scholarly journals Cell-surface translocation of annexin A2 contributes to bleomycin-induced pulmonary fibrosis by mediating inflammatory response in mice

2019 ◽  
Vol 133 (7) ◽  
pp. 789-804 ◽  
Author(s):  
Yunlong Lei ◽  
Kui Wang ◽  
Xuefeng Li ◽  
Yi Li ◽  
Xuping Feng ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Inflammatory Response ◽  
Cell Surface ◽  
Annexin A2 ◽  
Lung Epithelial Cells ◽  
Cancer Drug ◽  
Autophagic Flux ◽  
Lung Epithelial ◽  
Surface Translocation

Abstract Bleomycin, a widely used anti-cancer drug, may give rise to pulmonary fibrosis, a serious side effect which is associated with significant morbidity and mortality. Despite the intensive efforts, the precise pathogenic mechanisms of pulmonary fibrosis still remain to be clarified. Our previous study showed that bleomycin bound directly to annexin A2 (ANXA2, or p36), leading to development of pulmonary fibrosis by impeding transcription factor EB (TFEB)-induced autophagic flux. Here, we demonstrated that ANXA2 also played a critical role in bleomycin-induced inflammation, which represents another major cause of bleomycin-induced pulmonary fibrosis. We found that bleomycin could induce the cell surface translocation of ANXA2 in lung epithelial cells through exosomal secretion, associated with enhanced interaction between ANXA2 and p11. Knockdown of ANXA2 or blocking membrane ANXA2 mitigated bleomycin-induced activation of nuclear factor (NF)-κB pathway and production of pro-inflammatory cytokine IL-6 in lung epithelial cells. ANXA2-deficient (ANXA2−/−) mice treated with bleomycin exhibit reduced pulmonary fibrosis along with decreased cytokine production compared with bleomycin-challenged wild-type mice. Further, the surface ANXA2 inhibitor TM601 could ameliorate fibrotic and inflammatory response in bleomycin-treated mice. Taken together, our results indicated that, in addition to disturbing autophagic flux, ANXA2 can contribute to bleomycin-induced pulmonary fibrosis by mediating inflammatory response.

scholarly journals Congenital Deletion of Nedd4-2 in Lung Epithelial Cells Causes Progressive Alveolitis and Pulmonary Fibrosis in Neonatal Mice

2021 ◽  
Vol 22 (11) ◽  
pp. 6146
Author(s):  
Dominik H. W. Leitz ◽  
Julia Duerr ◽  
Surafel Mulugeta ◽  
Ayça Seyhan Agircan ◽  
Stefan Zimmermann ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Growth Failure ◽  
Lung Epithelial Cells ◽  
Na Channel ◽  
Preclinical Development ◽  
Neonatal Mice ◽  
Mucin Expression ◽  
Lung Epithelial ◽  
The Impact

Recent studies found that expression of Nedd4‑2 is reduced in lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and that the conditional deletion of Nedd4‑2 in lung epithelial cells causes IPF-like disease in adult mice via multiple defects, including dysregulation of the epithelial Na+ channel (ENaC), TGFβ signaling and the biosynthesis of surfactant protein-C proprotein (proSP-C). However, knowledge of the impact of congenital deletion of Nedd4‑2 on the lung phenotype remains limited. In this study, we therefore determined the effects of congenital deletion of Nedd4‑2 in the lung epithelial cells of neonatal doxycycline-induced triple transgenic Nedd4‑2fl/fl/CCSP‑rtTA2S‑M2/LC1 mice, with a focus on clinical phenotype, survival, lung morphology, inflammation markers in BAL, mucin expression, ENaC function and proSP‑C trafficking. We found that the congenital deletion of Nedd4‑2 caused a rapidly progressive lung disease in neonatal mice that shares key features with interstitial lung diseases in children (chILD), including hypoxemia, growth failure, sterile pneumonitis, fibrotic lung remodeling and high mortality. The congenital deletion of Nedd4‑2 in lung epithelial cells caused increased expression of Muc5b and mucus plugging of distal airways, increased ENaC activity and proSP-C mistrafficking. This model of congenital deletion of Nedd4‑2 may support studies of the pathogenesis and preclinical development of therapies for chILD.

