Endothelin-1 synthesis, receptors, and signal transduction in alveolar epithelium: evidence for an autocrine role

1995 ◽  
Vol 268 (2) ◽  
pp. L192-L200 ◽  
Author(s):  
B. A. Markewitz ◽  
D. E. Kohan ◽  
J. R. Michael
Keyword(s):  
Signal Transduction ◽  
Growth Factor ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial Cells ◽  
Pge2 Production ◽  
Endothelin 1 ◽  
Alveolar Epithelial ◽  
L2 Cells

In the lung, endothelin-1 (ET-1) is synthesized by several cell types and acts locally to cause vasoconstriction and bronchoconstriction, activate alveolar macrophages, and stimulate chloride secretion. We report ET-1 production, binding, and signal transduction by a previously unrecognized site, the alveolar epithelial cell. L2 cells, a cloned rat alveolar epithelial cell line, secreted ET-1 and contained ET-1 mRNA. Exposure of L2 cells to lipopolysaccharide, tumor necrosis factor-alpha, interleukin-1, or transforming growth factor-beta stimulated ET-1 release, whereas interferon-gamma or platelet-derived growth factor decreased ET-1 secretion. 125I-ET-1 binding to L2 cells revealed a single binding site with a maximal binding capacity of 22.4 fmol/mg protein and a dissociation constant of 4.03 nM. 125I-ET-1 binding was completely inhibited by ET receptor A (ETA) blockade and by unlabeled ET-1 >> ET-3 = sarafotoxin 6c, consistent with the presence of ETA. Exogenous ET-1 increased, whereas blockade of endogenous ET-1 decreased prostaglandin E2 (PGE2) production by L2 cells; exogenous ET-1 also increased adenosine 3',5'-cyclic monophosphate (cAMP) production. We conclude that 1) cloned rat alveolar epithelial cells synthesize ET-1; 2) inflammatory mediators modulate ET-1 production; 3) L2 cells express ETA; 4) ET-1 increases PGE2 and cAMP levels in these cells; and 5) BQ-123, an ETA antagonist, decreases their basal PGE2 production. These studies suggest that ET-1 may function as an autocrine factor in alveolar epithelial cells.

Protective effect of IL-6 on alveolar epithelial cell death induced by hydrogen peroxide

2005 ◽  
Vol 288 (2) ◽  
pp. L342-L349 ◽  
Author(s):  
Hiroshi Kida ◽  
Mitsuhiro Yoshida ◽  
Shigenori Hoshino ◽  
Koji Inoue ◽  
Yukihiro Yano ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial Cells ◽  
Lung Fibroblasts ◽  
Alveolar Epithelial ◽  
Epithelial Cell Death

The goal of this study was to examine whether IL-6 could directly protect lung resident cells, especially alveolar epithelial cells, from reactive oxygen species (ROS)-induced cell death. ROS induced IL-6 gene expression in organotypic lung slices of wild-type (WT) mice. ROS also induced IL-6 gene expression in mouse primary lung fibroblasts, dose dependently. The organotypic lung slices of WT were more resistant to ROS-induced DNA fragmentation than those of IL-6-deficient (IL-6−/−) mice. WT resistance against ROS was abrogated by treatment with anti-IL-6 antibody. TdT-mediated dUTP nick end labeling stain and electron microscopy revealed that DNA fragmented cells in the IL-6−/− slice included alveolar epithelial cells and endothelial cells. In vitro studies demonstrated that IL-6 reduced ROS-induced A549 alveolar epithelial cell death. Together, these data suggest that IL-6 played an antioxidant role in the lung by protecting lung resident cells, especially alveolar epithelial cells, from ROS-induced cell death.

