Phospholipid biosynthesis and secretion by a cell line (A549) which resembles type II alveolar epithelial cells

Shapiro, Donald L.; Nardone, Linda L.; Rooney, Seamus A.; Motoyama, Etsuro K.; Muñoz, José Luis Pedraz

doi:10.1016/0005-2760(78)90005-x

Cited by 93 publications

(48 citation statements)

References 15 publications

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“…We therefore next focused on this question, using the cultured lung epithelial cell lines A549 and BEAS-2B as model cell types for the alveolar and bronchial epithelium, respectively. Despite their tumor origin, A549 cells are widely employed as a representative cell for type II alveolar epithelial cells, and display characteristic phenotypic features, including polygonal morphology, apical microvilli, intracellular lamellar bodies, expression of surfactant proteins, and production of phospholipids (43,44). A549 cells were found to produce CCL2 constitutively in culture, as has been described previously (45).…”

Section: Par 1 Activation On Lung Epithelial Cells Induces the Expresmentioning

confidence: 66%

Pulmonary Epithelium Is a Prominent Source of Proteinase-activated Receptor-1–inducible CCL2 in Pulmonary Fibrosis

Mercer

Johns²,

Scotton³

et al. 2009

Am J Respir Crit Care Med

116

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Rationale: Studies in patients and experimental animals provide compelling evidence of the involvement of the major thrombin receptor, proteinase-activated receptor-1 (PAR 1 ), and the potent chemokine, chemokine (CC motif) ligand-2 (CCL2)/monocyte chemotactic protein-1, in the pathogenesis of idiopathic pulmonary fibrosis (IPF). PAR 1 knockout mice are protected from bleomycininduced lung inflammation and fibrosis and this protection is associated with marked attenuation in CCL2 induction. Objectives: The aim of this study was to determine which cell types represent the major source of PAR 1 -inducible CCL2 in the fibrotic lung. Methods: Using immunohistochemistry and dual immunofluorescence, we examined PAR 1 and CCL2 expression in the bleomycin model and human IPF lung. PAR 1 and CCL2 gene expression was also assessed in laser-captured alveolar septae from patients with IPF. The ability of PAR 1 to induce CCL2 production by lung epithelial cells was also examined in vitro. Measurements and Main Results: We report for the first time that PAR 1 and CCL2 are coexpressed and co-up-regulated on the activated epithelium in fibrotic areas in IPF. Similar observations were found in bleomycin-induced lung injury. Furthermore, we show that thrombin is a potent inducer of CCL2 gene expression and protein release by cultured lung epithelial cells via a PAR 1 -dependent mechanism. Conclusions: These data support the notion that PAR 1 activation on lung epithelial cells may represent an important mechanism leading to increased local CCL2 release in pulmonary fibrosis. Targeting PAR 1 on the pulmonary epithelium may offer a unique opportunity for therapeutic intervention in pulmonary fibrosis and other inflammatory and fibroproliferative conditions associated with excessive local generation of thrombin and CCL2 release.

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Section: Par 1 Activation On Lung Epithelial Cells Induces the Expresmentioning

confidence: 66%

Pulmonary Epithelium Is a Prominent Source of Proteinase-activated Receptor-1–inducible CCL2 in Pulmonary Fibrosis

Mercer

Johns²,

Scotton³

et al. 2009

Am J Respir Crit Care Med

116

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“…Morphologically they retain a cuboidal shape and bear a number of the ultrastructural characteristics, including lamellar bodies, consistent with those reported in AT2 cells in situ. They also manifest similar phospholipid biosynthetic properties and have been found to release and/or express a variety of cytokines and growth factors (7,60). We find that swellinginduced activation of the putative organic osmolyte permeability pathway VSOAC is potently suppressed by the pharmacological inhibitors of 5-LO (AA861) and the cysteinyl leukotriene receptor CysLT1 (Zafirlukast), but potentiated by reactive oxygen species, and ATP / extracellular Ca 2ϩ .…”

mentioning

confidence: 82%

Volume-sensitive release of organic osmolytes in the human lung epithelial cell line A549: role of the 5-lipoxygenase