Captopril inhibits apoptosis in human lung epithelial cells: a potential antifibrotic mechanism

1998 ◽  
Vol 275 (5) ◽  
pp. L1013-L1017 ◽  
Author(s):  
Bruce D. Uhal ◽  
Claudia Gidea ◽  
Raed Bargout ◽  
Antonio Bifero ◽  
Olivia Ibarra-Sunga ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Dna Fragmentation ◽  
Cell Apoptosis ◽  
Human Lung ◽  
Lung Epithelial Cells ◽  
Lung Epithelial ◽  
Epithelial Cell Apoptosis

The angiotensin-converting enzyme inhibitor captopril has been shown to inhibit fibrogenesis in the lung, but the mechanisms underlying this action are unclear. Apoptosis of lung epithelial cells is believed to be involved in the pathogenesis of pulmonary fibrosis. For these reasons, we studied the effect of captopril on Fas-induced apoptosis in a human lung epithelial cell line. Monoclonal antibodies that activate the Fas receptor induced epithelial cell apoptosis as detected by chromatin condensation, nuclear fragmentation, DNA fragmentation, and increased activities of caspase-1 and -3. Apoptosis was not induced by isotype-matched nonimmune mouse immunoglobulins or nonactivating anti-Fas monoclonal antibodies. When applied simultaneously with anti-Fas antibodies, 50 ng/ml of captopril completely abrogated apoptotic indexes based on morphology, DNA fragmentation, and inducible caspase-1 activity and significantly decreased the inducible activity of caspase-3. Inhibition of apoptosis by captopril was concentration dependent, with an IC50 of 70 pg/ml. These data suggest that the inhibitory actions of captopril on pulmonary fibrosis may be related to prevention of lung epithelial cell apoptosis.

Titanium dioxide nanoparticles induce an adaptive inflammatory response and invasion and proliferation of lung epithelial cells in chorioallantoic membrane

2015 ◽  
Vol 136 ◽  
pp. 424-434 ◽  
Author(s):  
Estefany I. Medina-Reyes ◽  
Alejandro Déciga-Alcaraz ◽  
Verónica Freyre-Fonseca ◽  
Norma L. Delgado-Buenrostro ◽  
José O. Flores-Flores ◽  
...  
Keyword(s):  
Titanium Dioxide ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Titanium Dioxide Nanoparticles ◽  
Chorioallantoic Membrane ◽  
Lung Epithelial Cells ◽  
Lung Epithelial

Dexamethasone inhibits inflammatory response via down regulation of AP-1 transcription factor in human lung epithelial cells

Gene ◽  
2018 ◽  
Vol 645 ◽  
pp. 85-94 ◽  
Author(s):  
Rajeshwari H. Patil ◽  
M. Naveen Kumar ◽  
K.M. Kiran Kumar ◽  
Rashmi Nagesh ◽  
K. Kavya ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Human Lung ◽  
Lung Epithelial Cells ◽  
Down Regulation ◽  
Lung Epithelial ◽  
Human Lung Epithelial Cells

scholarly journals Role of Nucleolin in Human Parainfluenza Virus Type 3 Infection of Human Lung Epithelial Cells

2004 ◽  
Vol 78 (15) ◽  
pp. 8146-8158 ◽  
Author(s):  
Santanu Bose ◽  
Mausumi Basu ◽  
Amiya K. Banerjee
Keyword(s):  
Epithelial Cells ◽  
Cell Surface ◽  
Human Lung ◽  
A549 Cells ◽  
Lung Epithelial Cells ◽  
Parainfluenza Virus ◽  
Lung Epithelial ◽  
Human Parainfluenza Virus ◽  
Type 3 ◽  
Human Lung Epithelial Cells

ABSTRACT Human parainfluenza virus type 3 (HPIV-3) is an airborne pathogen that infects human lung epithelial cells from the apical (luminal) plasma membrane domain. In the present study, we have identified cell surface-expressed nucleolin as a cellular cofactor required for the efficient cellular entry of HPIV-3 into human lung epithelial A549 cells. Nucleolin was enriched on the apical cell surface domain of A549 cells, and HPIV-3 interacted with nucleolin during entry. The importance of nucleolin during HPIV-3 replication was borne out by the observation that HPIV-3 replication was significantly inhibited following (i) pretreatment of cells with antinucleolin antibodies and (ii) preincubation of HPIV-3 with purified nucleolin prior to its addition to the cells. Moreover, HPIV-3 cellular internalization and attachment assays performed in the presence of antinucleolin antibodies and purified nucleolin revealed the requirement of nucleolin during HPIV-3 internalization but not during attachment. Thus, these results suggest that nucleolin expressed on the surfaces of human lung epithelial A549 cells plays an important role during HPIV-3 cellular entry.

