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

Andersson, Cecilia LU ; Claesson, Hans-Erik; Rydell-Törmänen, Kristina LU ; Swedmark, Stellan; Hallgren, Anneli and Erjefält, Jonas LU (2008) In American Journal of Respiratory Cell and Molecular Biology 39. p.648-656
Abstract
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... (More)
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 alpha-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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
American Journal of Respiratory Cell and Molecular Biology
volume
39
pages
648 - 656
publisher
American Thoracic Society
external identifiers
  • wos:000261259500004
  • pmid:18511709
  • scopus:57349164262
ISSN
1535-4989
DOI
10.1165/rcmb.2007-0443OC
language
English
LU publication?
yes
id
db1b4c59-25bf-4e03-a723-2123de661d8b (old id 1153677)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18511709?dopt=Abstract
date added to LUP
2008-06-02 10:33:52
date last changed
2017-11-05 04:44:09
@article{db1b4c59-25bf-4e03-a723-2123de661d8b,
  abstract     = {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 alpha-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.},
  author       = {Andersson, Cecilia and Claesson, Hans-Erik and Rydell-Törmänen, Kristina and Swedmark, Stellan and Hallgren, Anneli and Erjefält, Jonas},
  issn         = {1535-4989},
  language     = {eng},
  pages        = {648--656},
  publisher    = {American Thoracic Society},
  series       = {American Journal of Respiratory Cell and Molecular Biology},
  title        = {Mice Lacking 12/15-Lipoxygenase have Attenuated Airway Allergic Inflammation and Remodeling.},
  url          = {http://dx.doi.org/10.1165/rcmb.2007-0443OC},
  volume       = {39},
  year         = {2008},
}