Effect of cigarette smoke and its condensates on alveolar epithelial cell injury in vitro

1994 ◽  
Vol 266 (1) ◽  
pp. L92-L100 ◽  
Author(s):  
S. Lannan ◽  
K. Donaldson ◽  
D. Brown ◽  
W. MacNee
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Cell Injury ◽  
Cell Attachment ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial Cells ◽  
Type Ii ◽  
Alveolar Epithelial

The oxidant-antioxidant balance in the airspaces of the lungs may be critical in protecting the lungs from the effects of cigarette smoke. We studied the effect of cigarette smoke and its condensates on the detachment, attachment, and proliferation of the A549 human alveolar epithelial cell line, in an in vitro model of cell injury and regeneration and the protective effects of antioxidants. Whole and vapor phase cigarette smoke decreased 51Cr-labeled A549 cell attachment, increased cell detachment, and decreased cell proliferation, as assessed by [3H]thymidine uptake. Freshly isolated rat type II alveolar epithelial cells showed an enhanced susceptibility to smoke-induced cell lysis when compared with the A549 cell line. Reduced glutathione (GSH) (400 microM) protected against the effects of cigarette smoke exposure on cell attachment, proliferation, and detachment. Depletion of intracellular GSH with buthionine sulfoxamine enhanced the epithelial cell detachment injury produced by smoke condensates. We conclude that cigarette smoke and its condensates cause an oxidant-induced injury to A549 human type II alveolar epithelial cells. Both intra- and extracellular GSH have important roles in protecting epithelial cells from the injurious effects of cigarette smoke.

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

2014 ◽  
Vol 306 (8) ◽  
pp. L786-L796 ◽  
Author(s):  
Jibing Yang ◽  
Miranda Velikoff ◽  
Ernesto Canalis ◽  
Jeffrey C. Horowitz ◽  
Kevin K. Kim
Keyword(s):  
Growth Factor ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Cell Activation ◽  
Tissue Growth ◽  
Alveolar Epithelial Cells ◽  
Alveolar Epithelial ◽  
Lung Epithelial

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.

Evidence for amiloride-sensitive sodium channels in alveolar epithelial cells

1992 ◽  
Vol 262 (4) ◽  
pp. L405-L411 ◽  
Author(s):  
R. M. Russo ◽  
R. L. Lubman ◽  
E. D. Crandall
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Sodium Channel ◽  
Sodium Channels ◽  
Chloride Transport ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial Cells ◽  
Sodium Uptake ◽  
Alveolar Epithelial ◽  
22Na Uptake

To maintain alveolar air spaces relatively fluid free, the alveolar epithelium appears capable of vectorial transport of water and solutes. Active transepithelial transport of sodium by alveolar epithelial cell monolayers has previously been demonstrated, indicating that alveolar pneumocytes must possess ion transport mechanisms by which sodium can enter the cells apically for subsequent extrusion via Na(+)-K(+)-adenosinetriphosphatase activity at the basolateral surface. In this study, sodium entry mechanisms were investigated by directly measuring 22Na uptake into rat alveolar epithelial cells grown in primary culture. Cells exhibited increasing 22Na uptake with time over a 30-min interval. Total sodium uptake was compared in the presence and absence of several sodium transport inhibitors. Uptake was inhibited by the sodium channel blockers amiloride and benzamil but was not affected by two amiloride analogues (bromohexamethylene amiloride and dimethylamiloride) with diminished specificity for blocking sodium channels and enhanced specificity for inhibiting the Na(+)-H+ antiporter. Uptake was also unaffected by the chloride transport inhibitor bumetanide or by the absence of glucose. These data suggest that sodium uptake occurs primarily via sodium channel and that Na(+)-H+ antiport, Na(+)-K(+)-2Cl- cotransport, and Na(+)-glucose cotransport do not contribute significantly to sodium uptake under these experimental conditions. The presence of sodium channels in the alveolar epithelial cell membrane may provide the major entry mechanism by which sodium enters these cells for subsequent active extrusion, thereby effecting net salt and water reabsorption from the alveolar spaces.

Association of ICAM-1 with the cytoskeleton in rat alveolar epithelial cells in primary culture

1996 ◽  
Vol 271 (5) ◽  
pp. L707-L718 ◽  
Author(s):  
W. W. Barton ◽  
S. E. Wilcoxen ◽  
P. J. Christensen ◽  
R. Paine
Keyword(s):  
Endothelial Cells ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Alveolar Epithelial Cell ◽  
Inflammatory Cells ◽  
Alveolar Epithelial Cells ◽  
Type I ◽  
Type Ii Cells ◽  
Type Ii ◽  
Alveolar Epithelial

