scholarly journals Astragalin Inhibits Pulmonary Inflammation in Cigarette Smoking-Induced Embolism

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1526-1526
Author(s):  
Yun-Ho Kim ◽  
Young-Hee Kang

Abstract Objectives Thrombin generation is crucial to the regulation of hemostasis and thrombosis and is essential to the pathogenesis of cardiovascular disease and venous thrombosis. Pulmonary embolism is a blockage in one of the pulmonary arteries in your lung caused by blood clots due to risk factors including tobacco use. Astragalin (kaempferol 3-O-glucoside) is a flavonoid present in persimmon leaves and green tea seeds and exhibits diverse activities such as asthma and obstructive pulmonary disease. This study investigated that astragalin encumbered pulmonary inflammation caused by cigarette smoking-induced embolism. Methods Pulmonary embolism was evoked through exposure of BALB/c mice to cigarette smoke for 30 min, five days a week for eight weeks. Mice were orally administrated with 10 or 20 mg/kg astragalin for 8 weeks. For the in vitro studies, 10 U/ml thrombin was loaded to alveolar epithelial A549 cells in the absence and presence of 1–20 μM astragalin. Results Oral supplementation of astragalin reduced tissue factor and urokinase-type plasminogen activator elevated in cigarette smoking-exposed lungs. In addition, 1–20 μM astragalin attenuated the induction of protease activated receptor-1 known as coagulation factor II (thrombin) receptor-like-1, in 10 U/ml thrombin-loaded alveolar epithelial cells. Astragalin curtailed induction of the inflammatory mediators of cyclooxygenase-2, intercellular adhesion molecule-1 and inducible nitric oxide synthase in alveolar cells subjected to thrombin. Furthermore, astragalin inhibited inflammatory signaling entailing MAPK/ERK pathway. Conclusions Astragalin may be a potential agent alleviating pulmonary inflammation induced by cigarette smoking-induced embolism. Funding Sources This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2019R1A6A3A01094891).

2016 ◽  
Vol 310 (7) ◽  
pp. L639-L657 ◽  
Author(s):  
Rou-Ling Cho ◽  
Chien-Chung Yang ◽  
I-Ta Lee ◽  
Chih-Chung Lin ◽  
Pei-Ling Chi ◽  
...  

Upregulation of intercellular adhesion molecule-1 (ICAM-1) is frequently implicated in lung inflammation. Lipopolysaccharide (LPS) has been shown to play a key role in inflammation via adhesion molecule induction and then causes lung injury. However, the mechanisms underlying LPS-induced ICAM-1 expression in human pulmonary alveolar epithelial cells (HPAEpiCs) remain unclear. We showed that LPS induced ICAM-1 expression in HPAEpiCs, revealed by Western blotting, RT-PCR, real-time PCR, and promoter assay. Pretreatment with the inhibitor of c-Src (protein phosphatase-1, PP1), reactive oxygen species (ROS) (Edaravone), NADPH oxidase (apocynin and diphenyleneiodonium chloride), EGFR (AG1478), PDGFR (AG1296), phosphatidylinositol-3-kinase (PI3K) (LY294002), MEK1/2 (U0126), or NF-κB (Bay11-7082) and transfection with siRNAs of c-Src, EGFR, PDGFR, Akt, p47 phox, Nox2, Nox4, p42, and p65 markedly reduced LPS-induced ICAM-1 expression and monocyte adherence to HPAEpiCs challenged with LPS. In addition, we established that LPS stimulated phosphorylation of c-Src, EGFR, PDGFR, Akt, or p65, which was inhibited by pretreatment with their respective inhibitors. LPS induced Toll-like receptor 4 (TLR4), MyD88, TNF receptor-associated factor 6 (TRAF6), c-Src, p47 phox, and Rac1 complex formation 2, which was attenuated by transfection with c-Src or TRAF6 siRNA. Furthermore, LPS markedly enhanced NADPH oxidase activation and intracellular ROS generation, which were inhibited by PP1. We established that LPS induced p42/p44 MAPK activation via a c-Src/NADPH oxidase/ROS/EGFR, PDGFR/PI3K/Akt-dependent pathway in these cells. Finally, we observed that LPS significantly enhanced NF-κB and IκBα phosphorylation, NF-κB translocation, and NF-κB promoter activity, which were inhibited by PP1, Edaravone, apocynin, diphenyleneiodonium chloride, AG1478, AG1296, LY294002 , or U0126. These results demonstrated that LPS induces p42/p44 MAPK activation mediated through the TLR4/MyD88/TRAF6/c-Src/NADPH oxidase/ROS/EGFR, PDGFR/PI3K/Akt pathway, which in turn initiates the activation of NF-κB and ultimately induces ICAM-1 expression in HPAEpiCs.


