Contribution of collagen XIII to lung function and development of pulmonary fibrosis

Abstract

BackgroundCollagen 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.MethodsWe 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 exposedCol13a1-modified mice to bleomycin-induced pulmonary fibrosis.ResultsApparently 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.ConclusionsChanges 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.

Inhibiting autophagy affects collagen degradation by TGF-β1 in the bronchial fibroblasts of rats

“…The most highly expressed TGF-β subtype in the human airway is transforming growth factor beta-1 (TGF-β1), which is known as a brogenic factor, a powerful inducer of collagen synthesis, and an important mediator of extracellular matrix formation. They have a direct impact on the collagen deposited in the airway wall, which encourages the development of brosis [23][24][25]. TGF-β1 regulates collagen breakdown in MMPs and TIMPs and plays a crucial role in airway remodeling through TGF-β1/Smad and NF-κb-class signaling pathways [24].…”

“…They have a direct impact on the collagen deposited in the airway wall, which encourages the development of brosis [23][24][25]. TGF-β1 regulates collagen breakdown in MMPs and TIMPs and plays a crucial role in airway remodeling through TGF-β1/Smad and NF-κb-class signaling pathways [24]. McAlinden et al found that TGF-β1 inhibits autophagy and promotes the formation and deposition of ECM in myo broblasts, leading to enhanced brotic signaling [26].…”

TGF-β1 inhibits autophagy and collagen degradation in rat bronchial fibroblasts

“…The most highly expressed transforming growth factor beta (TGF-β) subtype in the human airway is TGF-β1, which is known as a brogenic factor, a powerful inducer of collagen synthesis, and an important mediator of extracellular matrix formation. TGF-β1 expression has a direct impact on the collagen deposited in the airway wall, which encourages the development of brosis [23][24][25]. TGF-β1 regulates collagen breakdown along with MMPs and TIMPs and plays a crucial role in airway remodeling through the TGF-β1/Smad and NF-κb-class signaling pathways [24].…”

“…TGF-β1 expression has a direct impact on the collagen deposited in the airway wall, which encourages the development of brosis [23][24][25]. TGF-β1 regulates collagen breakdown along with MMPs and TIMPs and plays a crucial role in airway remodeling through the TGF-β1/Smad and NF-κb-class signaling pathways [24]. McAlinden et al found that TGF-β1 inhibits autophagy and promotes the formation and deposition of ECM in myo broblasts, leading to enhanced brotic signaling [26].…”