Intercellular adhesion molecule-1 ICAM-1) is a transmembrane adhesion protein that is expressed constitutively on the apical surface of type I cells in vivo and on type II cells in vitro as they spread in culture, assuming type I cell-like characteristics. To investigate the possible interaction of ICAM-1 with the alveolar epithelial cell cytoskeleton, rat type II cells in primary culture were extracted with nonionic detergent, and residual ICAM-1 associated with the cytoskeletal remnants was determined using immunofluorescence microscopy, immunoprecipitation, and cell-based enzyme-linked immunosorbent assay. A large fraction of alveolar epithelial cell ICAM-1 remained associated with the cytoskeleton after detergent extraction, whereas two other transmembrane molecules, transferrin receptor and class II major histocompatibility complex, were completely removed. ICAM-1 was redistributed on the cell surface after the disruption of actin filaments with cytochalasin B, suggesting interaction with the actin cytoskeleton. In contrast, ICAM-1 was completely detergent soluble in rat pulmonary artery endothelial cells, human umbilical vein endothelial cells, and rat alveolar macrophages. The association of ICAM-1 with the alveolar epithelial cell cytoskeleton was not altered after stimulation with inflammatory cytokines. However, detergent resistant ICAM-1 was significantly increased after crosslinking of ICAM-1 on the cell surface, suggesting that this cytoskeletal association may be modulated by interactions of alveolar epithelial cells with inflammatory cells. The association of ICAM-1 with the cytoskeleton in alveolar epithelial cells may provide a fixed intermediary between mobile inflammatory cells and the alveolar surface.

scholarly journals Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice

2008 ◽  
Vol 294 (5) ◽  
pp. L882-L890 ◽  
Author(s):  
Saeko Takahashi ◽  
Hidetoshi Nakamura ◽  
Makoto Seki ◽  
Yoshiki Shiraishi ◽  
Miyuki Yamamoto ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Pulmonary Emphysema ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial Cells ◽  
Morphometric Parameter ◽  
Endothelial Cell Function ◽  
Alveolar Epithelial ◽  
Anti Inflammatory

Besides lowering cholesterol, statins exert multiple effects, such as anti-inflammatory activity and improvement of endothelial cell function. We examined whether simvastatin (SS) protects against the development of elastase-induced pulmonary emphysema in mice by using mean linear intercepts of alveoli (Lm) as a morphometric parameter of emphysema. After injection of intratracheal elastase on day 0, C57BL/6 mice were treated daily with SS (SS+ group) or PBS (SS− group) for 2 wk. A 21% decrease in Lm on day 7 was observed in the SS+ group vs. the SS− group. Anti-inflammatory effects of SS were observed as a decrease in percentage of neutrophils up to day 3, and in hydroxyproline concentration on day 3, in bronchoalveolar lavage fluid (BALF). SS also increased the number of proliferating cell nuclear antigen (PCNA)-positive alveolar epithelial cells between days 3 and 14. To confirm the role of statins in promoting proliferation of alveolar cells, mice were treated with SS (SS+) vs. PBS (SS−) for 12 days, starting 3 wk after elastase administration. After SS treatment, Lm decreased by 52% and PCNA-positive alveolar epithelial cells increased compared with the SS− group. Concentrations of vascular endothelial growth factor in BALF and endothelial nitric oxide synthase protein expression in pulmonary vessels tended to be higher in the SS+ group vs. the SS− group in this protocol. In conclusion, SS inhibited the development of elastase-induced pulmonary emphysema in mice. This therapeutic effect was due not only to anti-inflammation but also to the promotion of alveolar epithelial cell regeneration, partly mediated by restoring endothelial cell functions.