scholarly journals Prostasin regulates epithelial monolayer function: cell-specific Gpld1-mediated secretion and functional role for GPI anchor

2006 ◽  
Vol 291 (6) ◽  
pp. C1258-C1270 ◽  
Author(s):  
George M. Verghese ◽  
Michael F. Gutknecht ◽  
George H. Caughey
Keyword(s):  
Epithelial Cells ◽  
Cell Surface ◽  
Collecting Duct ◽  
Critical Role ◽  
Lung Epithelial Cells ◽  
Peptidase Activity ◽  
Apical Surface ◽  
Gpi Anchor ◽  
Epithelial Monolayer ◽  
Lung Epithelial

Prostasin, a trypsinlike serine peptidase, is highly expressed in prostate, kidney, and lung epithelia, where it is bound to the cell surface, secreted, or both. Prostasin activates the epithelial sodium channel (ENaC) and suppresses invasion of prostate and breast cancer cells. The studies reported here establish mechanisms of membrane anchoring and secretion in kidney and lung epithelial cells and demonstrate a critical role for prostasin in regulating epithelial monolayer function. We report that endogenous mouse prostasin is glycosylphosphatidylinositol (GPI) anchored to the cell surface and is constitutively secreted from the apical surface of kidney cortical collecting duct cells. Using site-directed mutagenesis, detergent phase separation, and RNA interference approaches, we show that prostasin secretion depends on GPI anchor cleavage by endogenous GPI-specific phospholipase D1 (Gpld1). Secretion of prostasin by kidney and lung epithelial cells, in contrast to prostate epithelium, does not depend on COOH-terminal processing at conserved Arg322. Using stably transfected M-1 cells expressing wild-type, catalytically inactive, or chimeric transmembrane (not GPI)-anchored prostasins we establish that prostasin regulates transepithelial resistance, current, and paracellular permeability by GPI anchor- and protease activity-dependent mechanisms. These studies demonstrate a novel role for prostasin in regulating epithelial monolayer resistance and permeability in kidney epithelial cells and, furthermore, show specifically that prostasin is a critical regulator of transepithelial ion transport in M-1 cells. These functions depend on the GPI anchor as well as the peptidase activity of prostasin. These studies suggest that cell-specific Gpld1- or peptidase-dependent pathways for prostasin secretion may control prostasin functions in a tissue-specific manner.

scholarly journals SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-κB pathway

2021 ◽  
Author(s):  
Shahanshah Khan ◽  
Mahnoush S. Shafiei ◽  
Christopher Longoria ◽  
John Schoggins ◽  
Rashmin C. Savani ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Lung Epithelial Cells ◽  
Dependent Manner ◽  
S Protein ◽  
Cytokines And Chemokines ◽  
Lung Epithelial ◽  
Mouse Macrophages ◽  
Human And Mouse

Pathogenesis of COVID-19 is associated with a hyperinflammatory response; however, the precise mechanism of SARS-CoV-2-induced inflammation is poorly understood. Here we investigated direct inflammatory functions of major structural proteins of SARS-CoV-2. We observed that spike (S) protein potently induces inflammatory cytokines and chemokines including IL-6, IL-1b, TNFa, CXCL1, CXCL2, and CCL2, but not IFNs in human and mouse macrophages. No such inflammatory response was observed in response to membrane (M), envelope (E), and neucleocapsid (N) proteins. When stimulated with extracellular S protein, human lung epithelial cells A549 also produce inflammatory cytokines and chemokines. Interestingly, epithelial cells expressing S protein intracellularly are non-inflammatory, but elicit an inflammatory response in macrophages when co-cultured. Biochemical studies revealed that S protein triggers inflammation via activation of the NF-kB pathway in a MyD88-dependent manner. Further, such an activation of the NF-kB pathway is abrogated in Tlr2-deficient macrophages. Consistently, administration of S protein induces IL-6, TNF-a, and IL-1b in wild-type, but not Tlr2-deficient mice. Together these data reveal a mechanism for the cytokine storm during SARS-CoV-2 infection and suggest that TLR2 could be a potential therapeutic target for COVID-19.

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