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Inhibition of neutrophil collagenase/MMP-8 and gelatinase B/MMP-9 and protection against endotoxin shock.

Qiu Z, Chen J, Xu H, Van den Steen PE, Opdenakker G, Wang M, Hu J - J Immunol Res (2014)

Bottom Line: However, little is known about the therapeutic time window of MMP inhibition.Here, a sublethal endotoxin shock mouse model was used to evaluate the effect of an MMP inhibiting peptide (P2) after intravenous or intraperitoneal injection and to study the time window between LPS and inhibitor injections.With the use of a specific ELISA the plasma P2 concentrations were monitored.

View Article: PubMed Central - PubMed

Affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.

ABSTRACT
Endotoxin shock is a life-threatening disorder, associated with the rapid release of neutrophil enzymes, including neutrophil collagenase/matrix metalloproteinase-8 (MMP-8) and gelatinase B/matrix metalloproteinase-9 (MMP-9). After activation, these enzymes cleave extracellular matrix components and cytokines and thus may contribute to shock syndrome development. MMP inhibitors have been suggested as immunotherapy of endotoxin shock. However, little is known about the therapeutic time window of MMP inhibition. Here, a sublethal endotoxin shock mouse model was used to evaluate the effect of an MMP inhibiting peptide (P2) after intravenous or intraperitoneal injection and to study the time window between LPS and inhibitor injections. With the use of a specific ELISA the plasma P2 concentrations were monitored. Whereas we corroborated the treatment strategy of MMP targeting in endotoxin shock with a new inhibitor, we also demonstrated that the time window, within which effective MMP inhibition increased the survival rates, is rather limited.

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Related in: MedlinePlus

P2 protects Swiss mice from endotoxin shock after intraperitoneal administration. For all the experiments, 35 mg/kg Regasepin 2 via intravenous injection was included as a positive control. (a) A single intravenous injection of 10 mg/kg P2 protected mice from endotoxin shock, whereas two injections of 10 mg/kg P2 at two hours interval decreased the survival rate of the mice. The protective effects of P2 at a dosage of 150 mg/kg via intraperitoneal injection 30 minutes (b), 60 minutes (c), and 90 minutes (d) before intravenous injection of LPS (200 μg per mouse) were shown. Kaplan-Meier survival curves were generated. The results of two parallel and independent experiments were pooled. The details of the animal experiments were tabulated in Tables 3 and 4.
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fig4: P2 protects Swiss mice from endotoxin shock after intraperitoneal administration. For all the experiments, 35 mg/kg Regasepin 2 via intravenous injection was included as a positive control. (a) A single intravenous injection of 10 mg/kg P2 protected mice from endotoxin shock, whereas two injections of 10 mg/kg P2 at two hours interval decreased the survival rate of the mice. The protective effects of P2 at a dosage of 150 mg/kg via intraperitoneal injection 30 minutes (b), 60 minutes (c), and 90 minutes (d) before intravenous injection of LPS (200 μg per mouse) were shown. Kaplan-Meier survival curves were generated. The results of two parallel and independent experiments were pooled. The details of the animal experiments were tabulated in Tables 3 and 4.

Mentions: The experimental strategies are shown in Tables 3 and 4. In Figure 4(a), P2-treated mice showed a significant difference with the LPS-treated control group, indicating that P2 at 10 mg/kg protected mice from endotoxin shock. A low dose of 10 mg/kg was selected here to study longer inhibition intervals in the case that the second intravenous injection of P2 provided further protective effect. The rationale of the experimental design (in G3) with two intravenous injections was indeed to prolong P2 concentrations at inhibitory levels in the circulation. However, the result showed that less mice survived (in G3 than in G2). This experiment was repeated two times with the same result. This implied that a second intravenous injection of P2 did not improve the outcome. In Figures 4(b), 4(c), and 4(d), groups of 6 mice were injected intraperitoneally with P2 (150 mg/kg) 30, 60, or 90 minutes before LPS challenge. As expected, Regasepin 2 via intravenous administration showed a significant protective effect. In the corresponding experiments, P2 via intraperitoneal injection showed significant protective effects (P < 0.0004, 30 minutes before LPS challenge; P = 0.0011, 60 minutes before LPS challenge; P = 0.0243, 90 minutes before LPS challenge). The mouse survival data indicated that P2 via intraperitoneal injection showed better protective effect when injection intervals between P2 and LPS decreased. All the experiments were performed two times with reproducible results.