Contrasting effects of alveolar macrophages and neutrophils on asbestos-induced pulmonary epithelial cell injury

1994 ◽  
Vol 266 (1) ◽  
pp. L84-L91 ◽  
Author(s):  
D. W. Kamp ◽  
M. M. Dunn ◽  
J. S. Sbalchiero ◽  
A. M. Knap ◽  
S. A. Weitzman
Keyword(s):  
Epithelial Cell ◽  
Incubation Period ◽  
Alveolar Macrophages ◽  
Cell Injury ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial Cells ◽  
51Cr Release ◽  
Alveolar Epithelial ◽  
L2 Cells ◽  
Epithelial Cell Injury

Pulmonary toxicity from asbestos may be due in part to oxidant-mediated mechanisms. The purpose of this study was to determine whether alveolar macrophages (AM) contribute to asbestos-induced alveolar epithelial cell injury by oxidant-dependent mechanisms similar to that previously described for polymorphonuclear leukocytes (PMN). We assessed 51Cr release from cultured rat alveolar epithelial cells (RAEC) and transformed human pulmonary epithelial-like cell lines (rat L2 and human WI-26: HPEC). Amosite asbestos caused dose-dependent injury to both RAEC and L2 cells after an 18-h incubation period. Rat PMN increased asbestos-induced injury to RAEC (11 vs. 20% 51Cr release). In contrast, rat AM diminished asbestos-induced injury to RAEC and L2 cells by 60-80%. Human monocytes cultured for 72 h also attenuated asbestos-induced HPEC damage. Asbestos stimulated more H2O2 release from PMN than from AM isolated from the same rats (5.3 +/- 0.6 vs. 0.3 +/- 0.1 nmol x 10(6) cells-1 x 2h-1). The protective effect of rat AM, as opposed to PMN, was not due to differences in asbestos-induced toxicity to each cell type, since > 90% of AM and PMN were nonviable after 18 h. Transmission electron microscopy demonstrated comparable uptake of asbestos by AM and PMN after a 2-h incubation period. However, after an 18-h exposure period, the PMN were completely lysed, whereas over 90% of the AM contained fibers, despite morphologic evidence of cytotoxicity. These results demonstrate that AM, unlike PMN, can reduce alveolar epithelial cell injury in this model.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Inhibition Mir-92a Alleviates Oxidative Stress and Apoptosis of Alveolar Epithelial Cells Induced by Lipopolysaccharide Exposure through TLR2/AP-1 Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-8 ◽  
Author(s):  
Jian Cui ◽  
Huanhuan Ding ◽  
Yongyuan Yao ◽  
Wei Liu
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Lung Tissue ◽  
Cell Apoptosis ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial Cells ◽  
Rat Lung ◽  
Alveolar Epithelial

Objective. To probe into the role of miR-92a in alleviating oxidative stress and apoptosis of alveolar epithelial cell (AEC) injury induced by lipopolysaccharide (LPS) exposure through the Toll-like receptor (TLR) 2/activator protein-1 (AP-1) pathway. Methods. Acute lung injury (ALI) rat model and ALI alveolar epithelial cell model were constructed to inhibit the expression of miR-92a/TLR2/AP-1 in rat and alveolar epithelial cells (AECs), to detect the changes of oxidative stress, inflammatory response, and cell apoptosis in rat lung tissues and AECs, and to measure the changes of wet-dry weight (W/D) ratio in rat lung tissues. Results. Both inhibition of miR-92a expression and knockout of TLR2 and AP-1 gene could reduce LPS-induced rat ALI, alleviate pulmonary edema, inhibit oxidative stress and inflammatory response, and reduce apoptosis of lung tissue cells. In addition, the TLR2 and AP-1 levels in the lung tissues of ALI rats were noticed to be suppressed when inhibiting the expression of miR-92a, and the AP-1 level was also decreased after the knockout of TLR2 gene. Further, we verified this relationship in AECs and found that inhibition of miR-92a/TLR2/AP-1 also alleviated LPS-induced AEC injury, reduced cell apoptosis, and inhibited oxidative stress and inflammatory response. What is more, like that in rat lung tissue, the phenomenon also existed in AECs, that is, when the expression of miR-92a was inhibited, the expression of TLR2 and AP-1 was inhibited, and silencing TLR2 can reduce the expression level of AP-1. Conclusion. MiR-92a/TLR2/AP-1 is highly expressed in ALI, and its inhibition can improve oxidative stress and inflammatory response and reduce apoptosis of AECs.

