Amelioration of Endotoxin-Induced Acute Lung Injury and Alveolar Epithelial Cells Apoptosis by Simvastatin Is Associated with Up-Regulation of Survivin/NF-KB/p65 Pathway
Authors
Nežić, LanaAmidžić, Ljiljana
Škrbić, Ranko
Gajanin, Radoslav
Mandić, Danijela
Dumanović, Jelena
Milovanović, Zoran
Jaćević, Vesna
Article (Published version)
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Disruption of the alveolar–endothelial barrier caused by inflammation leads to the progression of septic acute lung injury (ALI). In the present study, we investigated the beneficial effects of simvastatin on the endotoxin lipopolysaccharide (LPS)-induced ALI and its related mechanisms. A model of ALI was induced within experimental sepsis developed by intraperitoneal injection of a single non-lethal LPS dose after short-term simvastatin pretreatment (10–40 mg/kg orally). The severity of the lung tissue inflammatory injury was expressed as pulmonary damage scores (PDS). Alveolar epithelial cell apoptosis was confirmed by TUNEL assay (DNA fragmentation) and expressed as an apoptotic index (AI), and immunohistochemically for cleaved caspase-3, cytochrome C, and anti-apoptotic Bcl-xL, an inhibitor of apoptosis, survivin, and transcriptional factor, NF-kB/p65. Severe inflammatory injury of pulmonary parenchyma (PDS 3.33 ± 0.48) was developed after the LPS challenge, whereas simvastatin sig...nificantly and dose-dependently protected lung histology after LPS (p < 0.01). Simvastatin in a dose of 40 mg/kg showed the most significant effects in amelioration alveolar epithelial cells apoptosis, demonstrating this as a marked decrease of AI (p < 0.01 vs. LPS), cytochrome C, and cleaved caspase-3 expression. Furthermore, simvastatin significantly enhanced the expression of Bcl-xL and survivin. Finally, the expression of survivin and its regulator NF-kB/p65 in the alveolar epithelium was in strong positive correlation across the groups. Simvastatin could play a protective role against LPS-induced ALI and apoptosis of the alveolar–endothelial barrier. Taken together, these effects were seemingly mediated by inhibition of caspase 3 and cytochrome C, a finding that might be associated with the up-regulation of cell-survival survivin/NF-kB/p65 pathway and Bcl-xL.
Keywords:
alveolar epithelial cells / apoptosis / NF-kB/p65 / simvastatin / survivinSource:
International Journal of Molecular Sciences, 2022, 23, 5, 2596-Publisher:
- MDPI
Funding / projects:
- Ministry of Science and Technology, Republic of Srpska, Bosnia and Herzegovina.
- Medical Faculty of the Military Medical Academy, University of Defense in Belgrade, Republic of Serbia (MFVMA/04/20-22)
DOI: 10.3390/ijms23052596
ISSN: 1422-0067
WoS: 000771526400001
Scopus: 2-s2.0-85125418068
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Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Nežić, Lana AU - Amidžić, Ljiljana AU - Škrbić, Ranko AU - Gajanin, Radoslav AU - Mandić, Danijela AU - Dumanović, Jelena AU - Milovanović, Zoran AU - Jaćević, Vesna PY - 2022 UR - https://www.mdpi.com/1422-0067/23/5/2596 UR - http://cherry.chem.bg.ac.rs/handle/123456789/5208 AB - Disruption of the alveolar–endothelial barrier caused by inflammation leads to the progression of septic acute lung injury (ALI). In the present study, we investigated the beneficial effects of simvastatin on the endotoxin lipopolysaccharide (LPS)-induced ALI and its related mechanisms. A model of ALI was induced within experimental sepsis developed by intraperitoneal injection of a single non-lethal LPS dose after short-term simvastatin pretreatment (10–40 mg/kg orally). The severity of the lung tissue inflammatory injury was expressed as pulmonary damage scores (PDS). Alveolar epithelial cell apoptosis was confirmed by TUNEL assay (DNA fragmentation) and expressed as an apoptotic index (AI), and immunohistochemically for cleaved caspase-3, cytochrome C, and anti-apoptotic Bcl-xL, an inhibitor of apoptosis, survivin, and transcriptional factor, NF-kB/p65. Severe inflammatory injury of pulmonary parenchyma (PDS 3.33 ± 0.48) was developed after the LPS challenge, whereas simvastatin significantly and dose-dependently protected lung histology after LPS (p < 0.01). Simvastatin in a dose of 40 mg/kg showed the most significant effects in amelioration alveolar epithelial cells apoptosis, demonstrating this as a marked decrease of AI (p < 0.01 vs. LPS), cytochrome C, and cleaved caspase-3 expression. Furthermore, simvastatin significantly