Prophylactic effect of JTE-607 on LPS-induced acute lung injury in rats with CINC-1 inhibition.

Abstract

OBJECTIVE AND DESIGN:

JTE-607, a multiple cytokine inhibitor, was evaluated in lipopolysaccharide (LPS)-induced acute lung injury in rats in vivo and in vitro.

MATERIALS AND METHODS:

LPS instillation into airways of rats was performed. JTE-607 at 3-30 mg/kg and dexamethasone at 3 mg/kg were administered intravenously at 10 min and 0 min for JTE-607, and 60 min for dexamethasone prior to the LPS instillation (n = 8). Cytokine-induced neutrophil chemoattractant (CINC)-1 level and myeloperoxidase (MPO) activity in lung were measured at 4 h after LPS instillation, and at 24 h for lung wet weight measurement and histological study. LPS-induced CINC-1 production by rat alveolar macrophages were also measured in vitro.

RESULTS:

JTE-607 and dexamethasone showed a significant reduction of increased CINC-1 level and MPO activity in lung after LPS treatment in vivo. Increased wet weight was also significantly inhibited. Histological studies revealed that JTE-607 and dexamethasone significantly inhibited LPS-induced accumulation of peribronchial neutrophils and eosinophils, and perivascular edema. JTE-607 and dexamethasone suppressed CfNC-1 synthesis by rat alveolar macrophages in vitro with IC50 values of 12.4 microM and 2.3 nM, respectively.

CONCLUSIONS:

These results indicate that JTE-607 has an inhibitory effect on LPS-induced rat lung inflammation in parallel with CINC-1 reduction. The effect of JTE-607 was suggested to be through direct inhibition of CINC-1 production from rat alveolar macrophages. JTE-607 may thus be efficacious in cytokine-mediated lung inflammation such as acute respiratory distress syndrome.

• Authors: H Iwamura, K Inushima, K Takeuchi, M Kakutani, K Wakitani
• Journal: Inflammation research : official journal of the European Histamine Research Society ... [et al.] (Inflamm Res) Vol. 51 Issue 3 Pg. 160-6 (Mar 2002) ISSN: 1023-3830 [Print] Switzerland
• PMID: 12005207 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Chemokine CXCL1
• Chemokines
• Chemokines, CXC
• Chemotactic Factors
• Cxcl1 protein, rat
• Intercellular Signaling Peptides and Proteins
• JTE 607
• Lipopolysaccharides
• Piperazines
• Phenylalanine
• Dexamethasone

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Chemokine CXCL1
• Chemokines (antagonists & inhibitors, biosynthesis)
• Chemokines, CXC
• Chemotactic Factors (antagonists & inhibitors, biosynthesis)
• Dexamethasone (pharmacology)
• Intercellular Signaling Peptides and Proteins (biosynthesis)
• Lipopolysaccharides (toxicity)
• Macrophages, Alveolar (metabolism)
• Male
• Neutrophils (drug effects, physiology)
• Phenylalanine (analogs & derivatives, pharmacology)
• Piperazines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Respiratory Distress Syndrome (prevention & control)