Role of Alveolar Type II Epithelial Cells in Pulmonary Fibrosis

2003 ◽  
pp. 573-608
Author(s):  
Joshua Portnoy ◽  
Robert Mason
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Alveolar Type ◽  
Type Ii

Expression of the tyrosine phosphatase LAR-PTP2 is developmentally regulated in lung epithelia

1994 ◽  
Vol 267 (3) ◽  
pp. L263-L270 ◽  
Author(s):  
D. Rotin ◽  
B. J. Goldstein ◽  
C. A. Fladd
Keyword(s):  
Epithelial Cells ◽  
Lung Development ◽  
Tyrosine Phosphatase ◽  
A549 Cells ◽  
Alveolar Epithelial Cells ◽  
Alveolar Type ◽  
Type Ii ◽  
Adult Type ◽  
Alveolar Epithelial

The role of tyrosine kinases in regulating cell proliferation, differentiation, and development has been well documented. In contrast, little is known about the role of protein tyrosine phosphatases (PTPs) in mammalian development. To identify PTPs that may be involved in lung development, we have isolated (by polymerase chain reaction) from rat fetal alveolar epithelial cells a cDNA fragment which was identified as the recently cloned tyrosine phosphatase LAR-PTP2. Analysis of tissue expression of LAR-PTP2 identified a approximately 7.5-kb message in the lung, which is also expressed weakly in brain, and an alternatively spliced approximately 6.0-kb message (LAR-PTP2B) expressed in brain. In the fetal lung, LAR-PTP2 was preferentially expressed in lung epithelial (but not fibroblast) cells grown briefly in primary culture, and its expression was tightly regulated during lung development, peaking at 20 days of gestational age (term = 22 days), when mature alveolar type II epithelium first appears. Accordingly, immunoblot analysis revealed high expression of endogenous LAR-PTP2 protein in alveolar epithelial cells from 21-day gestation fetuses. LAR-PTP2 was also expressed in lungs of newborn rats, but transcripts (and protein) were barely detectable in adult lungs and in the nonproliferating adult alveolar type II cells. Interestingly, expression was restored in the transformed adult type II-like A549 cells. These results suggest that LAR-PTP2 may play a role in the proliferation and/or differentiation of epithelial cells during lung development.

scholarly journals Role of CXCL16 in BLM-induced epithelial–mesenchymal transition in human A549 cells

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Zhenzhen Ma ◽  
Chunyan Ma ◽  
Qingfeng Zhang ◽  
Yang Bai ◽  
Kun Mu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Alveolar Epithelial Cells ◽  
Alveolar Type ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Tgf Β1

AbstractAlveolar epithelial cells play an essential role in the initiation and progression of pulmonary fibrosis, and the occurrence of epithelial–mesenchymal transition (EMT) may be the early events of pulmonary fibrosis. Recent studies have shown chemokines are involved in the complex process of EMT, and CXC chemokine ligand 16 (CXCL16) is also associated with many fibrosis-related diseases. However, whether CXCL16 is dysregulated in alveolar epithelial cells and the role of CXCL16 in modulating EMT in pulmonary fibrosis has not been reported. In this study, we found that CXCL16 and its receptor C-X-C motif chemokine receptor 6 (CXCR6) were upregulated in bleomycin induced EMT in human alveolar type II-like epithelial A549 cells. Synergistic effect of CXCL16 and bleomycin in promoting EMT occurrence, extracellular matrix (ECM) excretion, as well as the pro-inflammatory and pro-fibrotic cytokines productions in A549 cells were observed, and those biological functions were impaired by CXCL16 siRNA. We further confirmed that CXCL16 regulated EMT in A549 cells via the TGF-β1/Smad3 pathways. These results indicated that CXCL16 could promote pulmonary fibrosis by promoting the process of EMT via the TGF-β1/Smad3 signaling pathway.

scholarly journals Mechanism of lipopolysaccharide-mediated induction of epithelial-mesenchymal transition of alveolar type II epithelial cells in absence of other inflammatory cells

2021 ◽  
Vol 19 ◽  
pp. 205873922110144
Author(s):  
Shuai Wu ◽  
Huan Ye ◽  
TianJiao Xue ◽  
Jiali Wang
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Cell ◽  
Expression Level ◽  
Alveolar Type ◽  
Type Ii ◽  
Gram Negative ◽  
Mesenchymal Transition ◽  
Tgf Β1

