Nontypeable Haemophilus influenzae induces COX-2 and PGE2 expression in lung epithelial cells via activation of p38 MAPK and NF-kappa B

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.

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Diminished COX-2/PGE2-Mediated Antiviral Response Due to Impaired NOX/MAPK Signaling in G6PD-Knockdown Lung Epithelial Cells

PLoS ONE ◽

10.1371/journal.pone.0153462 ◽

2016 ◽

Vol 11 (4) ◽

pp. e0153462 ◽

Cited By ~ 12

Author(s):

Hsin-Ru Lin ◽

Yi-Hsuan Wu ◽

Wei-Chen Yen ◽

Chuen-Mao Yang ◽

Daniel Tsun-Yee Chiu

Keyword(s):

Epithelial Cells ◽

Antiviral Response ◽

Mapk Signaling ◽

Lung Epithelial Cells ◽

Lung Epithelial ◽

Cox 2

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COX-2 inhibitory effect of luteolin through the regulation of NF-κB and ERK in phorbol ester activated human lung epithelial cells

Asia-pacific Journal of Multimedia services convergent with Art Humanities and Sociology ◽

10.14257/ajmahs.2017.05.18 ◽

2017 ◽

Vol 7 (5) ◽

pp. 467-474

Author(s):

Chung Mu Park

Keyword(s):

Epithelial Cells ◽

Phorbol Ester ◽

Human Lung ◽

Inhibitory Effect ◽

Lung Epithelial Cells ◽

Lung Epithelial ◽

Cox 2 ◽

Human Lung Epithelial Cells

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Phloretin inhibits interleukin-1β-induced COX-2 and ICAM-1 expression through inhibition of MAPK, Akt, and NF-κB signaling in human lung epithelial cells

Food & Function ◽

10.1039/c5fo00149h ◽

2015 ◽

Vol 6 (6) ◽

pp. 1960-1967 ◽

Cited By ~ 29

Author(s):

Wen-Chung Huang ◽

Shu-Ju Wu ◽

Rong-Syuan Tu ◽

You-Rong Lai ◽

Chian-Jiun Liou

Keyword(s):

Epithelial Cells ◽

Proinflammatory Cytokine ◽

Human Lung ◽

Lung Epithelial Cells ◽

Interleukin 1Β ◽

Lung Epithelial ◽

Cox 2 ◽

Human Lung Epithelial Cells

Phloretin inhibited proinflammatory cytokine and COX-2 expression in IL-1β-activated human lung epithelial cells.

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Oxidative stress by layered double hydroxide nanoparticles via an SFK-JNK and p38-NF-κB signaling pathway mediates induction of interleukin-6 and interleukin-8 in human lung epithelial cells

International Journal of Nanomedicine ◽

10.2147/ijn.s82061 ◽

2015 ◽

pp. 3217 ◽

Cited By ~ 8

Author(s):

Soo-Jin Choi ◽

Hee-Jeong Paek ◽

Jin Yu

Keyword(s):

Oxidative Stress ◽

Epithelial Cells ◽

Interleukin 6 ◽

Human Lung ◽

Lung Epithelial Cells ◽

Nf Kappa B ◽

Lung Epithelial ◽

Double Hydroxide ◽

Layered Double Hydroxide Nanoparticles ◽

Human Lung Epithelial Cells

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Oncogenic K-Ras Regulates Proliferation and Cell Junctions in Lung Epithelial Cells through Induction of Cyclooxygenase-2 and Activation of Metalloproteinase-9

Molecular Biology of the Cell ◽

10.1091/mbc.e08-07-0732 ◽

2009 ◽

Vol 20 (3) ◽

pp. 791-800 ◽

Cited By ~ 35

Author(s):

Xue-Qing Wang ◽

Howard Li ◽

Vicki Van Putten ◽

Robert A. Winn ◽

Lynn E. Heasley ◽

...

