Cellular metabolomics of pulmonary fibrosis, from amino acids to lipids.

2021 ◽  
Author(s):  
Willy Roque ◽  
Freddy Romero
Keyword(s):  
Amino Acids ◽  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Airway Remodeling ◽  
Treatment Options ◽  
Alveolar Epithelial Cells ◽  
Metabolic Reprogramming ◽  
Unknown Etiology ◽  
Alveolar Epithelial ◽  
Repetitive Injury

Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive lung disease of unknown etiology with limited treatment options. It is characterized by repetitive injury to alveolar epithelial cells and aberrant activation of numerous signaling pathways. Recent evidence suggests that metabolic reprogramming, metabolic dysregulation, and mitochondria dysfunction are distinctive features of the IPF lungs. Through numerous mechanisms, metabolomic abnormalities in alveolar epithelial cells, myofibroblast, macrophages, and fibroblasts contribute to the abnormal collagen synthesis and dysregulated airway remodeling described in lung fibrosis. This review summarizes the metabolomic changes in amino acids, lipids, glucose, and heme seen in IPF lungs. Simultaneously, we provide new insights into potential therapeutic strategies by targeting a variety of metabolites.

scholarly journals Epithelial–Mesenchymal Transition in the Pathogenesis of Idiopathic Pulmonary Fibrosis

Medicina ◽  
2019 ◽  
Vol 55 (4) ◽  
pp. 83 ◽  
Author(s):  
Francesco Salton ◽  
Maria Volpe ◽  
Marco Confalonieri
Keyword(s):  
Epithelial Cells ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Treatment Options ◽  
Alveolar Epithelium ◽  
Alveolar Epithelial Cells ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Serious Disease

Idiopathic pulmonary fibrosis (IPF) is a serious disease of the lung, which leads to extensive parenchymal scarring and death from respiratory failure. The most accepted hypothesis for IPF pathogenesis relies on the inability of the alveolar epithelium to regenerate after injury. Alveolar epithelial cells become apoptotic and rare, fibroblasts/myofibroblasts accumulate and extracellular matrix (ECM) is deposited in response to the aberrant activation of several pathways that are physiologically implicated in alveologenesis and repair but also favor the creation of excessive fibrosis via different mechanisms, including epithelial–mesenchymal transition (EMT). EMT is a pathophysiological process in which epithelial cells lose part of their characteristics and markers, while gaining mesenchymal ones. A role for EMT in the pathogenesis of IPF has been widely hypothesized and indirectly demonstrated; however, precise definition of its mechanisms and relevance has been hindered by the lack of a reliable animal model and needs further studies. The overall available evidence conceptualizes EMT as an alternative cell and tissue normal regeneration, which could open the way to novel diagnostic and prognostic biomarkers, as well as to more effective treatment options.

scholarly journals Aesculetin Attenuates Pulmonary Fibrosis Induced by Close Contact of Macrophages with Alveolar Epithelial Cells

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1531-1531
Author(s):  
Suyeon Oh ◽  
Young-Hee Kang
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
A549 Cells ◽  
Conditioned Media ◽  
Alveolar Epithelial Cells ◽  
Alveolar Cells ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Funding Sources ◽  
E Cadherin

Abstract Objectives Pulmonary fibrosis is a disease in which lung tissues become fibrous and causes severe respiratory disturbances. Various stimuli induce infiltration of macrophages to the respiratory tract. These macrophages secrete various inflammatory cytokines leading to development of pulmonary fibrosis via epithelial–mesenchymal transition (EMT) process. Aesculetin, a major component of Sancho tree and Chicory, is known to have antioxidant and anti-inflammatory effects in the vascular and immune system. Methods Human alveolar basal epithelial A549 cells were cultured in conditioned media of THP-1 monocyte-derived macrophages for 24 h. Aesculetin at the concentrations of 1–20 μM did not show cytotoxicity of A549 cells. Alveolar epithelial cells were incubated with interleukin (IL)-8. Western blotting examined EMT-associated fibrotic proteins from A549 cell lysates. Matrix metalloproteinase (MMP) activity was measured with gelatin zymography. In addition, inflammation- and fibrosis-related cytokines were measured by using ELISA kits. Results The epithelial markers of E-cadherin and ZO-1 were reduced in cells exposed to macrophage-conditioned media containing IL-8 and TNF-α. Macrophage-conditioned media enhanced expression of the mesenchymal fibrotic markers of α-smooth muscle actin (α-SMA), vimentin and fibronectin, and the fibrotic proteins of collagen I and collagen IV were enhanced. However, ≥10 μM aesculetin reciprocally manipulated the expression levels of these proteins of A549 cells. In addition, macrophage-conditioned media enhanced the expression and activity of MT1-MMP, MMP-2 and MMP-9. In contrast, the expression of tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 were reduced by exposure of alveolar cells to conditioned media. Proinflammatory and chemotactic IL-8 reduced E-cadherin and conversely enhanced N-cadherin and α-SMA in A549 cells, which was reciprocally modulated by ≥ 10 μM aesculetin. These results demonstrate that aesculetin may ameliorate EMT-associated pulmonary fibrosis caused by contact of blood-derived macrophages and alveolar cells. Conclusions Aesculetin maybe a promising agent treating progressive pulmonary disorders owing to macrophage-mediated inflammation. Funding Sources No funding sources to report.

