Abstract | BACKGROUND: METHODS: The in vitro model was performed using human alveolar A549 cells. Cells were exposed to lipopolysaccharide (LPS) 10 μg/ml and then, cells were treated with KYP-2047 at the concentrations of 1 μM, 10 μM and 50 μM. Cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) bromide colorimetric assay, while inflammatory protein expression was assessed by western blots analysis. The in vivo model was induced in mice by intra-tracheal administration of bleomycin (1 mg/kg) and then treated intraperitoneally with KYP-2047 at doses of 1, 2.5 and 5 mg/kg once daily for 12 days and then mice were sacrificed, and lung tissues were collected for analyses. RESULTS: The in vitro results demonstrated that KYP-2047 preserved cell viability, reduced inflammatory process by decreasing IL-18 and TNF-α, and modulated lipid peroxidation as well as nitrosative stress. The in vivo pulmonary fibrosis has demonstrated that KYP-2047 was able to restore histological alterations reducing lung injury. Our data demonstrated that KYP-2047 significantly reduced angiogenesis process and the fibrotic damage modulating the expression of fibrotic markers. Furthermore, KYP-2047 treatment modulated the IκBα/NF-κB pathway and reduced the expression of related pro-inflammatory enzymes and cytokines. Moreover, KYP-2047 was able to modulate the JAK2/STAT3 pathway, highly involved in pulmonary fibrosis. CONCLUSION: In conclusion, this study demonstrated the involvement of PREP in the pathogenesis of pulmonary fibrosis and that its inhibition by KYP-2047 has a protective role in lung injury induced by BLM, suggesting PREP as a potential target therapy for pulmonary fibrosis. These results speculate the potential protective mechanism of KYP-2047 through the modulation of JAK2/STAT3 and NF-κB pathways.
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Authors | Laura Cucinotta, Deborah Mannino, Giovanna Casili, Alberto Repici, Lelio Crupi, Irene Paterniti, Emanuela Esposito, Michela Campolo |
Journal | Respiratory research
(Respir Res)
Vol. 24
Issue 1
Pg. 211
(Aug 25 2023)
ISSN: 1465-993X [Electronic] England |
PMID | 37626373
(Publication Type: Journal Article)
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Copyright | © 2023. BioMed Central Ltd., part of Springer Nature. |
Chemical References |
- Prolyl Oligopeptidases
- NF-kappa B
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Topics |
- Humans
- Animals
- Mice
- Pulmonary Fibrosis
(chemically induced, drug therapy, prevention & control)
- Prolyl Oligopeptidases
- Lung Injury
- NF-kappa B
- Inflammation
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