Context
Histamine is an organic compound that plays a major role in the development of many allergic diseases. Mast cells are multifunctional bone marrow-derived tissue-dwelling cells that are responsible for a major part of histamine production in the body. Most allergic diseases are triggered by the interaction between an allergen and allergen-specific antibodies present on the membrane of mast cells and basophils. This interaction leads to the degranulation of these cells, which in turn provokes the release of many allergic and inflammatory biomarkers, including leukotrienes and histamine. Leukotrienes are inflammatory mediators produced in leukocytes from arachidonic acid by the enzyme 5-lipoxygenase (5-LO). For example in asthma, both the release of cysteinylleukotrienes and the release of histamine from degranulating mast cells are responsible for the narrowing of airways that happens during asthma attacks.
However, currently, there are no approved anti-asthma drugs that can simultaneously inhibit the biosynthesis of leukotrienes – by blocking the activity of the 5-LO enzyme – and mast cell degranulation. The only 5-LO inhibitor approved for the treatment of asthma, Zileuton, has limited efficacy which might be linked to its inability to affect mast cell degranulation [1]. Consequently, drugs that could simultaneously inhibit 5-LO and mast cell degranulation are increasingly being considered as promising therapeutic agents for asthma.
The objective of this study was to evaluate the ability of PH-251 – an oxazolidinone hydroxamic acid derivative known for its ability to strongly inhibit the 5-LO enzyme – to simultaneously inhibit mast cell degranulation. The Bertin Bioreagent Histamine ELISA kit (Bertin Bioreagent, Montigny-le-Bretonneux, France) was used to evaluate the anti-degranulatory effect of PH-251 on in vivo lung anaphylaxis (a severe allergic reaction to a chemical). Briefly, the kit was used to measure the histamine content in the lung lavage fluid of mice, as an indicator of mast cell degranulation.
