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Abstract：
BACKGROUND: Collagen XIII is a transmembrane collagen associated with neuromuscular junction development, and in humans its deficiency results in congenital myasthenic syndrome type 19 (CMS19), which leads to breathing difficulties. CMS19 patients usually have restricted lung capacity and one patient developed chronic lung disease. In single-cell RNA sequencing studies, collagen XIII has been identified as a marker for pulmonary lipofibroblasts, which have been implicated in the resolution of pulmonary fibrosis.
METHODS: We investigated the location and function of collagen XIII in the lung to understand the origin of pulmonary symptoms in human CMS19 patients. Additionally, we performed immunostainings on idiopathic pulmonary fibrosis (IPF) samples (N=5) and both normal and fibrotic mouse lung. To study whether the lack of collagen XIII predisposes to restrictive lung disease, we exposed Col13a1-modified mice to bleomycin-induced pulmonary fibrosis.
RESULTS: Apparently normal alveolar septum sections of IPF patients\' lungs stained faintly for collagen XIII, and its expression was pinpointed to the septal fibroblasts in the mouse lung. Lung capacity was increased in mice lacking collagen XIII by over 10%. In IPF samples, collagen XIII was expressed by basal epithelial cells, hyperplastic alveolar epithelial cells and stromal cells in fibrotic areas, but the development of pulmonary fibrosis was unaffected in collagen XIII-deficient mice.
CONCLUSIONS: Changes in mouse lung function appear to represent a myasthenic manifestation of collagen XIII deficiency. We suggest that respiratory muscle myasthenia is the primary cause of the breathing problems suffered by CMS19 patients in addition to skeletal deformities. Induction of collagen XIII expression in the IPF patients\' lungs warrants further studies to reveal collagen XIII-dependent disease mechanisms.
METHODS: We investigated the location and function of collagen XIII in the lung to understand the origin of pulmonary symptoms in human CMS19 patients. Additionally, we performed immunostainings on idiopathic pulmonary fibrosis (IPF) samples (N=5) and both normal and fibrotic mouse lung. To study whether the lack of collagen XIII predisposes to restrictive lung disease, we exposed Col13a1-modified mice to bleomycin-induced pulmonary fibrosis.
RESULTS: Apparently normal alveolar septum sections of IPF patients\' lungs stained faintly for collagen XIII, and its expression was pinpointed to the septal fibroblasts in the mouse lung. Lung capacity was increased in mice lacking collagen XIII by over 10%. In IPF samples, collagen XIII was expressed by basal epithelial cells, hyperplastic alveolar epithelial cells and stromal cells in fibrotic areas, but the development of pulmonary fibrosis was unaffected in collagen XIII-deficient mice.
CONCLUSIONS: Changes in mouse lung function appear to represent a myasthenic manifestation of collagen XIII deficiency. We suggest that respiratory muscle myasthenia is the primary cause of the breathing problems suffered by CMS19 patients in addition to skeletal deformities. Induction of collagen XIII expression in the IPF patients\' lungs warrants further studies to reveal collagen XIII-dependent disease mechanisms.
摘要：
背景：胶原蛋白XIII是一种与神经肌肉接头发育相关的跨膜胶原蛋白，在人类中，其缺乏导致19型先天性肌无力综合征（CMS19），导致呼吸困难.CMS19患者通常肺活量受限，一名患者出现慢性肺病。在单细胞RNA测序研究中，胶原蛋白XIII已被确定为肺脂成纤维细胞的标志物，这与肺纤维化的解决有关。
方法：我们研究了胶原蛋白XIII在肺中的位置和功能，以了解人类CMS19患者肺部症状的起源。此外,我们对特发性肺纤维化（IPF）样本（N=5）以及正常和纤维化小鼠肺进行了免疫染色。为了研究缺乏胶原蛋白XIII是否容易导致限制性肺病，我们将Col13a1修饰的小鼠暴露于博来霉素诱导的肺纤维化。
结果：IPF患者肺的肺泡隔切片明显正常，对胶原蛋白XIII有微弱的染色，其表达在小鼠肺中隔成纤维细胞中被精确定位。缺乏胶原蛋白XIII的小鼠的肺容量增加超过10%。在IPF样本中，胶原XIII由基底上皮细胞表达，增生性肺泡上皮细胞和纤维化区域的基质细胞，但是，在胶原蛋白XIII缺乏的小鼠中，肺纤维化的发展不受影响。
结论：小鼠肺功能的变化似乎代表了XIII型胶原缺乏的肌无力表现。我们建议呼吸肌肌无力是CMS19患者除骨骼畸形外还遭受呼吸问题的主要原因。IPF患者肺中胶原蛋白XIII表达的诱导值得进一步研究以揭示胶原蛋白XIII依赖性疾病机制。
方法：我们研究了胶原蛋白XIII在肺中的位置和功能，以了解人类CMS19患者肺部症状的起源。此外,我们对特发性肺纤维化（IPF）样本（N=5）以及正常和纤维化小鼠肺进行了免疫染色。为了研究缺乏胶原蛋白XIII是否容易导致限制性肺病，我们将Col13a1修饰的小鼠暴露于博来霉素诱导的肺纤维化。
结果：IPF患者肺的肺泡隔切片明显正常，对胶原蛋白XIII有微弱的染色，其表达在小鼠肺中隔成纤维细胞中被精确定位。缺乏胶原蛋白XIII的小鼠的肺容量增加超过10%。在IPF样本中，胶原XIII由基底上皮细胞表达，增生性肺泡上皮细胞和纤维化区域的基质细胞，但是，在胶原蛋白XIII缺乏的小鼠中，肺纤维化的发展不受影响。
结论：小鼠肺功能的变化似乎代表了XIII型胶原缺乏的肌无力表现。我们建议呼吸肌肌无力是CMS19患者除骨骼畸形外还遭受呼吸问题的主要原因。IPF患者肺中胶原蛋白XIII表达的诱导值得进一步研究以揭示胶原蛋白XIII依赖性疾病机制。
