Phospholipase Cε plays a crucial role in neutrophilic inflammation accompanying acute lung injury through augmentation of CXC chemokine production from alveolar epithelial cells

Umezawa, Kanoko; Nagano, Tatsuya; Kobayashi, Kazuyuki; Dokuni, Ryota; Katsurada, Masahiro; Yamamoto, Masatsugu; Yoshikawa, Yoko; Kataoka, Tohru; Nishimura, Yoshihiro

doi:10.1186/s12931-019-0975-4

Cited by 8 publications

(14 citation statements)

References 48 publications

(60 reference statements)

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“…CXCL5 is a neutrophil chemoattractant associated with lung inflammation in mice [31,32]. Moreover, neutralization of pulmonary CXCL5, suppressed neutrophilic inflammation in a mouse model of endotoxin-induced ALI, thereby indicating its prominent role in this pathology [32,33]. Our data showed that increased neutrophilic infiltration after twenty-four hours was paralleled by increased CXCL5 levels in the lungs.…”

Section: Discussionmentioning

confidence: 62%

Early Local Inhibition of Club Cell Protein 16 Following Chest Trauma Reduces Late Sepsis-Induced Acute Lung Injury

Störmann

Becker

Vollrath

et al. 2019

JCM

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Blunt thoracic trauma (TxT) deteriorates clinical post-injury outcomes. Ongoing inflammatory changes promote the development of post-traumatic complications, frequently causing Acute Lung Injury (ALI). Club Cell Protein (CC)16, a pulmonary anti-inflammatory protein, correlates with lung damage following TxT. Whether CC16-neutralization influences the inflammatory course during ALI is elusive. Ninety-six male CL57BL/6N mice underwent a double hit model of TxT and cecal ligation puncture (CLP, 24 h post-TxT). Shams underwent surgical procedures. CC16 was neutralized by the intratracheal application of an anti-CC16-antibody, either after TxT (early) or following CLP (late). Euthanasia was performed at 6 or 24 h post-CLP. Systemic and pulmonary levels of IL-6, IL-1β, and CXCL5 were determined, the neutrophils were quantified in the bronchoalveolar lavage fluid, and histomorphological lung damage was assessed. ALI induced a significant systemic IL-6 increase among all groups, while the local inflammatory response was most prominent after 24 h in the double-hit groups as compared to the shams. Significantly increased neutrophilic infiltration upon double hit was paralleled with the enhanced lung damage in all groups as compared to the sham, after 6 and 24 h. Neutralization of CC16 did not change the systemic inflammation. However, early CC16-neutralization increased the neutrophilic infiltration and lung injury at 6 h post-CLP, while 24 h later, the lung injury was reduced. Late CC16-neutralization increased neutrophilic infiltration, 24 h post-CLP, and was concurrent with an enhanced lung injury. The data confirmed the anti-inflammatory potential of endogenous CC16 in the murine double-hit model of ALI.

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Section: Discussionmentioning

confidence: 62%

Early Local Inhibition of Club Cell Protein 16 Following Chest Trauma Reduces Late Sepsis-Induced Acute Lung Injury

Störmann

Becker

Vollrath

et al. 2019

JCM

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“…Our results confirmed that the previous researches reveal LTB4 accelerates inflammatory activity through recruiting neutrophils and promoting cytokine and chemokine release. It is known to us that PLC-ε acts a proinflammatory role in ALI by inducing PMVEC permeability change and barrier disruption by activating proinflammatory cytokines and chemokines of neutrophils [14]. Previous studies have demonstrated that LTB4 recruits and activates of neutrophils, monocytes, and eosinophils by activating PLC [36,37].…”

Section: Discussionmentioning

confidence: 99%

“…Not only LTB4 but also phospholipase Cε (PLCε-1) acts a key role in neutrophil-mediated inflammation in ALI. Commonly, PLCε-1 is a member of the phospholipase (PLC) family and plays as a second messenger by generating inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) [14]. The Ca 2+ generation and protein kinase C (PKC) activation were further promoted by IP3 and DAG, respectively [15].…”

Section: Introductionmentioning

confidence: 99%

LTB4 Promotes Acute Lung Injury via Upregulating the PLCε-1/TLR4/NF-κB Pathway in One-Lung Ventilation

