Activated Alveolar Epithelial Cells Initiate Fibrosis through Secretion of Mesenchymal Proteins

Yang, Jie; Wheeler, Sarah E.; Velikoff, Miranda; Kleaveland, Kathryn R.; LaFemina, Michael J.; Frank, James A.; Chapman, Harold A.; Christensen, Paul J.; Kim, Kevin K.

doi:10.1016/j.ajpath.2013.07.016

Cited by 77 publications

(94 citation statements)

References 65 publications

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“…The increased release of collagen into the medium due to TNF-a stimulation could underlie the increased collagen content in both alveolar and small airway walls of SPC-TNF-a mice, as well as in patients with COPD, as we recently published (3,4). Evidence for the involvement of epithelial cells in fibrotic processes is also demonstrated by other work, which shows limitation of bleomycin-induced fibrosis in epithelial-specific collagen I knockout mice (5). Furthermore, because MMP2 and MMP9 expression increased after TNF-a stimulation of epithelial cells, and because MMPs were recently associated with the breakdown of elastin in SPC-TNF-a mice and patients with COPD, TNF-a could possibly contribute to the reported degradation of elastin (3,23).…”

Section: Discussionsupporting

confidence: 50%

Involvement of c-Jun N-Terminal Kinase in TNF-α–Driven Remodeling

Eurlings

Reynaert

Wetering

et al. 2017

Am J Respir Cell Mol Biol

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Lung tissue remodeling in chronic obstructive pulmonary disease (COPD) is characterized by airway wall thickening and/or emphysema. Although the bronchial and alveolar compartments are functionally independent entities, we recently showed comparable alterations in matrix composition comprised of decreased elastin content and increased collagen and hyaluronan contents of alveolar and small airway walls. Out of several animal models tested, surfactant protein C (SPC)-TNF-a mice showed remodeling in alveolar and airway walls similar to what we observed in patients with COPD. Epithelial cells are able to undergo a phenotypic shift, gaining mesenchymal properties, a process in which c-Jun N-terminal kinase (JNK) signaling is involved. Therefore, we hypothesized that TNF-a induces JNK-dependent epithelial plasticity, which contributes to lung matrix remodeling. To this end, the ability of TNF-a to induce a phenotypic shift was assessed in A549, BEAS2B, and primary bronchial epithelial cells, and phenotypic markers were studied in SPC-TNF-a mice. Phenotypic markers of mesenchymal cells were elevated both in vitro and in vivo, as shown by the expression of vimentin, plasminogen activator inhibitor-1, collagen, and matrix metalloproteinases. Concurrently, the expression of the epithelial markers, E-cadherin and keratin 7 and 18, was attenuated. A pharmacological inhibitor of JNK attenuated this phenotypic shift in vitro, demonstrating involvement of JNK signaling in this process. Interestingly, activation of JNK signaling was also clearly present in lungs of SPC-TNF-a mice and patients with COPD. Together, these data show a role for TNF-a in the induction of a phenotypic shift in vitro, resulting in increased collagen production and the expression of elastin-degrading matrix metalloproteinases, and provide evidence for involvement of the TNF-a-JNK axis in extracellular matrix remodeling.

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Section: Discussionsupporting

confidence: 50%

Involvement of c-Jun N-Terminal Kinase in TNF-α–Driven Remodeling

Eurlings

Reynaert

Wetering

et al. 2017

Am J Respir Cell Mol Biol

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“…Moreover, ECM secreted by lung fibroblasts from older animals further drove myofibroblast differentiation of fibrocytes in vitro [278]. Importantly, recent findings suggest that next to mesenchymal cells other structural cells, such as alveolar epithelial or circulating (progenitor) cells, contribute to ECM production [279][280]. All these cell types potentially exhibit age-related cell-autonomous alterations, as described earlier.…”

Section: Altered Intercellular Communicationmentioning

confidence: 83%

Hallmarks of the ageing lung

2015

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Ageing is the main risk factor for major non-communicable chronic lung diseases, including chronic obstructive pulmonary disease, most forms of lung cancer and idiopathic pulmonary fibrosis. While the prevalence of these diseases continually increases with age, their respective incidence peaks at different times during the lifespan, suggesting specific effects of ageing on the onset and/or pathogenesis of chronic obstructive pulmonary disease, lung cancer and idiopathic pulmonary fibrosis. Recently, the nine hallmarks of ageing have been defined as cell-autonomous and non-autonomous pathways involved in ageing. Here, we review the available evidence for the involvement of each of these hallmarks in the pathogenesis of chronic obstructive pulmonary disease, lung cancer, or idiopathic pulmonary fibrosis. Importantly, we propose an additional hallmark, "dysregulation of the extracellular matrix", which we argue acts as a crucial modifier of cell-autonomous changes and functions, and as a key feature of the above-mentioned lung diseases. @ERSpublications Hallmarks of ageing are selecting factors for the pathogenesis of COPD, lung cancer and IPF

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“…Deletion of type I collagen within lung epithelial cells led to attenuation of lung fibrosis (57). In the present study, we found an important role for epithelial-derived CTGF for activation of fibroblasts and epithelial cells and for lung fibrogenesis.…”

mentioning

confidence: 84%

Activated alveolar epithelial cells initiate fibrosis through autocrine and paracrine secretion of connective tissue growth factor

Yang

Velikoff

Canalis

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Fibrogenesis involves a pathological accumulation of activated fibroblasts and extensive matrix remodeling. Profibrotic cytokines, such as TGF-β, stimulate fibroblasts to overexpress fibrotic matrix proteins and induce further expression of profibrotic cytokines, resulting in progressive fibrosis. Connective tissue growth factor (CTGF) is a profibrotic cytokine that is indicative of fibroblast activation. Epithelial cells are abundant in the normal lung, but their contribution to fibrogenesis remains poorly defined. Profibrotic cytokines may activate epithelial cells with protein expression and functions that overlap with the functions of active fibroblasts. We found that alveolar epithelial cells undergoing TGF-β-mediated mesenchymal transition in vitro were also capable of activating lung fibroblasts through production of CTGF. Alveolar epithelial cell expression of CTGF was dramatically reduced by inhibition of Rho signaling. CTGF reporter mice demonstrated increased CTGF promoter activity by lung epithelial cells acutely after bleomycin in vivo. Furthermore, mice with lung epithelial cell-specific deletion of CTGF had an attenuated fibrotic response to bleomycin. These studies provide direct evidence that epithelial cell activation initiates a cycle of fibrogenic effector cell activation during progressive fibrosis. Therapy targeted at epithelial cell production of CTGF offers a novel pathway for abrogating this progressive cycle and limiting tissue fibrosis.

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Activated Alveolar Epithelial Cells Initiate Fibrosis through Secretion of Mesenchymal Proteins

Cited by 77 publications

References 65 publications

Involvement of c-Jun N-Terminal Kinase in TNF-α–Driven Remodeling

Involvement of c-Jun N-Terminal Kinase in TNF-α–Driven Remodeling

Hallmarks of the ageing lung

Activated alveolar epithelial cells initiate fibrosis through autocrine and paracrine secretion of connective tissue growth factor

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