MULTI-PRONGED INHIBITION OF AIRWAY HYPER-RESPONSIVENESS AND INFLAMMATION BY LIPOXIN A4

Abstract

Levy BD, De Sanctis GT, Devchand PR, et al. Nature Med. 2002;8:1018–1023To investigate the potential counterregulatory role of lipoxin A4 (LXA4) and lipoxin A4 receptors (ALX) in allergic pulmonary inflammation and bronchial hyperresponsiveness (BHR) in asthma.In a murine model of allergic asthma, pulmonary inflammation and BHR with administration of a lipoxin A4 analog (LXa) was studied. Transgenic mice expressing human LXA4 receptors were also studied.LXa, administered intravenously after allergen sensitization and before airways allergen exposure, significantly reduced both BHR and allergic pulmonary inflammation, including eosinophils, lymphocytes, interleukin (IL)-5, IL-13, eotaxin, and cysteinyl leukotrienes. Similar findings were observed in transgenic mice that constitutively expressed human LXA4 receptors.Lipoxin A4 and its analog offer a novel therapeutic approach to the treatment of BHR and pulmonary inflammation in asthma.Lipoxins are endogenously produced eicosanoids with antiinflammatory actions. LXA4, the best-studied member of this family, has antiinflammatory activities in in vitro and in vivo model systems. Its antiinflammatory actions include downregulation of proinflammatory cytokines and chemokines involved in neutrophil and eosinophil trafficking, inhibition of cytokine-stimulated metalloproteinase activity and cell proliferation, and stimulation of macrophage clearance of apoptotic cells from an inflammatory focus. LAX4 has recently been shown to interfere with cysteinyl leukotriene (cysLT)-mediated inflammation by competitively binding the cysLT1 receptor. This and another recent study (Bonnas C, et al, Am J Respir Crit Care Med. 2002;165:1531–1535) reveal the therapeutic potential of LXA4 in asthma. Other potential applications of LAX4 are for topical use as an antiinflammatory agent for inflammatory skin conditions (Schottelius AJ, et al, J Immunol. 2002;169:7063–7070). Given the efficacy of the compound, LAX4 may be a compelling alternative to corticosteroids in certain clinical settings. A commentary on this study, titled “Good Lipids for Asthma” by Peters-Golden on pages 931–932 of the same issue, and an article titled “Lipoxins: Revelations on Resolution” by McMahon et al in Trends in Pharmacological Sciences (2001;22:391–395) are suggested for further review.