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Mice Lacking 12/15-Lipoxygenase Have Attenuated Airway Allergic Inflammation and Remodeling

¹ Department of Lung Medicine, Lund University Hospital, Lund, Sweden; ² Orexo AB, Stockholm, Sweden; ³ Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; and ⁴ Department of Experimental Medical Science, Lund University, Lund, Sweden

Correspondence and requests for reprints should be addressed to Jonas Erjefält, Ph.D., Assoc. Prof., Department of Experimental Medical Science, Unit of Airway Inflammation, BMC D12, Lund University, 221 84, Lund, Sweden. E-mail: jonas.erjefalt{at}med.lu.se

Arachidonate 15-lipoxygenase (LO)-1 has been implicated in allergic inflammation and asthma. The overall effect of 15-LO in allergic inflammation in vivo is, however, unclear. This study investigates systemic allergen sensitization and local allergic airway inflammation and remodeling in mice lacking the murine 12/15-LO, the ortholog to human 15-LO-1. Upon systemic sensitization with intraperitoneal ovalbumin, 12/15-LO^–/– mice produced elevated levels of allergen-specific immunoglobulin E compared with wild-type (Wt) controls. However, when challenged with repeated aerosolized allergen, sensitized 12/15-LO^–/– mice had an impaired development of airway allergic inflammation compared with Wt controls, as indicated by reduced bronchoalveolar lavage fluid leukocytes (eosinophils, lymphocytes, macrophages) and Th₂ cytokines (IL-4, IL-5, IL-13), as well as tissue eosinophils. Allergen-induced airway epithelial proliferation was also significantly attenuated in 12/15-LO^–/– mice, whereas goblet cell hyperplasia was unaffected. However, 12/15-LO^–/– mice had significantly reduced luminal mucus secretions compared with Wt controls. The repeated allergen challenges resulted in a dramatic increase of -smooth muscle actin–positive alveolar cells in the peripheral airways, a phenomenon that was significantly less developed in 12/15-LO^–/– mice. In conclusion, our data suggest that 12/15-LO^–/– mice, although having a fully developed systemic sensitization, did not establish a fully developed allergic airway inflammation and associated manifestations of central and peripheral airway remodeling. These data suggest that 12/15-LO–derived metabolites play an important pathophysiologic role in allergen-induced inflammation and remodeling. Hence, pharmacologic targeting of the human 15-LO-1 may represent an attractive therapeutic strategy to control inflammation and remodeling in asthma.

Key Words: allergy • 15-LO • asthma • remodeling

CLINICAL RELEVANCE This study shows that while 12/15-lipoxygenase (LO) is not needed for allergen sensitization, it is crucial for manifestation of allergen-induced inflammation and remodeling. Hence, targeting 15-LO-1 represents an attractive therapeutic strategy in asthma control.