scholarly journals Spred2-deficiency enhances the proliferation of lung epithelial cells and alleviates pulmonary fibrosis induced by bleomycin

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Akina Kawara ◽  
Ryo Mizuta ◽  
Masayoshi Fujisawa ◽  
Toshihiro Ito ◽  
Chunning Li ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Tissue Repair ◽  
Bronchial Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Clara Cells ◽  
Bronchial Epithelial ◽  
Lung Epithelial

Abstract The mitogen-activated protein kinase (MAPK) pathways are involved in many cellular processes, including the development of fibrosis. Here, we examined the role of Sprouty-related EVH-1-domain-containing protein (Spred) 2, a negative regulator of the MAPK-ERK pathway, in the development of bleomycin (BLM)-induced pulmonary fibrosis (PF). Compared to WT mice, Spred2−/− mice developed milder PF with increased proliferation of bronchial epithelial cells. Spred2−/− lung epithelial cells or MLE-12 cells treated with spred2 siRNA proliferated faster than control cells in vitro. Spred2−/− and WT macrophages produced similar levels of TNFα and MCP-1 in response to BLM or lipopolysaccharide and myeloid cell-specific deletion of Spred2 in mice had no effect. Spred2−/− fibroblasts proliferated faster and produced similar levels of MCP-1 compared to WT fibroblasts. Spred2 mRNA was almost exclusively detected in bronchial epithelial cells of naïve WT mice and it accumulated in approximately 50% of cells with a characteristic of Clara cells, 14 days after BLM treatment. These results suggest that Spred2 is involved in the regulation of tissue repair after BLM-induced lung injury and increased proliferation of lung bronchial cells in Spred2−/− mice may contribute to faster tissue repair. Thus, Spred2 may present a new therapeutic target for the treatment of PF.

scholarly journals HIV-1 Productively Infects and Integrates in Bronchial Epithelial Cells

2021 ◽  
Vol 10 ◽  
Author(s):  
Dinesh Devadoss ◽  
Shashi P. Singh ◽  
Arpan Acharya ◽  
Kieu Chinh Do ◽  
Palsamy Periyasamy ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Bronchial Epithelial Cells ◽  
Lung Epithelial Cells ◽  
People Living With Hiv ◽  
Sequencing Analysis ◽  
Hiv Reservoirs ◽  
Bronchial Epithelial ◽  
Lung Epithelial ◽  
Hiv 1

BackgroundThe role of lung epithelial cells in HIV-1-related lung comorbidities remains unclear, and the major hurdle in curing HIV is the persistence of latent HIV reservoirs in people living with HIV (PLWH). The advent of combined antiretroviral therapy has considerably increased the life span; however, the incidence of chronic lung diseases is significantly higher among PLWH. Lung epithelial cells orchestrate the respiratory immune responses and whether these cells are productively infected by HIV-1 is debatable.MethodsNormal human bronchial epithelial cells (NHBEs) grown on air–liquid interface were infected with X4-tropic HIV-1LAV and examined for latency using latency-reversing agents (LRAs). The role of CD4 and CXCR4 HIV coreceptors in NHBEs were tested, and DNA sequencing analysis was used to analyze the genomic integration of HIV proviral genes, Alu-HIVgag-pol, HIV-nef, and HIV-LTR. Lung epithelial sections from HIV-infected humans and SHIV-infected macaques were analyzed by FISH for HIV-gag-pol RNA and epithelial cell-specific immunostaining.Results and DiscussionNHBEs express CD4 and CXCR4 at higher levels than A549 cells. NHBEs are infected with HIV-1 basolaterally, but not apically, by X4-tropic HIV-1LAV in a CXCR4/CD4-dependent manner leading to HIV-p24 antigen production; however, NHBEs are induced to express CCR5 by IL-13 treatment. In the presence of cART, HIV-1 induces latency and integration of HIV provirus in the cellular DNA, which is rescued by the LRAs (endotoxin/vorinostat). Furthermore, lung epithelial cells from HIV-infected humans and SHIV-infected macaques contain HIV-specific RNA transcripts. Thus, lung epithelial cells are targeted by HIV-1 and could serve as potential HIV reservoirs that may contribute to the respiratory comorbidities in PLWH.