Lung infection with γ-herpesvirus induces progressive pulmonary fibrosis in Th2-biased mice

2005 ◽  
Vol 289 (5) ◽  
pp. L711-L721 ◽  
Author(s):  
Ana L. Mora ◽  
Charles R. Woods ◽  
Anapatricia Garcia ◽  
Jianguo Xu ◽  
Mauricio Rojas ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Pulmonary Infection ◽  
Transforming Growth Factor ◽  
Light And Electron Microscopy ◽  
Transforming Growth Factor Β ◽  
Alveolar Epithelial Cells ◽  
Unknown Etiology ◽  
Type Ii ◽  
Alveolar Epithelial ◽  
Fibrotic Lung Disease

Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic lung disease of unknown etiology. A viral pathogenesis in IPF has been suggested since >95% of IPF patients have evidence of chronic pulmonary infection with one or more herpesviruses. To determine whether pulmonary infection with herpesvirus can cause lung fibrosis, we infected mice with the murine γ-herpesvirus 68 (MHV68). Because IPF patients have a T helper type 2 (Th2) pulmonary phenotype, we used IFN-γR−/−, a strain of mice biased to develop Th2 responses. Chronic MHV68 infection of IFN-γR−/− mice resulted in progressive deposition of interstitial collagen as shown by light and electron microscopy. A significant decrease in tidal volume paralleled the collagen deposition. Five features typically seen in IPF, increased transforming growth factor-β expression, myofibroblast transformation, production of Th2 cytokines, hyperplasia of type II cells, and increased expression of matrix metalloproteinase-7, were also present in chronically infected IFN-γR−/− mice. There also was altered synthesis of surfactant proteins, which is seen in some patients with familial IPF. MHV68 viral protein was found in type II alveolar epithelial cells, especially in lung areas with extensive alveolar remodeling. In summary, chronic herpesvirus pulmonary infection in IFN-γR−/− mice causes progressive pulmonary fibrosis and many of the pathological features seen in IPF.

In vivo blockade of KCa3.1 ion channel alleviates ER stress in type II alveolar epithelial cells and macrophages in pulmonary fibrosis

2019 ◽  
Author(s):  
K. Udari Eshani Perera ◽  
Sasika Nimanthi Vithana Dewage ◽  
Habtamu B. Derseh ◽  
Paul John Benham ◽  
Andrew Stent ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Ion Channel ◽  
Er Stress ◽  
Alveolar Epithelial Cells ◽  
Type Ii ◽  
Alveolar Epithelial

Release of biologically active TGF-β1 by alveolar epithelial cells results in pulmonary fibrosis

2003 ◽  
Vol 285 (3) ◽  
pp. L527-L539 ◽  
Author(s):  
Ying Dong Xu ◽  
Jiesong Hua ◽  
Alice Mui ◽  
Robert O'Connor ◽  
Gary Grotendorst ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Inflammatory Cells ◽  
Alveolar Epithelial Cells ◽  
Biologically Active ◽  
Aberrant Expression ◽  
Alveolar Epithelial ◽  
Fibrotic Lung Disease ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a progressive fatal fibrotic lung disease. Transforming growth factor (TGF)-β1 is present in a biologically active conformation in the epithelial cells lining lesions with advanced IPF. To determine the role of aberrant expression of biologically active TGF-β1 by alveolar epithelial cells (AECs), the AECs of explanted normal rat lungs were transfected with the TGF-β1 gene using the retrovirus pMX-L-s223,225-TGF-β1. In situ hybridization using a digoxigenin-labeled cDNA of the puromycin resistance gene contained in the pMX demonstrated that pMX-L-s233,225-TGF-β1 was selectively transfected into AECs of the explants. Conditioned media overlying explants obtained 7 days after being treated with pMX-L-s223,225-TGF-β1 contained 14.5 ± 3.15 pg/ml of active TGF-β1. With the use of Masson's trichrome staining of explant sections obtained 14 days after transfection, there were lesions similar to those in IPF, characterized by type II AEC hyperplasia, interstitial thickening, extensive increase in interstitial and subepithelial collagen, an increase in the number of fibroblasts, and areas resembling fibroblast buds. Collagens I, III, IV, and V and fibronectin were increased in explants treated with pMX-L-s223,225-TGF-β1. The findings in the current study suggest that IPF may be a disorder of epithelial cells and not inflammatory cells.

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