Jing

Tang

et al. 2022

Disease Markers

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Background. Mechanical ventilation (MV) can provoke acute lung injury (ALI) by increasing inflammation activation and disrupting the barrier in lung tissues even causing death. However, the inflammation-related molecules and pathways in MV-induced ALI remain largely unknown. Hence, the purposes of this study are to examine the role and mechanism of a novel inflammation-related molecule, leukotriene B4 (LTB4), in ALI. Methods. The functions of LTB4 in one-lung ventilation (OLV) model were detected by the loss-of-function experiments. H&E staining was used to examine the pathologic changes of lung tissues. Functionally, PLCε-1 knockdown and Toll-like receptor 4 (TLR4)/NF-κB pathway inhibitor were used to detect the regulatory effects of LTB4 on the phospholipase Cε (PLCε-1)/TLR4/nuclear factor-kappa B (NF-κB) pathway. The levels of genes and proteins were determined by RT-qPCR and western blotting assay. The levels of inflammation cytokines and chemokines were measured by ELISA. Results. Here, we found LTA4H, leukotriene B (4) receptor 1 (BLT1), LTB4, and PLCε-1 upregulated in OLV rats and associated with inflammatory activation and lung permeability changes of lung tissues. Inhibition of LTB4 alleviated the OLV-induced ALI by inhibiting inflammatory activation and lung permeability changes of lung tissues. For mechanism analyses, LTB4 promoted OLV-induced ALI by activating the PLCε-1/TLR4/NF-κB pathway. Conclusion. LTB4 induced ALI in OLV rats by activating the PLCε-1/TLR4/NF-κB pathway. Our findings might supply a new potential therapeutic for OLV-induced ALI.

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“…After termination of the mice, bronchoalveolar lavage (BAL) fluid was collected as previously described [ 25 ]. Briefly, after termination, 800 μL PBS was inserted and reaspirated via trachea three times using a blunted 18G needle and centrifuged at 1500 rpm for 10 min.…”

Section: Methodsmentioning

confidence: 99%

Budesonide/glycopyrronium/formoterol fumarate triple therapy prevents pulmonary hypertension in a COPD mouse model via NFκB inactivation

et al. 2022

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Background Chronic obstructive pulmonary disease (COPD) is a health problem that results in death, commonly due to the development of pulmonary hypertension (PH). Here, by utilizing a mouse model of intratracheal elastase-induced emphysema that presents three different phases of COPD, we sought to observe whether budesonide/glycopyrronium/formoterol fumarate (BGF) triple therapy could prevent COPD-PH in addition to ameliorating COPD progression. Methods We utilized intratracheal elastase-induced emphysema mouse model and performed experiments in three phases illustrating COPD progression: inflammatory (1 day post-elastase), emphysema (3 weeks post-elastase) and PH (4 weeks post-elastase), while treatments of BGF and controls (vehicle, one-drug, and two-drug combinations) were started in prior to elastase instillation (inflammatory phase), at day 7 (emphysema), or at day 14 (PH phase). Phenotype analyses were performed in each phase. In vitro, A549 cells or isolated mouse lung endothelial cells (MLEC) were treated with TNFα with/without BGF treatment to analyze NFκB signaling and cytokine expression changes. Results We observed significant reductions in the proinflammatory phenotype observed in the lungs and bronchoalveolar lavage fluid (BALF) 1 day after elastase administration in mice treated with BGF compared with that in mice administered elastase alone (BALF neutrophil percentage, p = 0.0011 for PBS/Vehicle vs. PBS/Elastase, p = 0.0161 for PBS/Elastase vs. BGF). In contrast, only BGF treatment significantly ameliorated the elastase-induced emphysematous lung structure and desaturation after three weeks of elastase instillation (mean linear intercept, p = 0.0156 for PBS/Vehicle vs. PBS/Elastase, p = 0.0274 for PBS/Elastase vs. BGF). Furthermore, BGF treatment prevented COPD-PH development, as shown by improvements in the hemodynamic and histological phenotypes four weeks after elastase treatment (right ventricular systolic pressure, p = 0.0062 for PBS/Vehicle vs. PBS/Elastase, p = 0.027 for PBS/Elastase vs. BGF). Molecularly, BGF acts by inhibiting NFκB-p65 phosphorylation and subsequently decreasing the mRNA expression of proinflammatory cytokines in both alveolar epithelial and pulmonary endothelial cells. Conclusion Our results collectively showed that BGF treatment could prevent PH in addition to ameliorating COPD progression via the inhibition of inflammatory NFκB signaling.

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Phospholipase Cε plays a crucial role in neutrophilic inflammation accompanying acute lung injury through augmentation of CXC chemokine production from alveolar epithelial cells

Cited by 8 publications

References 48 publications

Early Local Inhibition of Club Cell Protein 16 Following Chest Trauma Reduces Late Sepsis-Induced Acute Lung Injury

Early Local Inhibition of Club Cell Protein 16 Following Chest Trauma Reduces Late Sepsis-Induced Acute Lung Injury

LTB4 Promotes Acute Lung Injury via Upregulating the PLCε-1/TLR4/NF-κB Pathway in One-Lung Ventilation

Budesonide/glycopyrronium/formoterol fumarate triple therapy prevents pulmonary hypertension in a COPD mouse model via NFκB inactivation

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