15-Lipoxygenase-1 induces expression and release of chemokines in cultured human lung epithelial cells

2009 ◽  
Vol 297 (1) ◽  
pp. L196-L203 ◽  
Author(s):  
Cheng Liu ◽  
Dawei Xu ◽  
Li Liu ◽  
Frida Schain ◽  
Åsa Brunnström ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Human Lung ◽  
A549 Cells ◽  
Airway Epithelial Cells ◽  
Bronchial Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Epithelial Cell Line ◽  
Chronic Obstructive ◽  
Bronchial Epithelial ◽  
Lung Epithelial

15-Lipoxygenase-1 (15-LOX-1) has been proposed to be involved in various physiological and pathophysiological activities such as inflammation, atherosclerosis, cell maturation, and tumorigenesis. Asthma and chronic obstructive pulmonary disease are associated with increased expression of 15-LOX-1 in bronchial epithelial cells, but the potential functions of 15-LOX-1 in airway epithelial cells have not been well clarified. To study the function of 15-LOX-1 in bronchial epithelial cells, we ectopically expressed 15-LOX-1 in the human lung epithelial cell line A549. We found that overexpression of 15-LOX-1 in A549 cells leads to increased release of the chemokines MIP-1α, RANTES, and IP-10, and thereby to increased recruitment of immature dendritic cells, mast cells, and activated T cells. These results suggest that an increased expression and activity of 15-LOX-1 in lung epithelial cells is a proinflammatory event in the pathogenesis of asthma and other inflammatory lung disorders.

scholarly journals Lung Bronchial Epithelial Cells are HIV Targets for Proviral Genomic Integration

2020 ◽  
Author(s):  
Dinesh Devadoss ◽  
Shashi P. Singh ◽  
Arpan Acharya ◽  
Kieu Chinh Do ◽  
Palsamy Periyasamy ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Bronchial Epithelial Cells ◽  
Lung Epithelial Cells ◽  
People Living With Hiv ◽  
Bronchial Epithelial ◽  
Highly Active ◽  
The People ◽  
Lung Epithelial ◽  
Latent Hiv ◽  
Hiv 1

ABSTRACTIn the era of highly active anti-retroviral therapy (HAART), obstructive lung diseases (OLDs) are common among the people living with HIV (PLWH); however, the mechanism by which HIV induces OLDs is unclear. Although human bronchial epithelial cells (HBECs) express HIV coreceptors and are critical in regulating lung immune responses, their role in transmitting HIV remains unclear. Herein, we present evidence that HIV-1 infects normal HBECs and the viral DNA is integrated in the genome to establish the viral latency. To prove that HIV productively infects HBECs, we demonstrate: (a) along with CXCR4, HBECs express the HIV-receptor CD4, and are induced to express CCR5 by IL-13 treatment; (b) following infection with HIV, HBECs produce HIV-p24 and contain the latent HIV provirus, which is activated by endotoxin and/or vorinostat; (c) DNA from HIV-1 infected HBECs contains the HIV-specific gag and nef genes, along with Alu sequences, confirming the integration of HIV in the host DNA; (d) the lung epithelial cells of HIV-infected subjects and SHIV-infected cynomolgus macaques are positive for HIV-specific transcripts. Thus, these studies suggest that HIV establishes latency in lung epithelial cells, making them potential HIV reservoirs. The long-living lung epithelial cells, activated by commonly encountered lung infections, might represent an ideal HIV target/reservoir, contributing to OLDs and other HIV-associated lung comorbidities.

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.

Lung fibroblasts produce chemotactic factors for bronchial epithelial cells

1989 ◽  
Vol 257 (2) ◽  
pp. L71-L79 ◽  
Author(s):  
S. Shoji ◽  
K. A. Rickard ◽  
R. F. Ertl ◽  
J. Linder ◽  
S. I. Rennard
Keyword(s):  
Epithelial Cells ◽  
Tissue Repair ◽  
Bronchial Epithelial Cell ◽  
Bronchial Epithelial Cells ◽  
Chemotactic Activity ◽  
Lung Fibroblasts ◽  
Molecular Weight Range ◽  
Bronchial Epithelial ◽  
Chemotactic Factors ◽  
Two Peaks

The interaction between the epithelial cells and the subjacent mesenchymal cells in the airway is thought to play a major role during tissue repair and morphogenesis. To evaluate this interaction, we cultured human lung fibroblasts and bovine bronchial epithelial cells and determined that fibroblast-conditioned medium has chemotactic activity for bronchial epithelial cells. This activity was nondialyzable, heat labile, pepsin labile, acid stable, lipid inextractable, and eluted from Sephadex G-150 column chromatography in the high-molecular-weight range. DEAE-Sephacyl ion exchange and gelatin-Sepharose affinity chromatography revealed two peaks containing chemotactic activity, one of which may be fibronectin, since it binds to gelatin, reacts in a specific immunoassay, and is inhibited of chemotactic activity by anti-fibronectin antiserum, and another of which does not appear to be fibronectin, since it does not bind to gelatin nor react in the immunoassay. Thus lung fibroblasts can produce at least two chemotactic factors for bronchial epithelial cells that may play a role during lung tissue repair and morphogenesis by modulating bronchial epithelial cell migration.

