Effects of TNF-alpha-converting enzyme inhibition on acute lung injury induced by endotoxin in the rat.

Abstract

We studied the effects of TNF-converting enzyme inhibition with Y-41654, which down-regulates the production of soluble TNF-alpha (sTNF-alpha), on acute lung injury induced by intratracheal administration of LPS. We first verified in vitro that pretreatment of isolated alveolar macrophages from Sprague-Dawley male rats with 20 microL of 0.1-mM Y-41654, decreased significantly (P < 0.05) the concentration of sTNF-alpha in cell supernatants induced by 10 microg/mL of LPS. We then studied four groups of rats (each n = 10) including 1) a control group, 2) an LPS group (300 microg /kg, instilled intratracheally), 3) a Y-41654 group, and 4) a treatment group treated with Y-41654 after LPS instillation. Y-41654, 10 mg/kg in 0.7 mL of phosphate-buffered saline, was administered (i.v.), 15 min before and 0.5, 1.5, 2.5, and 3.5 h after saline or LPS instillation. The animals were observed for 4 h. In the animals treated with Y-41654, the concentrations of sTNF-alpha and protein in bronchoalveolar lavage fluid, and the number of neutrophils in lung tissue and bronchoalveolar lavage fluid were significantly lower at 4 h than in the LPS group (P < 0.05). In conclusion, sTNF-alpha plays an important role in the development of acute lung injury induced by intratracheal administration of LPS, in part modulating neutrophil kinetics.

• Authors: Mie Shimizu, Naoki Hasegawa, Tomoyasu Nishimura, Yoshihiko Endo, Yoshiki Shiraishi, Wakako Yamasawa, Hidefumi Koh, Sadatomo Tasaka, Hisato Shimada, Yasushi Nakano, Seitaro Fujishima, Kazuhiro Yamaguchi, Akitoshi Ishizaka
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 32 Issue 5 Pg. 535-40 (Nov 2009) ISSN: 1540-0514 [Electronic] United States
• PMID: 19295482 (Publication Type: Journal Article)

Chemical References

• Chemokine CXCL1
• Cxcl1 protein, rat
• Enzyme Inhibitors
• Hydroxamic Acids
• Interleukin-1beta
• Lipopolysaccharides
• Succinates
• Tumor Necrosis Factor-alpha
• Y 41654
• ADAM Proteins
• ADAM17 Protein

Topics

• ADAM Proteins (antagonists & inhibitors)
• ADAM17 Protein
• Acute Lung Injury (etiology)
• Animals
• Bronchoalveolar Lavage Fluid (chemistry)
• Cells, Cultured
• Chemokine CXCL1 (blood)
• Enzyme Inhibitors (pharmacology)
• Hydroxamic Acids (pharmacology)
• Immunohistochemistry
• Interleukin-1beta (blood, metabolism)
• Lipopolysaccharides (toxicity)
• Macrophages, Alveolar (drug effects, metabolism)
• Male
• Rats
• Rats, Sprague-Dawley
• Succinates (pharmacology)
• Tumor Necrosis Factor-alpha (blood, metabolism)