Asp-Tyr-Leu-Lys tetrapeptide inhibits airway inflammation in toluene-2,4-diisocyanate-induced asthma mice.
BACKGROUND
Airway inflammation and remodelling contribute to chronic airway obstruction of asthma. Currently, no medication effectively controls airway remodelling and related vascular changes. Therefore, new strategies need to be developed. The kringle 5 domain has anti-angiogenic activity resulting from the tetrapeptide Lys-Leu-Tyr-Asp (KLYD).


OBJECTIVE
To investigate the therapeutic effect of KLYD and its inverse form Asp-Tyr-Leu-Lys (DYLK) on the inflammation and remodelling of toluene-2,4-diisocyanate (TDI)-sensitization/challenged mice.


METHODS
Cell numbers were measured in the presence of various concentrations of KLYD and DYLK using in vitro endothelial cell proliferation assay. The changes of cell number and the level of vascular endothelial growth factor (VEGF) in bronchoalveolar lavage (BAL) fluid and response to methacholine (MCh) were measured using the in vivo TDI-sensitized/challenged mice model. Muc5ac, smooth muscle actin (SMA) and proliferating cell nuclear antigen (PCNA) protein expression was analysed on trachea and intrapulmonary bronchi using immunohistochemical stain.


RESULTS
Compared with KLYD, DYLK had a greater inhibitory effect on endothelial cell proliferation (P<0.05). Pre-treatment of DYLK showed dose-dependent reduction in the response to MCh (P<0.05) and numbers of inflammatory cells in BAL fluids of TDI-sensitized/challenged mice. TDI induced increases in Muc5ac, SMA and PCNA protein expression and VEGF levels, which were also abolished by DYLK treatment.


CONCLUSIONS
Local administration of DYLK effectively inhibits the airway inflammation and airway remodelling of TDI-sensitized/challenged mice via down-regulation of VEGF. These findings suggest that anti-angiogenic peptide therapies, such as local administration of DYLK, are an effective strategy for the treatment of remodelling in asthma.
Ahn
M-H
MH
Genome Research Center for Allergy and Respiratory Diseases, Soonchunhyang University Hospital, Wonmi-gu, Bucheon, Gyeonggi-do, Korea.
Park
B-J
BJ
Kwon
J-H
JH
An
S-H
SH
Park
J-W
JW
Jang
A S
AS
Rhim
T
T
Park
C-S
CS
D000199:Actins / Q000378:metabolism; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D007150:Immunohistochemistry; D008297:Male; D016210:Methacholine Chloride; D051379:Mice; D008807:Mice, Inbred BALB C; D055271:Mucin 5AC; D009077:Mucins / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D018709:Statistics, Nonparametric; D014051:Toluene 2,4-Diisocyanate; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D000199:Actins; C530320:Asp-Tyr-Leu-Lys; C530321:Lys-Leu-Tyr-Asp; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D009077:Mucins; D009842:Oligopeptides; D018809:Proliferating Cell Nuclear Antigen; D042461:Vascular Endothelial Growth Factor A; D016210:Methacholine Chloride; D014051:Toluene 2,4-Diisocyanate