Targeted Alveolar Type II Epithelial Cell Apoptosis Augments Fibrosis in a MUC5B-Overexpression Model

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Abstract Rationale: The gain-of-function minor T allele variant in the MUC5B promoter (rs35705950) is a major risk factor for the development of idiopathic pulmonary fibrosis (IPF), increasing the odds of disease over 20-fold due to misexpression in distal airway epithelia. However, the mechanisms linking MUC5B misexpression in distal airways to the development of fibrosis are not well understood. We hypothesized that MUC5B misexpression in distal airways increases the sensitivity of the alveolar epithelium to injury leading to increased fibrosis. We tested this hypothesis using an ablation strategy targeting type II alveolar epithelial cells (AEC2s) in mice overexpressing Muc5b in airway epithelial cells. Methods: We used transgenic mice overexpressing Muc5b in CCSP+ distal airway cells crossed to mice with diphtheria toxin (DTR) receptor expression in SPC+ type AEC2 (SPC-DTR;Ccsp-Muc5bTg). Five mice per group received diphtheria toxin (10ng/g) or saline daily for 7 days by intratracheal instillation and assessed after 3 weeks. SPC-DTR and Ccsp-Muc5bTg mice served as controls. Lung fibrosis was assessed using hydroxyproline to measure collagen, trichome staining and quantitation of fibroblasts and AEC2 using flow cytometry. Sections were immunostained for PDGFRα, PDGFRβ, pro-SPC, CCSP and Muc5b. Results: After intratracheal administration of DT, there was a significant decrease in AEC2 cells in the SPC-DTR and SPC-DTR:Ccsp-Muc5bTg mice compared to the Ccsp-Muc5bTg controls. Using hydroxyproline as a marker for collagen, there was increased collagen deposition in SPC-DTR mice following treatment with DT, which was further increased in the setting of Muc5b overexpression in the distal airway. This was also associated with an increase in PDGFRα+ fibroblast accumulation in the lungs of SPC-DTR;Ccsp-Muc5b mice after DT administration and AEC2 ablation. Conclusion: Our results show that while AEC2 death can initiate a mild fibrotic response, fibrosis is increased in the setting Muc5b-overexpression by airway epithelial cells, resulting in increased fibroblast accumulation and collagen deposition. Thus, further studies are warranted to elucidate the mechanistic relationship between epithelial cells with Muc5b misexpression and the fibroblast response after distal lung injury.

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