Idiopathic pulmonary fibrosis (IPF) is an incurable genetic disease that affects 5 million people worldwide. The gain-of-function MUC5B promoter variant rs35705950 is the dominant genetic risk factor for IPF yet has a low penetrance. This raises the possibility that other genes and transcripts affect the penetrance of MUC5B. Previously, we have shown that the concentration of Muc5b in bronchoalveolar epithelia is directly associated with the extent and persistence of bleomycin-induced lung fibrosis in mice. In this study, we investigated whether bleomycin-induced lung injury is Muc5b dependent in genetically divergent strains of mice. Specifically, mice from the eight Diversity Outbred (DO) founders were phenotyped for Muc5b expression and lung fibrosis three weeks after intratracheal bleomycin administration. While we identified strains with low Muc5b expression and minimal lung fibrosis (CAST/EiJ and PWK/PhJ) and strains with high Muc5b expression and extensive lung fibrosis (NZO/H1LtJ and WSB/EiJ), there also were strains that did not demonstrate a clear relationship between Muc5b expression and lung fibrosis (129S1/SvlmJ, NOD/ShiLtJ, and C57BL/6J, A/J). Hierarchical clustering suggests that other factors may work in concert with or potentially independent of Muc5b to promote bleomycin-induced lung injury and fibrosis. This study suggests that these strains and their recombinant inbred crosses may prove helpful in identifying the genes and transcripts that interact with Muc5b and cause lung fibrosis.

中文翻译：

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Muc5b 以外的基因在博来霉素诱导的肺纤维化中发挥作用

特发性肺纤维化 (IPF) 是一种无法治愈的遗传病，影响着全世界 500 万人。功能获得性 MUC5B 启动子变体 rs35705950 是 IPF 的主要遗传风险因素，但外显率较低。这增加了其他基因和转录物影响 MUC5B 外显率的可能性。以前，我们已经表明，支气管肺泡上皮细胞中 Muc5b 的浓度与博来霉素诱导的小鼠肺纤维化的程度和持续性直接相关。在这项研究中，我们调查了博来霉素诱导的肺损伤是否依赖于基因不同品系的小鼠的 Muc5b。具体来说，在气管内给予博来霉素三周后，对来自八个多样性杂交 (DO) 创始人的小鼠进行 Muc5b 表达和肺纤维化的表型分析。虽然我们确定了具有低 Muc5b 表达和最小肺纤维化的菌株（CAST/EiJ 和 PWK/PhJ）和具有高 Muc5b 表达和广泛肺纤维化的菌株（NZO/H1LtJ 和 WSB/EiJ），但也有一些菌株没有表现出Muc5b 表达与肺纤维化之间的明确关系（129S1/SvlmJ、NOD/ShiLtJ 和 C57BL/6J、A/J）。层次聚类表明，其他因素可能与 Muc5b 协同作用或可能独立于 Muc5b，以促进博来霉素诱导的肺损伤和纤维化。这项研究表明，这些菌株及其重组近交系可能有助于鉴定与 Muc5b 相互作用并导致肺纤维化的基因和转录物。