Negative feedback between secretory and cytosolic phospholipase A2 and their opposing roles in ovalbumin-induced bronchoconstriction in rats

2005 ◽  
Vol 288 (3) ◽  
pp. L523-L529 ◽  
Author(s):  
Sarit Offer ◽  
Saul Yedgar ◽  
Ouri Schwob ◽  
Miron Krimsky ◽  
Haim Bibi ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Inflammatory Cells ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Membrane Phospholipids ◽  
Cytosolic Phospholipase ◽  
Inflammatory Processes ◽  
A Cell ◽  
First Time

Phospholipase A2 (PLA2) hydrolyzes cell membrane phospholipids (PL) to produce arachidonic acid and lyso-PL. The PLA2 enzymes include the secretory (sPLA2) and cytosolic (cPLA2) isoforms, which are assumed to act synergistically in production of eicosanoids that are involved in inflammatory processes. However, growing evidence raises the possibility that in airways and asthma-related inflammatory cells (eosinophils, basophils), the production of the bronchoconstrictor cysteinyl leukotrienes (CysLT) is linked exclusively to sPLA2, whereas the bronchodilator prostaglandin PGE2 is produced by cPLA2. It has been further reported that the capacity of airway epithelial cells to produce CysLT is inversely proportional to PGE2 production. This seems to suggest that sPLA2 and cPLA2 play opposing roles in asthma pathophysiology and the possibility of a negative feedback between the two isoenzymes. To test this hypothesis, we examined the effect of a cell-impermeable extracellular sPLA2 inhibitor on bronchoconstriction and PLA2 expression in rats with ovalbumin (OVA)-induced asthma. It was found that OVA-induced bronchoconstriction was associated with elevation of lung sPLA2 expression and CysLT production, concomitantly with suppression of cPLA2 expression and PGE2 production. These were reversed by treatment with the sPLA2 inhibitor, resulting in amelioration of bronchoconstriction and reduced CysLT production and sPLA2 expression, concomitantly with enhanced PGE2 production and cPLA2 expression. This study demonstrates, for the first time in vivo, a negative feedback between sPLA2 and cPLA2 and assigns opposing roles for these enzymes in asthma pathophysiology: sPLA2 activation induces production of the bronchoconstrictor CysLT and suppresses cPLA2 expression and the subsequent production of the bronchodilator PGE2.

Transgenic overexpression of β2-adrenergic receptors in airway epithelial cells decreases bronchoconstriction

2000 ◽  
Vol 279 (2) ◽  
pp. L379-L389 ◽  
Author(s):  
Dennis W. McGraw ◽  
Susan L. Forbes ◽  
Judith C. W. Mak ◽  
David P. Witte ◽  
Patricia E. Carrigan ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Airway Epithelium ◽  
Adrenergic Receptors ◽  
Airway Epithelial Cells ◽  
Airway Responsiveness ◽  
Ozone Exposure ◽  
Clara Cell ◽  
Whole Body ◽  
Airway Epithelial

Airway epithelial cells express β2-adrenergic receptors (β2-ARs), but their role in regulating airway responsiveness is unclear. With the Clara cell secretory protein (CCSP) promoter, we targeted expression of β2-ARs to airway epithelium of transgenic (CCSP-β2-AR) mice, thereby mimicking agonist activation of receptors only in these cells. In situ hybridization confirmed that transgene expression was confined to airway epithelium, and autoradiography showed that β2-AR density in CCSP-β2-AR mice was approximately twofold that of nontransgenic (NTG) mice. Airway responsiveness measured by whole body plethysmography showed that the methacholine dose required to increase enhanced pause to 200% of baseline (ED200) was greater for CCSP-β2-AR than for NTG mice (345 ± 34 vs. 157 ± 14 mg/ml; P < 0.01). CCSP-β2-AR mice were also less responsive to ozone (0.75 ppm for 4 h) because enhanced pause in NTG mice acutely increased to 77% over baseline ( P < 0.05) but remained unchanged in the CCSP-β2-AR mice. Although both groups were hyperreactive to methacholine 6 h after ozone exposure, the ED200for ozone-exposed CCSP-β2-AR mice was equivalent to that for unexposed NTG mice. These findings show that epithelial cell β2-ARs regulate airway responsiveness in vivo and that the bronchodilating effect of β-agonists results from activation of receptors on both epithelial and smooth muscle cells.

