title: 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.affiliation: Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Department of Anesthesiology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei 112, Taiwan; Division of Natural Products, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
authors.forename: Shun-Chin
authors.initials: SC
authors.lastname: Yang
authors.affiliation: Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Research Center for Industry of Human Ecology, Research Center for Chinese Herbal Medicine, and Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan.
authors.forename: Shih-Hsin
authors.initials: SH
authors.lastname: Chang
authors.affiliation: Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Division of Natural Products, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Research Center for Industry of Human Ecology, Research Center for Chinese Herbal Medicine, and Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Hsieh
authors.affiliation: Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
authors.forename: Yin-Ting
authors.initials: YT
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Chiu-Ming
authors.initials: CM
authors.lastname: Ho
authors.affiliation: Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
authors.forename: Yung-Fong
authors.initials: YF
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Division of Natural Products, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Research Center for Industry of Human Ecology, Research Center for Chinese Herbal Medicine, and Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan. Electronic address: htl@mail.cgu.edu.tw.
authors.forename: Tsong-Long
authors.initials: TL
authors.lastname: Hwang
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D002633:Chemotaxis / Q000187:drug effects; D004151:Dipeptides / Q000008:administration & dosage* / Q000138:chemical synthesis; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D018375:Neutrophil Activation / Q000187:drug effects* / Q000235:genetics; D020556:Neutrophil Infiltration / Q000187:drug effects; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism
chemical_list: D004151:Dipeptides; C469986:FPR1 protein, human; D008070:Lipopolysaccharides; D044042:Receptors, Formyl Peptide; D013481:Superoxides
keywords: Chemotaxis; Elastase; Formyl peptide receptor 1; HCH6-1; Neutrophil; Superoxide anion