Published ahead of print on May 29, 2008, doi:10.1165/rcmb.2007-0443OC Am. J. Respir. Cell Mol. Biol., Volume 39, Number 6, December 2008, 648-656 A more recent version of this article appeared on December 1, 2008
Submitted on December 10, 2007 Mice Lacking 12/15-Lipoxygenase have Attenuated Airway Allergic Inflammation and RemodelingCecilia K Andersson1,1 Department of Lung Medicine, Lund University Hospital, Lund, Sweden, 2 Orexo AB, Stockholm, Sweden; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden, 3 Department of Experimental Medical Science, Lund University, Lund, Sweden, 4 Orexo AB, Stockholm, Sweden, 5 Department of Lung Medicine, Lund University Hospital, Lund, Sweden; Department of Experimental Medical Science, Lund University, Lund, Sweden * To whom correspondence should be addressed. 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 IgE compared to 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 to Wt controls, as indicated by reduced BAL 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 to Wt controls. The repeated allergen challenges resulted in a dramatic increase of
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-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 pathophysiological 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.