Regulation of type II alveolar epithelial cell proliferation by TGF-beta during bleomycin-induced lung injury in rats

1994 ◽  
Vol 267 (5) ◽  
pp. L498-L507 ◽  
Author(s):  
N. Khalil ◽  
R. N. O'Connor ◽  
K. C. Flanders ◽  
W. Shing ◽  
C. I. Whitman
Keyword(s):  
Cell Proliferation ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial Cells ◽  
Type Ii ◽  
Epithelial Cell Proliferation ◽  
Tgf Beta ◽  
Alveolar Epithelial

Three isoforms of transforming growth factor-beta (TGF-beta) are found in mammalian cells and are potent regulators of inflammation, connective tissue synthesis, cellular proliferation, and differentiation. To determine the distribution and regulation of TGF-beta isoforms during pulmonary injury, a rat model of bleomycin-induced lung inflammation and repair was used. Using immunohistochemistry, we demonstrate that TGF-beta 2 and TGF-beta 3 were localized to alveolar macrophages as well as epithelial and smooth muscle cells of both normal rat lungs and rat lungs obtained at all time intervals after bleomycin administration. Early in bleomycin-induced lung injury, when there is active proliferation of type II alveolar epithelial cells, there was an increase in the number of type II alveolar epithelial cells isolated per lung and an increase in DNA synthesis by explanted type II alveolar epithelial cells. At this time, the secretion of biologically active TGF-beta 1–3, which are potent inhibitors of epithelial cell proliferation, was decreased. However, the secretion of TGF-beta 1–3 activity was markedly increased later in the injury response and coincided with a reduction in the number of type II alveolar epithelial cells isolated per lung and DNA synthesis in vitro. Furthermore, the addition of TGF-beta 1, 2, and 3 to cultures of actively proliferating type II alveolar epithelial cells resulted in inhibition of [3H]thymidine incorporation, whereas, in the presence of anti-TGF-beta 1-3 antibody, there was an increase in [3H]thymidine incorporation. Our findings suggest that altered secretion of TGF-beta 1-3 activity by type II alveolar epithelial cells during bleomycin-induced lung injury may regulate pulmonary alveolar epithelial cell proliferation during injury and repair phases.

STAT3 Promotes Apoptosis of Alveolar Epithelial Cells by Inhibiting AKT Signaling

2021 ◽  
Vol 7 (4) ◽  
pp. 741-748
Author(s):  
Jianhua Liu ◽  
Liqing Zheng ◽  
Liang Cao ◽  
Changhong Zhang ◽  
Chen Li
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Signaling Pathway ◽  
Alveolar Epithelial Cell ◽  
Akt Signaling ◽  
Alveolar Epithelial Cells ◽  
Type Ii ◽  
Akt Signaling Pathway ◽  
Alveolar Epithelial ◽  
Epithelial Cell Apoptosis

Type II alveolar epithelial cells are a crucial component of alveolar epithelium, and transcriptional activator 3 (STAT3) have functions in regulating alveolar epithelial cell proliferation. Therefore, based on the modular approach, we analyzed the effects of silencing STAT3 on type II alveolar epithelial cells and studied its mechanism of action. Initially, in the GEO database, we downloaded data on type II alveolar epithelial cells. For transcript to me data in alveolar epithelial cell samples, we performed a differential analysis. Secondly, protein interaction network analysis (PPIs) were performed on the differential genes, and the PPIs were analyzed modularly. The module gene was subjected to enrichment analysis of GO function and KEGG pathway. Non-coding RNAs and transcription factors that regulate the module are predicted based on hyper geometric testing. Thus, we have a total of 13 dysfunction modules. These modular genes are significantly involved in biological processes such as nuclear membranes, embryonic organ development, and regulate the insulin signaling pathway and the PI3K-Akt signaling pathway substantially. We identified vital ncRNA pivots (miR-205-5p) and TF pivot (Eomes, Etsl, Nfkbl, Spi1, Statl, Usfl) to regulate dysfunction modules significantly. Our work deciphered a co-expression network that involved essential gene regulation of type II alveolar epithelial cell apoptosis. It helps to reveal the regulation of silencing STAT3 gene on alveolar epithelial cell apoptosis and deepen our understanding of the mechanism. More importantly, we explained that the silencing gene STAT3 inhibits the apoptosis of alveolar epithelial cells by activating the AKT signaling pathway, providing a new theoretical reference for the study of alveolar epithelial cells.

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