Asthma is now thought to affect 155 million people worldwide. In the United States alone there has been a recent two-fold increase in the number of cases of asthma driving pharmaceutical market values up to as high as $8 billion worldwide. Despite a large number of drugs available to clinicians, up to 15% of patients suffer from uncontrollable disease symptoms, increasing the demand for novel therapies that possess new modes of action. Asthma is an inflammatory disorder of the airways characterized by Th2 lymphocyte activation and hence the production of interleukin-4 (IL-4), IL-5, IL-9 and IL-13. This produces airway hyper-responsiveness (AHR), excessive mucus production and chronic eosinophilic inflammation. Although the development of anti-inflammatories represents an obvious way forward for the treatment of asthma, the identification of suitable targets represents a considerable challenge. Lipoxins (LX) are leukocyte-derived eicosanoids generated during inflammation that act to down-regulate the inflammatory process. Boston based researchers have recently published data from a murine model of asthma that supports the targeting of the leukocyte receptor for LXA4 during pulmonary inflammation. This research group found that allergen challenge initiated airway biosynthesis of LXA4 and increased expression of its receptor. Administration of a stable analog of LXA4 blocked both airway hyper-responsiveness and pulmonary inflammation, as shown by decreased leukocytes and mediators, including interleukin-5, interleukin-13, eotaxin, prostanoids and cysteinyl leukotrienes. Moreover, transgenic expression of human LXA4 receptors in murine leukocytes led to significant inhibition of pulmonary inflammation and eicosanoid-initiated eosinophil tissue infiltration. These anti-inflammatory effects along with earlier studies showing that LXA4 modulates LTC4-induced airway obstruction in human asthmatics suggest that pharmaceutical development of LXA4 mimics may offer an advance in the treatment of asthma. To date however few such molecules have been developed and LXA4 therefore represents an under-exploited field.

Entry date October, 2002

Adapted from Levy et al, Nat Med 2002 Sep;8(9):1018-23

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk