens, initiated either immediately or seven days after infection, were compared. Our results demonstrate that only the chronic P. aeruginosa infection model reliably detected therapeutic effects, making it the most appropriate for evaluating anti-inflammatory therapies in respiratory conditions. All tested drugs improved body weight and reduced inflammatory markers in the lung, including cell recruitment, myeloperoxidase, neutrophil elastase, and key cytokines, whereas blood cell measurements proved less reliable. Bacterial load was shown to improve alongside the amelioration of the immune response. In contrast, dexamethasone alone was effective in the LPS model, while the acute infection model showed worsening inflammation. These findings highlight the value of the chronic P. aeruginosa model, which remains underused in preclinical research, and support its broader adoption in testing anti-inflammatory therapies for respiratory diseases.