Treating inflammation in respiratory diseases by inhaled aryl hydrocarbon receptor ligands and activators
M Puccetti1, M. Pariano 2, D. Traini3, W. Paulina1, A. Schoubben1, M. Ricci1 & S. Giovagnoli1
1Department of Pharmaceutical Science, University of Perugia, Perugia,06123,Italy
2Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy
3Macquarie Medical School, Faculty of Medicine, Health, and Human Sciences, Macquarie University, Sydney, NSW 2109, & The Woolcock Institute of Medical Research, Sydney, NSW, 2031, Australia
Summary
Due to mechanical, chemical and immunological barriers to the respiratory tract, pulmonary drug delivery is complex and demands strategies and formulations that maximize airway selectivity. The association between inflammation and chronic disease is still under investigation and how to translate the body of knowledge into effective strategies for the prevention and treatment of pathologic inflammation is lagging. In this regard, in this study, a dry powder formulation acting on the xenobiotic aryl hydrocarbon receptor (AhR) to regulate lung function and inflammation is presented and in vivo pharmacological properties and toxicity are assessed. Targeting of AhR is of great medical and pharmaceutical interest for inhaled therapies targeting diseases in which immunopathology plays a pathogenetic role. However, despite the availability of several structurally diverse ligands of AhR, the bottleneck in targeting this receptor is its ubiquitous expression and its functional activity that is both contexts and ligand-dependent. In this study, we provide a proof-of-concept demonstration of the druggability of AhR in lung inflammation via inhalable dry powders of either the tryptophan metabolite of microbial origin, indole-3-aldehyde, an AhR ligand, or of the recombinant form of the endogenous IL-1 receptor antagonist (anakinra), an AhR modulator. Either immunomodulatory treatment resolved inflammation without compromising the ability of the immune system to respond to pathogens and with no signs of unwanted toxicities and off-target effects.
Key Message
This study provides proof of concept for the development of inhaled medicines targeting xenobiotic receptors as an anti-inflammatory therapy for respiratory diseases.