Muc5b Enhances Murine Honeycomb-like Cyst Formation

Kurche, Jonathan S.; Dobrinskikh, Evgenia; Hennessy, Corinne E.; Huber, Jonathan; Estrella, A.M.; Hancock, Laura A.; Schwarz, Marvin I.; Okamoto, Tsukasa; Cool, Carlyne D.; Yang, Ivana V.; Evans, Christopher M.; Schwartz, David A.

doi:10.1165/rcmb.2019-0138le

Cited by 21 publications

(14 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To determine whether SOX2+ progenitors have similar migratory capacity in a fibrotic model, we adapted a repetitive bleomycin model of lung fibrosis that better captured features of IPF compared to the single dose model, including the appearance of cystic airspaces and metaplastic basal cells in the alveoli ( Extended Data Fig. 1a , b ) 17 , 18 . Our genetic lineage tracing confirms that Sox2 lineage traced ( Sox2 Lin+) airway progenitors expand and differentiate into metaplastic KRT5+/SOX2+ or endogenous SFTPC+/SOX2-epithelium in the alveoli in this model of severe fibrotic injury ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Gli1+ mesenchymal stromal cells form a pathological niche to promote airway progenitor metaplasia in the fibrotic lung

Cassandras¹,

Wang²,

Kathiriya³

et al. 2020

Nat Cell Biol

View full text Add to dashboard Cite

Aberrant epithelial reprogramming can induce metaplastic differentiation at sites of tissue injury, culminating in transformed barriers composed of scar and metaplastic epithelium. While the plasticity of epithelial stem cells is well-characterized, the identity and role of the niche has not been delineated in metaplasia. Here we show that Gli1 + mesenchymal stromal cells (MSCs), previously shown to contribute to myofibroblasts during scarring, promote metaplastic differentiation of airway progenitors into KRT5+ basal cells. During fibrotic repair, Gli1 + MSCs integrate hedgehog activation to upregulate BMP antagonism in the progenitor niche that promotes metaplasia. Restoring the balance towards BMP activation attenuated metaplastic KRT5+ differentiation while promoting adaptive alveolar differentiation into SFTPC+ epithelium. Finally, fibrotic human lungs demonstrate altered BMP activation in the metaplastic epithelium. These findings show that Gli1 + MSCs integrate hedgehog signaling as a rheostat to control BMP activation in the progenitor niche to determine regenerative outcome in fibrosis.

show abstract

Section: Resultsmentioning

confidence: 99%

Gli1+ mesenchymal stromal cells form a pathological niche to promote airway progenitor metaplasia in the fibrotic lung

Cassandras¹,

Wang²,

Kathiriya³

et al. 2020

Nat Cell Biol

View full text Add to dashboard Cite

show abstract

“…Mucus plugging may further lead to repeated micro-injuries and chronic inflammation in alveolar regions, resulting in scar tissue formation, persistent fibroproliferation, and, hence, development of IPF (Hancock et al, 2018;Kurche et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Mucus Hypersecretion and Ciliary Impairment in Conducting Airway Contribute to Alveolar Mucus Plugging in Idiopathic Pulmonary Fibrosis

Peng

Wang

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease attributed to the complex interplay of genetic and environmental risks. The muco-ciliary clearance (MCC) system plays a critical role in maintaining the conduit for air to and from the alveoli, but it remains poorly understood whether the MCC abnormalities in conducting airway are involved in IPF pathogenesis. In this study, we obtained the surgically resected bronchi and peripheral lung tissues from 31 IPF patients and 39 control subjects, and we sought to explore the morphologic characteristics of MCC in conducting airway by using immunostaining and scanning and transmission electron microscopy. In the submucosal regions of the bronchi, we found that the areas of mucus glands (MUC5B+) were significantly larger in IPF patients as compared with control subjects (p < 0.05). In the surface epithelium of three airway regions (bronchi, proximal bronchioles, and distal bronchioles), increased MUC5B and MUC5AC expression of secretory cells, decreased number of ciliated cells, and increased ciliary length were observed in IPF patients than control subjects (all p < 0.05). In addition, the mRNA expression levels of MUC5B were up-regulated in both the bronchi and peripheral lung of IPF patients than those of control subjects (p < 0.05), accompanied with 93.55% IPF subjects who had obvious MUC5B+ mucus plugs in alveolar regions. No MUC5B rs35705950 single-nucleotide polymorphism allele was detected in both IPF patients and control subjects. Our study shows that mucus hypersecretion and ciliary impairment in conducting airway are major causes of mucus plugs in alveolar regions and may be closely related to the alveolar injuries in IPF patients.

show abstract

“…In lung fibrosis, Nedd4-2 deficiency enhances MUC5B expression by increasing surface expression and activity of ENaC on airway epithelia cells [ 91 ]. The previous data showed that the overexpressed MUC5B is located in the epithelia cells from honeycomb cysts zone in the IPF lungs, and the ectopic expression of MUC5B may enhance the honeycomb-like cyst formation [ 92 , 93 ].…”

Section: The Mechanism Underlying Progressive Development Of Irreversible Pulmonary Fibrosismentioning

confidence: 99%

“…In the BLM-induced pulmonary fibrosis mouse model, high concentration of MUC5B in airways causes mucociliary dysfunction and enhances the severity of pulmonary fibrosis [ 94 ]. The ectopic expression of MUC5B may lead to more severe and irreversible fibrosis by increasing the sensitivity of ATIIs to BLM and promoting formation of honeycomb structures [ 93 ]. Over-secreted MUC5B may not only break the mucosal host defense but also damage ATIIs and interfere with alveolar repair.…”

Section: The Mechanism Underlying Progressive Development Of Irreversible Pulmonary Fibrosismentioning

confidence: 99%

Irreversibility of Pulmonary Fibrosis

Yu¹,

Tang²

2022

Aging and disease

View full text Add to dashboard Cite

Pulmonary fibrosis, a kind of terminal pathological changes in the lung, is caused by aberrant wound healing, deposition of extracellular matrix (ECM), and eventually replacement of lung parenchyma by ECM. Pulmonary fibrosis induced by acute lung injury and some diseases is reversible under treatment. While idiopathic pulmonary fibrosis is persistent and irreversible even after treatment. Currently, the pathogenesis of irreversible pulmonary fibrosis is not fully elucidated. The known factors associated with the development of irreversible fibrosis include apoptosis resistance of (myo)fibroblasts, dysfunction of pulmonary vessel, cell mitochondria and autophagy, aberrant epithelia hyperplasia and lipid metabolism disorder. In this review, other than a brief introduction of reversible pulmonary fibrosis, we focus on the underlying pathogenesis of irreversible pulmonary fibrosis from the above aspects as well as preclinical disease models, and also suggest directions for future studies.

show abstract

Muc5b Enhances Murine Honeycomb-like Cyst Formation

Cited by 21 publications

References 11 publications

Gli1+ mesenchymal stromal cells form a pathological niche to promote airway progenitor metaplasia in the fibrotic lung

Gli1+ mesenchymal stromal cells form a pathological niche to promote airway progenitor metaplasia in the fibrotic lung

Mucus Hypersecretion and Ciliary Impairment in Conducting Airway Contribute to Alveolar Mucus Plugging in Idiopathic Pulmonary Fibrosis

Irreversibility of Pulmonary Fibrosis

Contact Info

Product

Resources

About