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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 orcid ; Swedmark, Stellan ; Hallgren, Anneli and Erjefält, Jonas LU (2008) In American Journal of Respiratory Cell and Molecular Biology 39(6). 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
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Allergens, Animals, Antibodies, Antibody Specificity, Apoptosis, Arachidonate 12-Lipoxygenase, Arachidonate 15-Lipoxygenase, Caspase 3, Cell Count, Cytokines, Eosinophilia, Goblet Cells, Hyperplasia, Hypersensitivity, Immunization, Inflammation, Leukocytes, Lung, Mice, Mice, Inbred C57BL, Ovalbumin, Journal Article, Research Support, Non-U.S. Gov't
in
American Journal of Respiratory Cell and Molecular Biology
volume
39
issue
6
pages
9 pages
publisher
American Thoracic Society
external identifiers
  • wos:000261259500004
  • pmid:18511709
  • scopus:57349164262
  • pmid:18511709
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
2016-04-04 08:50:06
date last changed
2022-04-23 18:04:38
@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}},
  keywords     = {{Allergens; Animals; Antibodies; Antibody Specificity; Apoptosis; Arachidonate 12-Lipoxygenase; Arachidonate 15-Lipoxygenase; Caspase 3; Cell Count; Cytokines; Eosinophilia; Goblet Cells; Hyperplasia; Hypersensitivity; Immunization; Inflammation; Leukocytes; Lung; Mice; Mice, Inbred C57BL; Ovalbumin; Journal Article; Research Support, Non-U.S. Gov't}},
  language     = {{eng}},
  number       = {{6}},
  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}},
  doi          = {{10.1165/rcmb.2007-0443OC}},
  volume       = {{39}},
  year         = {{2008}},
}