scholarly journals Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ivy Aneas ◽  
Donna C. Decker ◽  
Chanie L. Howard ◽  
Débora R. Sobreira ◽  
Noboru J. Sakabe ◽  
...  
Keyword(s):  
Association Studies ◽  
Regulatory Region ◽  
Airway Epithelial Cells ◽  
Genome Wide Association Studies ◽  
Airway Epithelial ◽  
Allele Specific ◽  
Enhancer Blocking ◽  
Underlying Mechanisms

AbstractGenome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear. Here, we identify a 5 kb region within the GWAS-defined segment that acts as an enhancer-blocking element in vivo and in vitro. Chromatin conformation capture showed that this 5 kb region loops to the IL33 promoter, potentially regulating its expression. We show that the asthma-associated single nucleotide polymorphism (SNP) rs1888909, located within the 5 kb region, is associated with IL33 gene expression in human airway epithelial cells and IL-33 protein expression in human plasma, potentially through differential binding of OCT-1 (POU2F1) to the asthma-risk allele. Our data demonstrate that asthma-associated variants at the IL33 locus mediate allele-specific regulatory activity and IL33 expression, providing a mechanism through which a regulatory SNP contributes to genetic risk of asthma.

scholarly journals Benzisothiazolinone upregulates the MUC5AC expression via ERK1/2, p38, and NF-κB pathways in airway epithelial cells

2019 ◽  
Vol 8 (5) ◽  
pp. 704-710
Author(s):  
Soyoung Kwak ◽  
Yoon Seok Choi ◽  
Hyung Gyun Na ◽  
Chang Hoon Bae ◽  
Si-Youn Song ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Inflammatory Diseases ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Mucus Hypersecretion ◽  
Human Airway ◽  
Airway Diseases ◽  
Extracellular Signal ◽  
Human Airway Epithelial Cells

Abstract Mucus plays an important role in protecting the respiratory tract from irritants. However, mucus hypersecretion is a major indicator of airway diseases. 1,2-Benzisothiazolin-3-one (BIT), as a microbicide, induces asthmatic inflammation. Therefore, we focused on the effects of BIT-related mucin secretion in airway epithelial cells. Our in vivo study showed increased mucus and MUC5AC expressions in the bronchioles of mice that inhaled BIT. For investigating the signaling pathways, we performed experiments in human airway epithelial cells. BIT induced the MUC5AC expression and significantly increased the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). The specific inhibitors of ERK1/2, p38, and NF-κB blocked the BIT-induced MUC5AC expression. Therefore, these results suggest that BIT induces the MUC5AC expression via the ERK1/2, p38, and NF-κB pathways in human airway epithelial cells, which may be involved in mucus hypersecretion associated with airway inflammatory diseases.

scholarly journals High-content screening of Thai medicinal plants reveals Boesenbergia rotunda extract and its component Panduratin A as anti-SARS-CoV-2 agents

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Phongthon Kanjanasirirat ◽  
Ampa Suksatu ◽  
Suwimon Manopwisedjaroen ◽  
Bamroong Munyoo ◽  
Patoomratana Tuchinda ◽  
...  
Keyword(s):  
Severe Pneumonia ◽  
Inhibitory Effect ◽  
Airway Epithelial Cells ◽  
High Content Screening ◽  
Target Cells ◽  
Airway Epithelial ◽  
Plaque Reduction Assay ◽  
Boesenbergia Rotunda ◽  
First Time ◽  
Panduratin A

