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Asthma-associated allergen Alternaria induces STAT6 dependent epithelial FIZZ1 that promotes airway fibrosis


Alternaria is a fungal allergen whereby sensitization to it serves as a risk factor for the development, persistence, and severity of asthma. Naïve WT C57/B6 mice received one intranasal challenge with Alternaria, Candida, or Aspergillus allergen extracts and airway eosinophil numbers analyzed 24 hours later. RNA from airway epithelial cells was processed for gene microarray analysis. Lung cells from naïve WT and collagen-1 GFP mice were incubated with rFIZZ1, stained for cell type, and analyzed by FACS. Mice received rFIZZ1 repetitively and airway eosinophils and lung histology were analyzed. Finally, WT and STAT6-/- bone marrow chimeric mice were challenged with Alternaria and airway eosinophil levels determined. Only naïve mice that received one Alternaria challenge developed significant airway eosinophilia. Gene microarray analysis of airway epithelial cells demonstrated that Alternaria-challenged WT mice had an over 20-fold increase in expression of "Found in Inflammatory Zone 1" (FIZZ1/Retnla). Epithelial FIZZ1 and BAL eosinophils were reduced in STAT6-deficient, but not PAR-2-deficient mice. rFIZZ1 displayed binding to CD45⁺CD11c⁺ (macrophages and dendritic cells) and collagen -1 producing CD45⁻ cells (fibroblasts). Administration of rFIZZ1 to naïve WT mice led to airway eosinophilia, peribronchial fibrosis, and increased thickness of the airway epithelium. Irradiated WT mice that received STAT6- deficient bone marrow showed reduced airway eosinophils after Alternaria challenge compared with irradiated STAT6- deficient mice that received WT bone marrow. Alternaria induces acute airway eosinophilia dependent on STAT6 expressed in hematopoetic cells. Epithelial FIZZ1 expression is induced by Alternaria that binds to collegen -1 producing cells and promotes airway fibrosis and epithelial thickness

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