Holm

Grygorczyk

Lambert

2013

American Journal of Physiology-Cell Physiology

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Holm JB, Grygorczyk R, Lambert IH. Volume-sensitive release of organic osmolytes in the human lung epithelial cell line A549: role of the 5-lipoxygenase. Am J Physiol Cell Physiol 305: C48-C60, 2013. First published March 13, 2013; doi:10.1152/ajpcell.00412.2012.-Pathophysiological conditions challenge cell volume homeostasis and perturb cell volume regulatory mechanisms leading to alterations of cell metabolism, active transepithelial transport, cell migration, and death. We report that inhibition of the 5-lipoxygenase (5-LO) with AA861 or ETH 615-139, the cysteinyl leukotriene 1 receptor (CysLT1) with the antiasthmatic drug Zafirlukast, or the volume-sensitive organic anion channel (VSOAC) with DIDS blocks the release of organic osmolytes (taurine, meAIB) and the concomitant cell volume restoration following hypoosmotic swelling of human type II-like lung epithelial cells (A549). Reactive oxygen species (ROS) are produced in A549 cells upon hypotonic cell swelling by a diphenylene iodonium-sensitive NADPH oxidase. The swelling-induced taurine release is suppressed by ROS scavenging (butylated hydroxytoluene, N-acetyl cysteine) and potentiated by H 2O2. Ca 2ϩ mobilization with ionomycin or ATP stimulates the swelling-induced taurine release whereas calmodulin inhibition (W7) inhibits the release. Chelation of the extracellular Ca 2ϩ (EGTA) had no effect on swelling-induced taurine release but prevented ATP-induced stimulation. H2O2, ATP, and ionomycin were unable to stimulate the taurine release in the presence of AA861 or Zafirlukast, placing 5-LO and CysLT1 as essential elements in the swelling-induced activation of VSOAC with ROS and Ca 2ϩ as potent modulators. Inhibition of tyrosine kinases (genistein, cucurbitacin) reduces volume-sensitive taurine release, adding tyrosine kinases (Janus kinase) as regulators of VSOAC activity. Caspase-3 activity during hypoxia is unaffected by inhibition of 5-LO/CysLT1 but reduced when swelling-induced taurine loss via VSOAC is prevented by DIDS excess extracellular taurine, indicating a beneficial role of taurine under hypoxia. 5-lipoxygenase; lung adenocarcinoma; cysteinyl leukotriene 1 receptor; hypoxia; ischemia; cell volume regulation; reactive oxygen species; taurine homeostasis WITHIN RECENT YEARS it has become clear that cell volume regulation under isotonic conditions and cell volume restoration following osmotic perturbations are important for regulation of the intracellular milieu and cellular functions, such as cell metabolism, cell migration, and control of cell death (see refs. 16, 39). Cells maintain a steady cell volume by regulating the intracellular concentrations of ions (mainly Na ϩ , K ϩ , and Cl Ϫ ) and organic osmolytes (16,39). A consequence of hypotonic cell swelling is net loss of KCl and amino acids including the ␤-amino ethane sulfonic acid, taurine.Taurine: a multifunctional amino acid. Taurine is the most abundant free amino acid of the human body and has been estimated to account for up to 38% of the total free amino acid pool in rat heart ce...

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“…This is different from carcinoma-derived cell lines, which are beneficial for studying cancer development, e.g., a blastoma-derived cell line (Camerlingo et al, 2011) or an in vitro carcinogenesis model, where ATII cells are exposed to tobacco-specific carcinogens (Mennecier et al, 2014) but hardly represent normal epithelial cells. The widely used A549 cell line, derived from an adenocarcinoma, which is commonly employed as a model of the lung epithelium, has a rather ATIIlike phenotype, including lamellar bodies (Shapiro et al, 1978). However, it has been used in drug transport studies (Wang and Zhang, 2004) despite its lack of barrier formation ability.…”

Section: Discussionmentioning

confidence: 99%

Human alveolar epithelial cells expressing tight junctions to model the air-blood barrier

Kuehn

Kletting

Carvalho-Wodarz

et al. 2016

ALTEX

104

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Phospholipid biosynthesis and secretion by a cell line (A549) which resembles type II alveolar epithelial cells

Cited by 93 publications

References 15 publications

Pulmonary Epithelium Is a Prominent Source of Proteinase-activated Receptor-1–inducible CCL2 in Pulmonary Fibrosis

Pulmonary Epithelium Is a Prominent Source of Proteinase-activated Receptor-1–inducible CCL2 in Pulmonary Fibrosis

Volume-sensitive release of organic osmolytes in the human lung epithelial cell line A549: role of the 5-lipoxygenase

Human alveolar epithelial cells expressing tight junctions to model the air-blood barrier

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