AbstractSince December 2019, the emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused severe pneumonia, a disease named COVID-19, that became pandemic and created an acute threat to public health. The effective therapeutics are in urgent need. Here, we developed a high-content screening for the antiviral candidates using fluorescence-based SARS-CoV-2 nucleoprotein detection in Vero E6 cells coupled with plaque reduction assay. Among 122 Thai natural products, we found that Boesenbergia rotunda extract and its phytochemical compound, panduratin A, exhibited the potent anti-SARS-CoV-2 activity. Treatment with B. rotunda extract and panduratin A after viral infection drastically suppressed SARS-CoV-2 infectivity in Vero E6 cells with IC50 of 3.62 μg/mL (CC50 = 28.06 µg/mL) and 0.81 μΜ (CC50 = 14.71 µM), respectively. Also, the treatment of panduratin A at the pre-entry phase inhibited SARS-CoV-2 infection with IC50 of 5.30 µM (CC50 = 43.47 µM). Our study demonstrated, for the first time, that panduratin A exerts the inhibitory effect against SARS-CoV-2 infection at both pre-entry and post-infection phases. Apart from Vero E6 cells, treatment with this compound was able to suppress viral infectivity in human airway epithelial cells. This result confirmed the potential of panduratin A as the anti-SARS-CoV-2 agent in the major target cells in human. Since B. rotunda is a culinary herb generally grown in China and Southeast Asia, its extract and the purified panduratin A may serve as the promising candidates for therapeutic purposes with economic advantage during COVID-19 situation.

A system to impose prescribed homogenous strains on cultured cells

2001 ◽  
Vol 91 (4) ◽  
pp. 1600-1610 ◽  
Author(s):  
Christopher M. Waters ◽  
Matthew R. Glucksberg ◽  
Eugene P. Lautenschlager ◽  
Chyh-Woei Lee ◽  
Reed M. Van Matre ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cultured Cells ◽  
Large Strain ◽  
Mechanical Strain ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Degree Of Anisotropy ◽  
High Degree ◽  
Membrane Shape ◽  
First Time

There is presently significant interest in cellular responses to physical forces, and numerous devices have been developed to apply stretch to cultured cells. Many of the early devices were limited by the heterogeneity of deformation of cells in different locations and by the high degree of anisotropy at a particular location. We have therefore developed a system to impose cyclic, large-strain, homogeneous stretch on a multiwell surface-treated silicone elastomer substrate plated with pulmonary epithelial cells. The pneumatically driven mechanism consists of four plates each with a clamp to fix one edge of the cruciform elastomer substrate. Four linear bearings set at predetermined angles between the plates ensure a constant ratio of principal strains throughout the stretch cycle. We present the design of the device and membrane shape, the surface modifications of the membrane to promote cell adhesion, predicted and experimental measurements of the strain field, and new data using cultured airway epithelial cells. We present for the first time the relationship between the magnitude of cyclic mechanical strain and the extent of wound closure and cell spreading.

scholarly journals Virus Infection-Induced Bronchial Asthma Exacerbation

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Mutsuo Yamaya
Keyword(s):  
Epithelial Cells ◽  
Viral Infection ◽  
Airway Inflammation ◽  
Bronchial Asthma ◽  
Inflammatory Mediators ◽  
Asthma Exacerbation ◽  
Viral Infections ◽  
Inflammatory Cells ◽  
Airway Epithelial Cells ◽  
Airway Epithelial

Infection with respiratory viruses, including rhinoviruses, influenza virus, and respiratory syncytial virus, exacerbates asthma, which is associated with processes such as airway inflammation, airway hyperresponsiveness, and mucus hypersecretion. In patients with viral infections and with infection-induced asthma exacerbation, inflammatory mediators and substances, including interleukins (ILs), leukotrienes and histamine, have been identified in the airway secretions, serum, plasma, and urine. Viral infections induce an accumulation of inflammatory cells in the airway mucosa and submucosa, including neutrophils, lymphocytes and eosinophils. Viral infections also enhance the production of inflammatory mediators and substances in airway epithelial cells, mast cells, and other inflammatory cells, such as IL-1, IL-6, IL-8, GM-CSF, RANTES, histamine, and intercellular adhesion molecule-1. Viral infections affect the barrier function of the airway epithelial cells and vascular endothelial cells. Recent reports have demonstrated augmented viral production mediated by an impaired interferon response in the airway epithelial cells of asthma patients. Several drugs used for the treatment of bronchial asthma reduce viral and pro-inflammatory cytokine release from airway epithelial cells infected with viruses. Here, I review the literature on the pathogenesis of the viral infection-induced exacerbation of asthma and on the modulation of viral infection-induced airway inflammation.

Sign in / Sign up

Export Citation Format

Share Document