Allergic airway disease is characterized by a T helper type 2 cell-mediated airway inflammation and airway hyperresponsiveness. Little is known about the role of hypoxia-mediated signaling in the progression of the disease. To address this knowledge gap, a mouse model was created in which doxycycline exposure induces the functional deletion of hypoxia inducible factor-1α/2α, or 1/2α from alveolar type II and Clara cells of the lung. When hypoxia inducible factor-1α deletion was induced during the early post-natal development period of the lung, the mice displayed an enhanced response to the ovalbumin model of allergic airway disease. These hypoxia inducible factor-1α-deficient mice exhibit increased cellular infiltrates, eosinophilia in the lavage fluid and parenchyma, and T helper type 2 cytokines, as compared with ovalbumin-treated control mice. Moreover, these hypoxia inducible factor-1α deficient mice displayed increased airway resistance when compared to their control counterparts. Interestingly, if the loss of hypoxia inducible factor-1α was induced in early adulthood, the exacerbated phenotype was not observed. When the HIF2α deletion was induced during the early post-natal development period of the lung, the HIF2α-deficient mice were not significantly different from their HIF2α-sufficient counterparts. When the HIF1/2α deletion was induced in the early post-natal development period of the lung, the HIF1/2α-deficient mice seemed to be somewhat protected from the increase in cellular infiltrates and eosinophils. Taken together, these results suggest that epithelial hypoxia inducible factor-1α plays an important role in establishing the innate immunity of the lung, and epithelial-specific deficiency in the transcription factor during early post-natal development increases the severity of inflammation and functional airway resistance, following ovalbumin challenge. Also, the balance between HIF1α and HIF2α levels seems to be important when mounting an immune response. Hyperoixa experiments were also used to aid in identification of potential epithelial signaling factors responsible for the changes in immunity. Different populations of dendritic cells were examined via flow cytometry to determine if they were different after loss of HIF1α. There was a slight increase in plasmacytoid dendritic cells in HIF1α-deficient lungs. These results might explain some of the chronic respiratory pathology observed in premature infants, especially those who receive supplemental oxygen. This early hyperoxic exposure, from normal ambient and supplemental oxygen, would presumably inhibit normal hypoxia inducible factor-1α signaling, mimicking the functional deletion described.
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