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.

Mechanotransduction of stretch-induced prostanoid release by fetal lung epithelial cells

2006 ◽  
Vol 291 (3) ◽  
pp. L487-L495 ◽  
Author(s):  
Ian B. Copland ◽  
Denis Reynaud ◽  
Cecil Pace-Asciak ◽  
Martin Post
Keyword(s):  
Mechanical Ventilation ◽  
Arachidonic Acid ◽  
Epithelial Cells ◽  
Fetal Lung ◽  
Lung Epithelial Cells ◽  
Cyclic Stretch ◽  
Mitogen Activated Protein Kinase ◽  
Lung Epithelial ◽  
The Media ◽  
Cox 2

Mechanical ventilation is the primary supportive treatment for infants and adults suffering from severe respiratory failure. Adverse mechanical ventilation (overdistension of the lung) triggers a proinflammatory response. Along with cytokines, inflammatory mediators such as bioactive lipids are involved in the regulation of the inflammatory response. The arachidonic acid pathway is a key source of bioactive lipid mediators, including prostanoids. Although ventilation has been shown to influence the production of prostanoids in the lung, the mechanotransduction pathways are unknown. Herein, we established that cyclic stretch of fetal lung epithelial cells, but not fibroblasts, can evoke an extremely sensitive, rapid alteration in eicosanoid metabolism through a cyclooxygenase (COX)-2 dependent mechanism. Cyclic stretch significantly increased PGI2, PGF2α, PGD2, PGE2, and thromboxane B2 levels in the media of epithelial cells, but did not alter leukotriene B4 or 12-hydroxyeicosatetraenoic acid levels. Inhibition of COX-2, but not COX-1, attenuated the cyclic stretch-induced PG increase in the media, suggesting that cyclic stretch primarily affected PG synthesis. Substrate (free arachidonic acid) availability for PG generation was increased because of a cyclic stretch-induced activation of cytosolic phospholipase A2 (cPLA2) via an influx of extracellular calcium and phosphorylation by mitogen-activated protein kinase, p44/42MAPK. The data are compatible with cPLA2 and COX-2 being intimately involved in regulating the injury response to adverse mechanical ventilation.

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.

scholarly journals Regulation of apoptosis by Bcl-2 cysteine oxidation in human lung epithelial cells

2013 ◽  
Vol 24 (6) ◽  
pp. 858-869 ◽  
Author(s):  
Sudjit Luanpitpong ◽  
Pithi Chanvorachote ◽  
Christian Stehlik ◽  
William Tse ◽  
Patrick S. Callery ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cells ◽  
Human Lung ◽  
Critical Role ◽  
B Cell Lymphoma ◽  
Lung Epithelial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Cysteine Oxidation ◽  
Lung Epithelial ◽  
Human Lung Epithelial Cells

Hydrogen peroxide is a key mediator of oxidative stress known to be important in various cellular processes, including apoptosis. B-cell lymphoma-2 (Bcl-2) is an oxidative stress–responsive protein and a key regulator of apoptosis; however, the underlying mechanisms of oxidative regulation of Bcl-2 are not well understood. The present study investigates the direct effect of H2O2on Bcl-2 cysteine oxidation as a potential mechanism of apoptosis regulation. Exposure of human lung epithelial cells to H2O2induces apoptosis concomitant with cysteine oxidation and down-regulation of Bcl-2. Inhibition of Bcl-2 oxidation by antioxidants or by site-directed mutagenesis of Bcl-2 at Cys-158 and Cys-229 abrogates the effects of H2O2on Bcl-2 and apoptosis. Immunoprecipitation and confocal microscopic studies show that Bcl-2 interacts with mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2 [ERK1/2]) to suppress apoptosis and that this interaction is modulated by cysteine oxidation of Bcl-2. The H2O2-induced Bcl-2 cysteine oxidation interferes with Bcl-2 and ERK1/2 interaction. Mutation of the cysteine residues inhibits the disruption of Bcl-2–ERK complex, as well as the induction of apoptosis by H2O2. Taken together, these results demonstrate the critical role of Bcl-2 cysteine oxidation in the regulation of apoptosis through ERK signaling. This new finding reveals crucial redox regulatory mechanisms that control the antiapoptotic function of Bcl-2.

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