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Effect of PD98059, a selective MAPK3/MAPK1 inhibitor, on acute lung injury in mice
R Di Paola1, C Crisafulli, E Mazzon
1IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy.
Abstract:
The aim of the present study is to evaluate the contribution of mitogen-activated protein kinase 1-3 MAPK3/MAPK1) in a model of acute lung inflammation in mice. Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by: accumulation of fluid containing a large number of neutrophils (PMNs) in the pleural cavity, infiltration of PMNs in lung tissues and subsequent adhesion molecule expression (I-CAM and P-selectin), lipid peroxidation, and increased production of tumour necrosis factor-alpha, (TNF-alpha) and interleukin-1beta (IL-1beta). Furthermore, carrageenan induced lung apoptosis (Bax and Bcl-2 expression) as well as nitrotyrosine formation, NF-kB activation, and pJNK expression, as determined by immunohistochemical analysis of lung tissues and the degree of lung inflammation and tissue injury (histological score). Administration of PD98059, an inhibitor of MAPK3/MAPK1 (10 mg/kg) 1 h after carrageenan caused a reduction in all the parameters of inflammation measured. Thus, based on these findings we propose that inhibitors of the MAPK3/MAPK1 signaling pathways, such as PD98059, may be useful in the treatment of various inflammatory diseases.
Insights
Mitogen-activated protein kinase (MAPK) pathways contribute to acute lung inflammation. Inhibiting MAPK3/MAPK1 with PD98059 reduced inflammatory markers and tissue damage in mice, suggesting therapeutic potential.
Area of Science:
- Immunology
- Molecular Biology
- Pharmacology
Background:
- Acute lung inflammation involves complex cellular and molecular signaling pathways.
- Mitogen-activated protein kinase (MAPK) signaling is implicated in inflammatory responses.
Purpose of the Study:
- To investigate the role of MAPK3/MAPK1 in a mouse model of acute lung inflammation.
- To evaluate the therapeutic potential of MAPK3/MAPK1 inhibition in this model.
Main Methods:
- Carrageenan-induced acute lung inflammation model in mice.
- Assessment of inflammatory cell infiltration, adhesion molecule expression, oxidative stress, cytokine production, apoptosis, and NF-kB activation.
- Immunohistochemical analysis and histological scoring of lung tissues.
- Administration of PD98059, a specific inhibitor of MAPK3/MAPK1.
Main Results:
- Carrageenan induced significant inflammatory responses, including neutrophil accumulation, increased pro-inflammatory cytokines (TNF-alpha, IL-1beta), oxidative stress, apoptosis, and NF-kB activation.
- PD98059 treatment significantly reduced all measured parameters of inflammation and lung injury.
- MAPK3/MAPK1 activation (pJNK expression) was observed in inflamed lung tissues.
Conclusions:
- MAPK3/MAPK1 signaling pathways play a critical role in mediating acute lung inflammation.
- Inhibitors targeting MAPK3/MAPK1, such as PD98059, demonstrate potential for treating inflammatory lung diseases.
