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Carbon Monoxide Releasing Molecule-2-Upregulated ROS-Dependent Heme Oxygenase-1 Axis Suppresses Lipopolysaccharide-Induced Airway Inflammation
- Source :
- International Journal of Molecular Sciences, International Journal of Molecular Sciences, Vol 20, Iss 13, p 3157 (2019), Volume 20, Issue 13
- Publication Year :
- 2019
- Publisher :
- MDPI, 2019.
-
Abstract
- The up-regulation of heme oxygenase-1 (HO-1) is mediated through nicotinamaide adenine dinucleotide phosphate (NADPH) oxidases (Nox) and reactive oxygen species (ROS) generation, which could provide cytoprotection against inflammation. However, the molecular mechanisms of carbon monoxide-releasing molecule (CORM)-2-induced HO-1 expression in human tracheal smooth muscle cells (HTSMCs) remain unknown. Here, we found that pretreatment with CORM-2 attenuated the lipopolysaccharide (LPS)-induced intercellular adhesion molecule (ICAM-1) expression and leukocyte count through the up-regulation of HO-1 in mice, which was revealed by immunohistochemistrical staining, Western blot, real-time PCR, and cell count. The inhibitory effects of HO-1 by CORM-2 were reversed by transfection with HO-1 siRNA. Next, Western blot, real-time PCR, and promoter activity assay were performed to examine the HO-1 induction in HTSMCs. We found that CORM-2 induced HO-1 expression via the activation of protein kinase C (PKC)&alpha<br />and proline-rich tyrosine kinase (Pyk2), which was mediated through Nox-derived ROS generation using pharmacological inhibitors or small interfering ribonucleic acids (siRNAs). CORM-2-induced HO-1 expression was mediated through Nox-(1, 2, 4) or p47phox, which was confirmed by transfection with their own siRNAs. The Nox-derived ROS signals promoted the activities of extracellular signal-regulated kinase 1/2 (ERK1/2). Subsequently, c-Fos and c-Jun&mdash<br />activator protein-1 (AP-1) subunits&mdash<br />were up-regulated by activated ERK1/2, which turned on transcription of the HO-1 gene by regulating the HO-1 promoter. These results suggested that in HTSMCs, CORM-2 activates PKC&alpha<br />/Pyk2-dependent Nox/ROS/ERK1/2/AP-1, leading to HO-1 up-regulation, which suppresses the lipopolysaccharide (LPS)-induced airway inflammation.
- Subjects :
- Lipopolysaccharides
Male
Small interfering RNA
MAP Kinase Signaling System
Myocytes, Smooth Muscle
HO-1
Anti-Inflammatory Agents
Catalysis
Article
Inorganic Chemistry
lcsh:Chemistry
Mice
Western blot
medicine
Organometallic Compounds
Animals
Humans
Physical and Theoretical Chemistry
Molecular Biology
lcsh:QH301-705.5
Spectroscopy
Protein kinase C
Cells, Cultured
Mice, Inbred ICR
medicine.diagnostic_test
NADPH oxidase
Kinase
Chemistry
Organic Chemistry
NADPH Oxidases
ROS
General Medicine
Transfection
Intercellular adhesion molecule
AP-1
Intercellular Adhesion Molecule-1
Molecular biology
Cytoprotection
Cyclic AMP-Dependent Protein Kinases
Computer Science Applications
Heme oxygenase
Trachea
Focal Adhesion Kinase 2
lcsh:Biology (General)
lcsh:QD1-999
Tracheitis
Reactive Oxygen Species
CORM-2
Heme Oxygenase-1
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Volume :
- 20
- Issue :
- 13
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....3af254df236de5b70d6a39c0c1d83692