Dipeptide HCH6-1 inhibits neutrophil activation and protects against acute lung injury by blocking FPR1.

Abstract

Formyl peptide receptor 1 (FPR1) is an emerging therapeutic target for the discovery of drugs to treat neutrophilic inflammatory diseases. However, development of FPR1 antagonists for clinical use is still inadequate. The purpose of this study was to identify a synthetic dipeptide N-(N-benzoyl-L-tryptophanyl)-D-phenylanlanine methyl ester (HCH6-1) as a FPR1 inhibitor and to investigate its protective effects against acute lung injury (ALI). HCH6-1 inhibited superoxide anion generation, elastase release, and chemotaxis in human neutrophils specifically activated by formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLF), an FPR1 agonist. HCH6-1 produced right shifts in the concentration-response curves of fMLF, suggesting that HCH6-1 was a competitive antagonist of FPR1. Indeed, HCH6-1 bound to FPR1 in human neutrophils and neutrophil-like THP-1 as well as hFPR1-transfected HEK293 cells. Also, the FPR1 downstream signaling pathways were competitively inhibited by HCH6-1. Furthermore, HCH6-1 prevented pulmonary neutrophil infiltration and edema along with alveolar damage in LPS-induced ALI in mice. Our findings suggest that HCH6-1, a FPR1 antagonist, may have potential as a new therapeutic agent for treating FPR1-involved inflammatory lung diseases.

• Authors: Shun-Chin Yang, Shih-Hsin Chang, Pei-Wen Hsieh, Yin-Ting Huang, Chiu-Ming Ho, Yung-Fong Tsai, Tsong-Long Hwang
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 106 Pg. 254-269 (05 2017) ISSN: 1873-4596 [Electronic] United States
• PMID: 28232203 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Dipeptides
• FPR1 protein, human
• Lipopolysaccharides
• Receptors, Formyl Peptide
• Superoxides

Topics

• Acute Lung Injury (chemically induced, drug therapy, genetics, pathology)
• Animals
• Chemotaxis (drug effects)
• Dipeptides (administration & dosage, chemical synthesis)
• Disease Models, Animal
• HEK293 Cells
• Humans
• Lipopolysaccharides (toxicity)
• Mice
• Neutrophil Activation (drug effects, genetics)
• Neutrophil Infiltration (drug effects)
• Receptors, Formyl Peptide (antagonists & inhibitors, genetics)
• Signal Transduction (drug effects)
• Superoxides (metabolism)