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Blockade of the JNK signalling as a rational therapeutic approach to modulate the early and late steps of the inflammatory cascade in polymicrobial sepsis.

Pizzino G, Bitto A, Pallio G, Irrera N, Galfo F, Interdonato M, Mecchio A, De Luca F, Minutoli L, Squadrito F, Altavilla D - Mediators Inflamm. (2015)

Bottom Line: CB57BL/6J mice were subjected to CLP or sham operation.To evaluate survival, a group of animals was monitored every 24 hours for 120 hours.Two other animals were sacrificed 4 or 18 hours after surgical procedures; lung and liver samples were collected for biomolecular and histopathologic analysis.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

ABSTRACT
Cecal ligation and puncture (CLP) is an experimental polymicrobial sepsis induced systemic inflammation that leads to acute organ failure. Aim of our study was to evaluate the effects of SP600125, a specific c-Jun NH2-terminal kinase (JNK) inhibitor, to modulate the early and late steps of the inflammatory cascade in a murine model of CLP-induced sepsis. CB57BL/6J mice were subjected to CLP or sham operation. Animals were randomized to receive either SP600125 (15 mg/kg) or its vehicle intraperitoneally 1 hour after surgery and repeat treatment every 24 hours. To evaluate survival, a group of animals was monitored every 24 hours for 120 hours. Two other animals were sacrificed 4 or 18 hours after surgical procedures; lung and liver samples were collected for biomolecular and histopathologic analysis. The expression of p-JNK, p-ERK, TNF-α, HMGB-1, NF-κB, Ras, Rho, Caspase 3, Bcl-2, and Bax was evaluated in lung and liver samples; SP600125 improved survival, reduced CLP induced activation of JNK, NF-κB, TNF-α, and HMGB-1, inhibited proapoptotic pathway, preserved Bcl-2 expression, and reduced histologic damage in both lung and liver of septic mice. SP600125 protects against CLP induced sepsis by blocking JNK signalling; therefore, it can be considered a therapeutic approach in human sepsis.

No MeSH data available.


Related in: MedlinePlus

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Mentions: The early signalling culminating in MAPKs activation involves the priming of the Rho and Ras protein. Rho and Ras proteins were overexpressed in CLP animals compared with sham mice (Figure 4) 4 hrs after the surgical procedures. Treatment with SP600125 did not affect Rho and Ras overexpression (Figure 4), thus confirming the specificity of SP600125 on MAPKs.


Blockade of the JNK signalling as a rational therapeutic approach to modulate the early and late steps of the inflammatory cascade in polymicrobial sepsis.

Pizzino G, Bitto A, Pallio G, Irrera N, Galfo F, Interdonato M, Mecchio A, De Luca F, Minutoli L, Squadrito F, Altavilla D - Mediators Inflamm. (2015)

© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4385695&req=5

Mentions: The early signalling culminating in MAPKs activation involves the priming of the Rho and Ras protein. Rho and Ras proteins were overexpressed in CLP animals compared with sham mice (Figure 4) 4 hrs after the surgical procedures. Treatment with SP600125 did not affect Rho and Ras overexpression (Figure 4), thus confirming the specificity of SP600125 on MAPKs.

Bottom Line: CB57BL/6J mice were subjected to CLP or sham operation.To evaluate survival, a group of animals was monitored every 24 hours for 120 hours.Two other animals were sacrificed 4 or 18 hours after surgical procedures; lung and liver samples were collected for biomolecular and histopathologic analysis.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

ABSTRACT
Cecal ligation and puncture (CLP) is an experimental polymicrobial sepsis induced systemic inflammation that leads to acute organ failure. Aim of our study was to evaluate the effects of SP600125, a specific c-Jun NH2-terminal kinase (JNK) inhibitor, to modulate the early and late steps of the inflammatory cascade in a murine model of CLP-induced sepsis. CB57BL/6J mice were subjected to CLP or sham operation. Animals were randomized to receive either SP600125 (15 mg/kg) or its vehicle intraperitoneally 1 hour after surgery and repeat treatment every 24 hours. To evaluate survival, a group of animals was monitored every 24 hours for 120 hours. Two other animals were sacrificed 4 or 18 hours after surgical procedures; lung and liver samples were collected for biomolecular and histopathologic analysis. The expression of p-JNK, p-ERK, TNF-α, HMGB-1, NF-κB, Ras, Rho, Caspase 3, Bcl-2, and Bax was evaluated in lung and liver samples; SP600125 improved survival, reduced CLP induced activation of JNK, NF-κB, TNF-α, and HMGB-1, inhibited proapoptotic pathway, preserved Bcl-2 expression, and reduced histologic damage in both lung and liver of septic mice. SP600125 protects against CLP induced sepsis by blocking JNK signalling; therefore, it can be considered a therapeutic approach in human sepsis.

No MeSH data available.


Related in: MedlinePlus