enhanced the expression of Bcl-xL and survivin. Finally, the expression of survivin and its regulator NF-kB/p65 in the alveolar epithelium was in strong positive correlation across the groups. Simvastatin could play a protective role against LPS-induced ALI and apoptosis of the alveolar–endothelial barrier. Taken together, these effects were seemingly mediated by inhibition of caspase 3 and cytochrome C, a finding that might be associated with the up-regulation of cell-survival survivin/NF-kB/p65 pathway and Bcl-xL. PB - MDPI T2 - International Journal of Molecular Sciences T2 - International Journal of Molecular Sciences T1 - Amelioration of Endotoxin-Induced Acute Lung Injury and Alveolar Epithelial Cells Apoptosis by Simvastatin Is Associated with Up-Regulation of Survivin/NF-KB/p65 Pathway VL - 23 IS - 5 SP - 2596 DO - 10.3390/ijms23052596 ER -
@article{ author = "Nežić, Lana and Amidžić, Ljiljana and Škrbić, Ranko and Gajanin, Radoslav and Mandić, Danijela and Dumanović, Jelena and Milovanović, Zoran and Jaćević, Vesna", year = "2022", abstract = "Disruption of the alveolar–endothelial barrier caused by inflammation leads to the progression of septic acute lung injury (ALI). In the present study, we investigated the beneficial effects of simvastatin on the endotoxin lipopolysaccharide (LPS)-induced ALI and its related mechanisms. A model of ALI was induced within experimental sepsis developed by intraperitoneal injection of a single non-lethal LPS dose after short-term simvastatin pretreatment (10–40 mg/kg orally). The severity of the lung tissue inflammatory injury was expressed as pulmonary damage scores (PDS). Alveolar epithelial cell apoptosis was confirmed by TUNEL assay (DNA fragmentation) and expressed as an apoptotic index (AI), and immunohistochemically for cleaved caspase-3, cytochrome C, and anti-apoptotic Bcl-xL, an inhibitor of apoptosis, survivin, and transcriptional factor, NF-kB/p65. Severe inflammatory injury of pulmonary parenchyma (PDS 3.33 ± 0.48) was developed after the LPS challenge, whereas simvastatin significantly and dose-dependently protected lung histology after LPS (p < 0.01). Simvastatin in a dose of 40 mg/kg showed the most significant effects in amelioration alveolar epithelial cells apoptosis, demonstrating this as a marked decrease of AI (p < 0.01 vs. LPS), cytochrome C, and cleaved caspase-3 expression. Furthermore, simvastatin significantly enhanced the expression of Bcl-xL and survivin. Finally, the expression of survivin and its regulator NF-kB/p65 in the alveolar epithelium was in strong positive correlation across the groups. Simvastatin could play a protective role against LPS-induced ALI and apoptosis of the alveolar–endothelial barrier. Taken together, these effects were seemingly mediated by inhibition of caspase 3 and cytochrome C, a finding that might be associated with the up-regulation of cell-survival survivin/NF-kB/p65 pathway and Bcl-xL.", publisher = "MDPI", journal = "International Journal of Molecular Sciences, International Journal of Molecular Sciences", title = "Amelioration of Endotoxin-Induced Acute Lung Injury and Alveolar Epithelial Cells Apoptosis by Simvastatin Is Associated with Up-Regulation of Survivin/NF-KB/p65 Pathway", volume = "23", number = "5", pages = "2596", doi = "10.3390/ijms23052596" }
Nežić, L., Amidžić, L., Škrbić, R., Gajanin, R., Mandić, D., Dumanović, J., Milovanović, Z.,& Jaćević, V.. (2022). Amelioration of Endotoxin-Induced Acute Lung Injury and Alveolar Epithelial Cells Apoptosis by Simvastatin Is Associated with Up-Regulation of Survivin/NF-KB/p65 Pathway. in International Journal of Molecular Sciences MDPI., 23(5), 2596. https://doi.org/10.3390/ijms23052596
Nežić L, Amidžić L, Škrbić R, Gajanin R, Mandić D, Dumanović J, Milovanović Z, Jaćević V. Amelioration of Endotoxin-Induced Acute Lung Injury and Alveolar Epithelial Cells Apoptosis by Simvastatin Is Associated with Up-Regulation of Survivin/NF-KB/p65 Pathway. in International Journal of Molecular Sciences. 2022;23(5):2596. doi:10.3390/ijms23052596 .
Nežić, Lana, Amidžić, Ljiljana, Škrbić, Ranko, Gajanin, Radoslav, Mandić, Danijela, Dumanović, Jelena, Milovanović, Zoran, Jaćević, Vesna, "Amelioration of Endotoxin-Induced Acute Lung Injury and Alveolar Epithelial Cells Apoptosis by Simvastatin Is Associated with Up-Regulation of Survivin/NF-KB/p65 Pathway" in International Journal of Molecular Sciences, 23, no. 5 (2022):2596, https://doi.org/10.3390/ijms23052596 . .