2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1531-1531
Author(s):  
Suyeon Oh ◽  
Young-Hee Kang

Abstract Objectives Pulmonary fibrosis is a disease in which lung tissues become fibrous and causes severe respiratory disturbances. Various stimuli induce infiltration of macrophages to the respiratory tract. These macrophages secrete various inflammatory cytokines leading to development of pulmonary fibrosis via epithelial–mesenchymal transition (EMT) process. Aesculetin, a major component of Sancho tree and Chicory, is known to have antioxidant and anti-inflammatory effects in the vascular and immune system. Methods Human alveolar basal epithelial A549 cells were cultured in conditioned media of THP-1 monocyte-derived macrophages for 24 h. Aesculetin at the concentrations of 1–20 μM did not show cytotoxicity of A549 cells. Alveolar epithelial cells were incubated with interleukin (IL)-8. Western blotting examined EMT-associated fibrotic proteins from A549 cell lysates. Matrix metalloproteinase (MMP) activity was measured with gelatin zymography. In addition, inflammation- and fibrosis-related cytokines were measured by using ELISA kits. Results The epithelial markers of E-cadherin and ZO-1 were reduced in cells exposed to macrophage-conditioned media containing IL-8 and TNF-α. Macrophage-conditioned media enhanced expression of the mesenchymal fibrotic markers of α-smooth muscle actin (α-SMA), vimentin and fibronectin, and the fibrotic proteins of collagen I and collagen IV were enhanced. However, ≥10 μM aesculetin reciprocally manipulated the expression levels of these proteins of A549 cells. In addition, macrophage-conditioned media enhanced the expression and activity of MT1-MMP, MMP-2 and MMP-9. In contrast, the expression of tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 were reduced by exposure of alveolar cells to conditioned media. Proinflammatory and chemotactic IL-8 reduced E-cadherin and conversely enhanced N-cadherin and α-SMA in A549 cells, which was reciprocally modulated by ≥ 10 μM aesculetin. These results demonstrate that aesculetin may ameliorate EMT-associated pulmonary fibrosis caused by contact of blood-derived macrophages and alveolar cells. Conclusions Aesculetin maybe a promising agent treating progressive pulmonary disorders owing to macrophage-mediated inflammation. Funding Sources No funding sources to report.


2002 ◽  
Vol 70 (1) ◽  
pp. 140-146 ◽  
Author(s):  
Luiz E. Bermudez ◽  
Felix J. Sangari ◽  
Peter Kolonoski ◽  
Mary Petrofsky ◽  
Joseph Goodman

ABSTRACT The mechanism(s) by which Mycobacterium tuberculosis crosses the alveolar wall to establish infection in the lung is not well known. In an attempt to better understand the mechanism of translocation and create a model to study the different stages of bacterial crossing through the alveolar wall, we established a two-layer transwell system. M. tuberculosis H37Rv was evaluated regarding the ability to cross and disrupt the membrane. M. tuberculosis invaded A549 type II alveolar cells with an efficiency of 2 to 3% of the initial inoculum, although it was not efficient in invading endothelial cells. However, bacteria that invaded A549 cells were subsequently able to be taken up by endothelial cells with an efficiency of 5 to 6% of the inoculum. When incubated with a bicellular transwell monolayer (epithelial and endothelial cells), M. tuberculosis translocated into the lower chamber with efficiency (3 to 4%). M. tuberculosis was also able to efficiently translocate across the bicellular layer when inside monocytes. Infected monocytes crossed the barrier with greater efficiency when A549 alveolar cells were infected with M. tuberculosis than when A549 cells were not infected. We identified two potential mechanisms by which M. tuberculosis gains access to deeper tissues, by translocating across epithelial cells and by traveling into the blood vessels within monocytes.


2002 ◽  
Vol 283 (1) ◽  
pp. L180-L187 ◽  
Author(s):  
Robert Paine ◽  
Susan B. Morris ◽  
Hong Jin ◽  
Carlos E. O. Baleeiro ◽  
Steven E. Wilcoxen

We postulate that intercellular adhesion molecule-1 (ICAM-1) on type I alveolar epithelial cells (AEC) facilitates phagocytic activity of alveolar macrophages (AM) in the alveolus. When wild-type and ICAM-1-deficient mice were inoculated intratracheally with FITC-labeled microspheres, AM phagocytosis of beads (after 1 and 4 h) was significantly reduced in ICAM-1−/− mice compared with controls. To focus on ICAM-1-mediated interactions specifically involving AM and AEC, rat AM were placed in culture with rat AEC treated with neutralizing anti-ICAM-1 F(ab′)2fragments. Blocking ICAM-1 significantly decreased the AM phagocytosis of beads. Planar chemotaxis of AM over the surface of AEC was also significantly impaired by neutralization of AEC ICAM-1. ICAM-1 in rat AEC is associated with the actin cytoskeleton. Planar chemotaxis of AM was also significantly reduced by pretreatment of the AEC monolayer with cytochalasin B to disrupt the actin cytoskeleton. These studies indicate that ICAM-1 on the AEC surface promotes mobility of AM in the alveolus and is critically important for the efficient phagocytosis of particulates by AM.