Inhibition of neutrophil collagenase/MMP-8 and gelatinase B/MMP-9 and protection against endotoxin shock.

Qiu Z, Chen J, Xu H, Van den Steen PE, Opdenakker G, Wang M, Hu J - J Immunol Res (2014)

P2 protects Swiss mice from endotoxin shock after intraperitoneal administration. For all the experiments, 35 mg/kg Regasepin 2 via intravenous injection was included as a positive control. (a) A single intravenous injection of 10 mg/kg P2 protected mice from endotoxin shock, whereas two injections of 10 mg/kg P2 at two hours interval decreased the survival rate of the mice. The protective effects of P2 at a dosage of 150 mg/kg via intraperitoneal injection 30 minutes (b), 60 minutes (c), and 90 minutes (d) before intravenous injection of LPS (200 μg per mouse) were shown. Kaplan-Meier survival curves were generated. The results of two parallel and independent experiments were pooled. The details of the animal experiments were tabulated in Tables 3 and 4.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4265539&req=5

fig4: P2 protects Swiss mice from endotoxin shock after intraperitoneal administration. For all the experiments, 35 mg/kg Regasepin 2 via intravenous injection was included as a positive control. (a) A single intravenous injection of 10 mg/kg P2 protected mice from endotoxin shock, whereas two injections of 10 mg/kg P2 at two hours interval decreased the survival rate of the mice. The protective effects of P2 at a dosage of 150 mg/kg via intraperitoneal injection 30 minutes (b), 60 minutes (c), and 90 minutes (d) before intravenous injection of LPS (200 μg per mouse) were shown. Kaplan-Meier survival curves were generated. The results of two parallel and independent experiments were pooled. The details of the animal experiments were tabulated in Tables 3 and 4.
Mentions: The experimental strategies are shown in Tables 3 and 4. In Figure 4(a), P2-treated mice showed a significant difference with the LPS-treated control group, indicating that P2 at 10 mg/kg protected mice from endotoxin shock. A low dose of 10 mg/kg was selected here to study longer inhibition intervals in the case that the second intravenous injection of P2 provided further protective effect. The rationale of the experimental design (in G3) with two intravenous injections was indeed to prolong P2 concentrations at inhibitory levels in the circulation. However, the result showed that less mice survived (in G3 than in G2). This experiment was repeated two times with the same result. This implied that a second intravenous injection of P2 did not improve the outcome. In Figures 4(b), 4(c), and 4(d), groups of 6 mice were injected intraperitoneally with P2 (150 mg/kg) 30, 60, or 90 minutes before LPS challenge. As expected, Regasepin 2 via intravenous administration showed a significant protective effect. In the corresponding experiments, P2 via intraperitoneal injection showed significant protective effects (P < 0.0004, 30 minutes before LPS challenge; P = 0.0011, 60 minutes before LPS challenge; P = 0.0243, 90 minutes before LPS challenge). The mouse survival data indicated that P2 via intraperitoneal injection showed better protective effect when injection intervals between P2 and LPS decreased. All the experiments were performed two times with reproducible results.

Bottom Line: However, little is known about the therapeutic time window of MMP inhibition.Here, a sublethal endotoxin shock mouse model was used to evaluate the effect of an MMP inhibiting peptide (P2) after intravenous or intraperitoneal injection and to study the time window between LPS and inhibitor injections.With the use of a specific ELISA the plasma P2 concentrations were monitored.

View Article: PubMed Central - PubMed

Affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.

ABSTRACT
Endotoxin shock is a life-threatening disorder, associated with the rapid release of neutrophil enzymes, including neutrophil collagenase/matrix metalloproteinase-8 (MMP-8) and gelatinase B/matrix metalloproteinase-9 (MMP-9). After activation, these enzymes cleave extracellular matrix components and cytokines and thus may contribute to shock syndrome development. MMP inhibitors have been suggested as immunotherapy of endotoxin shock. However, little is known about the therapeutic time window of MMP inhibition. Here, a sublethal endotoxin shock mouse model was used to evaluate the effect of an MMP inhibiting peptide (P2) after intravenous or intraperitoneal injection and to study the time window between LPS and inhibitor injections. With the use of a specific ELISA the plasma P2 concentrations were monitored. Whereas we corroborated the treatment strategy of MMP targeting in endotoxin shock with a new inhibitor, we also demonstrated that the time window, within which effective MMP inhibition increased the survival rates, is rather limited.

Show MeSH
Related in: MedlinePlus