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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: In order to assess the impact of treatment on sepsis-induced mortality, C57BL/6 mice subjected to CLP or sham operation were treated 1 hour after the surgical procedures with SP600125 (15 mg/kg/i.p.) or vehicle. The treatment was repeated every 24 hrs. All the CLP animals were fluid resuscitated via administration of sterile 0.9% NaCl saline solution (1 mL/mouse). Animal survival was monitored for up to 120 hours. CLP-induced sepsis in mice produced a significantly higher mortality compared with sham animals (Figure 1). SP600125 administration was able to increase the survival rate in treated animals and reduced mortality in CLP mice (Figure 1).


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: In order to assess the impact of treatment on sepsis-induced mortality, C57BL/6 mice subjected to CLP or sham operation were treated 1 hour after the surgical procedures with SP600125 (15 mg/kg/i.p.) or vehicle. The treatment was repeated every 24 hrs. All the CLP animals were fluid resuscitated via administration of sterile 0.9% NaCl saline solution (1 mL/mouse). Animal survival was monitored for up to 120 hours. CLP-induced sepsis in mice produced a significantly higher mortality compared with sham animals (Figure 1). SP600125 administration was able to increase the survival rate in treated animals and reduced mortality in CLP mice (Figure 1).

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