Author(s):  
Ludwig Traby ◽  
Marietta Kollars ◽  
Manuel Kussmann ◽  
Matthias Karer ◽  
Hana Sinkovec ◽  
...  

Objectives Pulmonary thrombus formation is a hallmark of coronavirus disease 2019 (COVID-19). A dysregulated immune response culminating in thromboinflammation has been described, but the pathomechanisms remain unclear. Methods We studied 41 adult COVID-19 patients with positive results on reverse-transcriptase polymerase-chain-reaction assays and 37 sex-and age-matched healthy controls. Number and surface characteristics of extracellular vesicles (EV) and citrullinated histone H 3 levels were determined in plasma upon inclusion by flowcytometry and immunoassay. Results 20 patients had severe and 21 non-severe disease. The number of EV [median, (25th, 75th percentile)] was significantly higher in patients compared with controls [658.8 (353.2, 876.6) vs 435.5 (332.5, 585.3), geometric mean ratio (95% confidence intervals): 2.6 (1.9, 3.6); p<0.001]. Patients exhibited significantly higher numbers of EV derived from platelets, endothelial cells, leukocytes, or neutrophils than controls. EV from alveolar-macrophages and alveolar-epithelial-cells were detectable in plasma and were significantly higher in patients. Intercellular Adhesion Molecule 1-positive EV levels were higher in patients, while no difference between tissue factor-positive and angiotensin converting enzyme-positive EV was seen between both groups. Levels of EV did not differ between patients with severe and non-severe COVID-19. Citrullinated histone H 3 levels [ng/ml, median (25th, 75th percentile)] were higher in patients than in controls [1.42 (0.6, 3.4) vs 0.31 (0.1, 0.6), geometric mean ratio: 4.44 (2.6, 7.7); p<0.001], and were significantly lower in patients with non-severe disease compared to those with severe disease. Conclusion EV and citrullinated histone H 3 are associated with COVID-19 and could provide information regarding pathophysiology of the disease.


2000 ◽  
Vol 278 (3) ◽  
pp. L572-L579 ◽  
Author(s):  
Caveh Madjdpour ◽  
Beat Oertli ◽  
Urs Ziegler ◽  
John M. Bonvini ◽  
Thomas Pasch ◽  
...  

Lipopolysaccharide (LPS)-induced lung inflammation is known to increase pulmonary intercellular adhesion molecule-1 (ICAM-1) expression. In the present study, L2 cells, a cell line of alveolar epithelial cells, were stimulated with LPS, and ICAM-1 expression was studied. ICAM-1 protein on L2 cells peaked at 6 (38% increase; P < 0.01) and 10 (48% increase; P < 0.001) h after stimulation with Escherichia coli and Pseudomonas aeruginosa LPS, respectively. ICAM-1 mRNA expression was markedly increased, with a peak at 2–4 ( E. coli) and 4–6 ( P. aeruginosa) h. Adherence assays of neutrophils to LPS-stimulated L2 cells showed a threefold increase in adherence ( P < 0.001). Pretreatment of the neutrophils with anti-lymphocyte function-associated antigen-1 and anti-Mac-1 antibodies reduced adherence by 54% ( P < 0.001). Analysis of immunofluorescence staining for ICAM-1 showed an exclusive apical expression of ICAM-1. These results indicate that LPS upregulates functional active ICAM-1 on the apical part of the membrane in rat pneumocytes.


Critical Care ◽  
2021 ◽  
Vol 25 (1) ◽  
Author(s):  
Savino Spadaro ◽  
Alberto Fogagnolo ◽  
Gianluca Campo ◽  
Ottavio Zucchetti ◽  
Marco Verri ◽  
...  

Abstract Background Biomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aims of this study were to evaluate whether the plasma concentration of the above-mentioned biomarkers was different 1) in survivors and non-survivors of COVID-19-related ARDS and 2) in COVID-19-related and classical ARDS. Methods This prospective study was performed in two COVID-19-dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 11 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7 ± 2 days (T2) and 14 ± 2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non-survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non-survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS. Results In COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p = 0.04 and p = 0.03, respectively), whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19-related ARDS (all p < 0.001). Conclusions COVID-19 ARDS is characterized by an early pulmonary endothelial injury, as detected by Ang-2 and ICAM-1. COVID-19 ARDS and classical ARDS exhibited a different expression of biomarkers, suggesting different pathological pathways. Trial registration NCT04343053, Date of registration: April 13, 2020


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