Keyword(s):

Epithelial Cells ◽

Biological Effects ◽

Three Dimensional ◽

Lung Epithelial Cells ◽

Cell Junctions ◽

Prostaglandin E ◽

Erk Activation ◽

Lung Epithelial ◽

Cox 2 ◽

E Cadherin

Expression of oncogenic K-Ras is frequently observed in non–small-cell lung cancer. However, oncogenic K-Ras is not sufficient to transform lung epithelial cells and requires collaborating signals that have not been defined. To examine the biological effects of K-Ras in nontransformed lung epithelial cells, stable transfectants were generated in RL-65 cells, a spontaneously immortalized lung epithelial cell line. Expression of K-Ras resulted in extracellular signal-regulated kinase (ERK) activation, which mediated induction of cyclooxygenase (COX)-2 and increased prostaglandin E2 production. Epithelial cells expressing oncogenic K-Ras showed increased proliferation in two- and three-dimensional tissue culture and delayed formation of hollow acinar structures in three-dimensional matrigel cultures. These affects were mediated through COX-2–dependent activation of β-catenin signaling and inhibition of apoptosis. ERK activation also led to induction of metalloproteinase (MMP)-9 and cleavage of E-cadherin at two specific sites. This resulted in partial disruption of adherens junctions as determined by decreased transepithelial resistance (TER), and disruption of E-cadherin/β-catenin interactions. An MMP-9 inhibitor reversed the decrease in TER and inhibited β-catenin signaling. These data indicate that although expression of oncogenic K-Ras does not transform lung epithelial cells, it alters the phenotype of the cells by increasing proliferation and decreasing cell–cell contacts characteristic of epithelial cells.

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Streptococcus pneumoniae induced p38 MAPK- and NF-κB-dependent COX-2 expression in human lung epithelium

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00383.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. L1131-L1138 ◽

Cited By ~ 41

Author(s):

Philippe Dje N’Guessan ◽

Stefan Hippenstiel ◽

Mirabelle O. Etouem ◽

Janine Zahlten ◽

Wiebke Beermann ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Epithelial Cells ◽

Rna Polymerase Ii ◽

P38 Mapk ◽

Pneumococcal Pneumonia ◽

Community Acquired Pneumonia ◽

Dominant Negative ◽

Alveolar Epithelial Cells ◽

Lung Epithelial Cells ◽

Cox 2

Streptococcus pneumoniae is a major cause of community-acquired pneumonia and death from infectious diseases in industrialized countries. Lung airway and alveolar epithelial cells comprise an important barrier against airborne pathogens. Cyclooxygenase (COX)-derived prostaglandins, such as PGE2, are considered to be important regulators of lung function. Herein, we tested the hypothesis that pneumococci induced COX-2-dependent PGE2 production in pulmonary epithelial cells. Pneumococci-infected human pulmonary epithelial BEAS-2B cells released PGE2. Expression of COX-2 but not COX-1 was dose and time dependently increased in S. pneumoniae-infected BEAS-2B cells as well as in lungs of mice with pneumococcal pneumonia. S. pneumoniae induced degradation of IκBα and DNA binding of NF-κB. A specific peptide inhibitor of the IκBα kinase complex blocked pneumococci-induced PGE2 release and COX-2 expression. In addition, we noted activation of p38 MAPK and JNK in pneumococci-infected BEAS-2B cells. PGE2 release and COX-2 expression were reduced by p38 MAPK inhibitor SB-202190 but not by JNK inhibitor SP-600125. We analyzed interaction of kinase pathways and NF-κB activation: dominant-negative mutants of p38 MAPK isoforms α, β2, γ, and δ blocked S. pneumoniae-induced NF-κB activation. In addition, recruitment of NF-κB subunit p65/RelA and RNA polymerase II to the cox2 promoter depended on p38 MAPK but not on JNK activity. In summary, p38 MAPK- and NF-κB-controlled COX-2 expression and subsequent PGE2 release by lung epithelial cells may contribute significantly to the host response in pneumococcal pneumonia.

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