Several studies have shown that gram-negative bacilli infection can cause acute lung injury, and that consequent pulmonary fibrosis is caused when alveolar type-II epithelial cells undergo epithelial-mesenchymal transition (EMT). However, the mechanism underlying this change remains unclear. This study aimed to elucidate whether the main toxin of gram-negative bacteria, lipopolysaccharide (LPS), can induce EMT in human alveolar epithelial cells, and the underlying molecular mechanisms. Human alveolar type-II epithelial cells (A549) were used in EMT induction experiments. Cells were collected after LPS exposure, and changes in the expression levels of epithelial and mesenchymal cell markers were determined. Further, the effect of LPS exposure on the expression of Toll-like Receptor 4 (TLR4), Transforming Growth Factor-beta 1 (TGF-β1) and Smad2/3 was assessed. The expression level of a mesenchymal cell marker was also assessed after pharmacological inhibition of TLR4 and TGF-β1 prior to addition of LPS, to identify downstream pathways involved in EMT induction. Results showed that LPS exposure caused significant downregulation of epithelial marker E-cadherin, and upregulation of mesenchymal marker vimentin, together with increased expression of TGF-β1 and activation of the TGF-β1/Smad2/3 pathway. Furthermore, pretreatment with TGF-β1 and TLR4 inhibitors suppressed EMT, and treatment with the latter also reduced the expression level of TGF-β1. Overall, we conclude that LPS directly induces EMT in A549 cells through upregulation of TLR4 and activation of the TGF-β1/Smad2/3 signalling pathway. Our results suggest that LPS-mediated pulmonary fibrosis may occur in ALI patients even if the LPS-induced inflammatory response is inhibited.

The role of the receptor for advanced glycation end-products in lung fibrosis

2007 ◽  
Vol 293 (6) ◽  
pp. L1427-L1436 ◽  
Author(s):  
Mei He ◽  
Hiroshi Kubo ◽  
Kota Ishizawa ◽  
Ahmed E. Hegab ◽  
Yasuhiko Yamamoto ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Advanced Glycation End Products ◽  
Lung Fibrosis ◽  
Alveolar Type ◽  
Type Ii ◽  
Wild Type ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products

The pathogenesis of pulmonary fibrosis remains unclear. The receptor for advanced glycation end-products (RAGE) is a multi-ligand receptor known to be involved in the process of fibrotic change in several organs, such as peritoneal fibrosis and kidney fibrosis. The aim of this study was to examine the contribution of RAGE during the acute inflammation and chronic fibrotic phases of lung injury induced by intratracheal instillation of bleomycin in mice. Bleomycin-induced lung fibrosis was evaluated in wild-type and RAGE-deficient (RAGE−/−) mice. Bleomycin administration to wild-type mice caused an initial pneumonitis that evolved into fibrosis. While RAGE−/− mice developed a similar early inflammatory response, the mice were largely protected from the late fibrotic effects of bleomycin. The protection afforded by RAGE deficiency was accompanied by reduced pulmonary levels of the potent RAGE-inducible profibrotic cytokines transforming growth factor (TGF)-β and PDGF. In addition, bleomycin administration induced high mobility group box 1 (HMGB-1) production, one of the ligands of RAGE, from inflammatory cells that accumulated within the air space. Coculture with HMGB-1 induced epithelial-mesenchymal transition (EMT) in alveolar type II epithelial cells from wild-type mice. However, alveolar type II epithelial cells derived from RAGE−/− mice did not respond to HMGB-1 treatment, such that the RAGE/HMGB-1 axis may play an important role in EMT. Also, bleomycin administration induced profibrotic cytokines TGF-β and PDGF only in wild-type mouse lungs. Our results suggested that RAGE contributes to bleomycin-induced lung fibrosis through EMT and profibrotic cytokine production. Thus, RAGE may be a new therapeutic target for pulmonary fibrosis.

scholarly journals Alveolar epithelial cells express mesenchymal proteins in patients with idiopathic pulmonary fibrosis

2011 ◽  
Vol 301 (1) ◽  
pp. L71-L78 ◽  
Author(s):  
Cecilia Marmai ◽  
Rachel E. Sutherland ◽  
Kevin K. Kim ◽  
Gregory M. Dolganov ◽  
Xiaohui Fang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Mesenchymal Cells ◽  
Alveolar Type ◽  
Type I ◽  
Type Ii Cells ◽  
Type Ii ◽  
Alveolar Type Ii Cells ◽  
Mesenchymal Transition

Prior work has shown that transforming growth factor-β (TGF-β) can mediate transition of alveolar type II cells into mesenchymal cells in mice. Evidence this occurs in humans is limited to immunohistochemical studies colocalizing epithelial and mesenchymal proteins in sections of fibrotic lungs. To acquire further evidence that epithelial-to-mesenchymal transition occurs in the lungs of patients with idiopathic pulmonary fibrosis (IPF), we studied alveolar type II cells isolated from fibrotic and normal human lung. Unlike normal type II cells, type II cells isolated from the lungs of patients with IPF express higher levels of mRNA for the mesenchymal proteins type I collagen, α-smooth muscle actin (α-SMA), and calponin. When cultured on Matrigel/collagen, human alveolar type II cells maintain a cellular morphology consistent with epithelial cells and expression of surfactant protein C (SPC) and E-cadherin. In contrast, when cultured on fibronectin, the human type II cells flatten, spread, lose expression of pro- SPC, and increase expression of vimentin, N-cadherin, and α-SMA; markers of mesenchymal cells. Addition of a TGF-β receptor kinase inhibitor (SB431542) to cells cultured on fibronectin inhibited vimentin expression and maintained pro-SPC expression, indicating persistence of an epithelial phenotype. These data suggest that alveolar type II cells can acquire features of mesenchymal cells in IPF lungs and that TGF-β can mediate this process.

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