title: A novel peptide ADAM8 inhibitor attenuates bronchial hyperresponsiveness and Th2 cytokine mediated inflammation of murine asthmatic models.
abstract: A disintegrin and metalloproteinase 8 (ADAM8) has been identified as a signature gene associated with moderate and severe asthma. Studies in mice have demonstrated that the severity of asthma can be reduced by either transgenic knock-out or by antibodies blocking ADAM8 function, highlighting ADAM8 as potential drug target for asthma therapy. Here, we examined the therapeutic effect of an ADAM8 inhibitor peptide (BK-1361) that specifically blocks cellular ADAM8 activity in ovalbumin-sensitized and challenged Balb/c mice. We found that BK-1361 (25 μg/g body weight) attenuated airway responsiveness to methacholine stimulation by up to 42%, concomitantly reduced tissue remodeling by 50%, and decreased inflammatory cells (e.g. eosinophils down by 54%)/inflammatory factors (e.g. sCD23 down by 50%)/TH2 cytokines (e.g. IL-5 down by 70%)/ADAM8-positive eosinophils (down by 60%) in the lung. We further verified that BK-1361 specifically targets ADAM8 in vivo as the peptide caused significantly reduced levels of soluble CD23 in wild-type but not in ADAM8-deficient mice. These findings suggest that BK-1361 blocks ADAM8-dependent asthma effects in vivo by inhibiting infiltration of eosinophils and TH2 lymphocytes, thus leading to reduction of TH2-mediated inflammation, tissue remodeling and bronchial hyperresponsiveness. Taken together, pharmacological ADAM8 inhibition appears as promising novel therapeutic strategy for the treatment of asthma.
authors.affiliation: Changzhou Key Laboratory of Respiratory Medical Engineering, Institute of Biomedical Engineering and Health Sciences, Changzhou University, Changzhou, Jiangsu, China.|Key Lab of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Changzhou Key Laboratory of Respiratory Medical Engineering, Institute of Biomedical Engineering and Health Sciences, Changzhou University, Changzhou, Jiangsu, China.|Key Lab of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China.
authors.forename: Linhong
authors.initials: L
authors.lastname: Deng
authors.affiliation: Institute of Pharmacology and Toxicology, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Dreymüller
authors.affiliation: Key Lab of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Key Lab of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China.
authors.forename: Jiaoyue
authors.initials: J
authors.lastname: Long
authors.affiliation: Key Lab of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China.
authors.forename: Yiyuan
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Changzhou Key Laboratory of Respiratory Medical Engineering, Institute of Biomedical Engineering and Health Sciences, Changzhou University, Changzhou, Jiangsu, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Changzhou Key Laboratory of Respiratory Medical Engineering, Institute of Biomedical Engineering and Health Sciences, Changzhou University, Changzhou, Jiangsu, China.
authors.forename: Mingzhi
authors.initials: M
authors.lastname: Luo
authors.affiliation: Key Lab of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Lin
authors.affiliation: Jiangsu Asialand Bio-med Technology Co. Ltd., Changzhou, Jiangsu, China.
authors.forename: Lizhen
authors.initials: L
authors.lastname: Mao
authors.affiliation: Laboratory of Respiratory Cell Biology, Division of Pneumology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Müller
authors.affiliation: KCLDI Biomaterials, Biomimetics and Biophotonics Group. King's College London, London SE1 9RT, United Kingdom.|Department of Neurosurgery, Philipps-University Marburg, Baldinger Str., 35033 Marburg, Germany.
authors.forename: Garrit
authors.initials: G
authors.lastname: Koller
authors.affiliation: Department of Neurosurgery, Philipps-University Marburg, Baldinger Str., 35033 Marburg, Germany.
authors.forename: Jörg W
authors.initials: JW
authors.lastname: Bartsch
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D001980:Bronchi / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid; D002452:Cell Count; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000150:complications / Q000473:pathology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D016210:Methacholine Chloride; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017455:Receptors, IgE / Q000378:metabolism; D012995:Solubility; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D008565:Membrane Proteins; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D017455:Receptors, IgE; D016210:Methacholine Chloride; D051722:ADAM Proteins; C489402:Adam8 protein, mouse