期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 21, 页码 8084-8089出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0602357103
关键词
asthma; allergy; innate immunity; lung
资金
- NHLBI NIH HHS [R01 HL061005, HL-36577, HL-61005, P01 HL036577-21A15977, P01 HL036577] Funding Source: Medline
- NIAID NIH HHS [AI-31105, R01 AI031105] Funding Source: Medline
- NIDDK NIH HHS [K08 DK064790, K08 DK064790-01] Funding Source: Medline
Exposure to inhaled allergens leads to increases in airway hyper-responsiveness (AHR) and inflammation, associated with increased levels of biologically active fragments derived from the complement C3 and C5 family of proteins. Further, complement activation during allergen challenge in sensitized animals is necessary for the development of AHR and airway inflammation. To define the complement pathway involved, we studied mice deficient in complement factor 4 (C4-/-), a critical component of the classical pathway, or factor B (fB-/-), an essential protein in the alternative complement pathway. WT, C4-/-, and fB-/- mice were sensitized to ovalbumin and subsequently exposed to nebulized ovalbumin (1% in saline) on 3 consecutive days. After allergen sensitization and challenge, fB-/- mice demonstrated significantly lower airway responsiveness to methacholine and less airway inflammation. In contrast, C4-/- mice showed no reduction in AHR and airway inflammation compared with WT mice. Tissue inflammation, goblet cell hyperplasia, and IL-4, IL-5, and IL-13 levels in BAL fluid were significantly reduced in fB-/- mice compared with C4-/- and WT mice. The development of AHR and airway inflammation in sensitized fB-/- mice could be restored after intranasal administration of purified factor B before the airway challenge. In addition, administration of a neutralizing anti-factor B mAb to sensitized mice before airway challenge reduced the development of AHR and airway inflammation. These results demonstrate that in sensitized hosts complement activation through the alternative pathway after allergen exposure is critical to the development of AHR and airway inflammation.
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