Met-RANTES ameliorates fibrous airway obliteration and decreases ERK expression in a murine model of bronchiolitis obliterans.
OBJECTIVE
Bronchiolitis obliterans (BO) is the main cause of late mortality among long-term survivors of lung transplantation. Chemokine-chemokine receptor (CCR) interaction and subsequent recruitment of infiltrating cells to the graft are early events in the development of chronic rejection of transplanted lungs. The present study investigated whether blockade of chemokine receptors CCR1 and CCR5 with Met-regulated-on-activation, normal T cells expressed and secreted (RANTES), an amino-terminal modified derivative of RANTES/CCL5, affects the development of BO in murine model and we sought to determine the expression of RANTES/CCL5 and their relationship with extracellular signal-regulated kinase (ERK).


METHODS
BALB/c mouse tracheas were heterotopically transplanted into C57Black6 recipients and treated for 21 days with either Met-RANTES at 20 microg/day or vehicle. Animals were killed at 21 days after transplantation for histologic examination of ERK expression.


RESULTS
RANTES/CCL5 was highly expressed in allografts compare to isografts. Met-RANTES treatment ameliorated fibrous airway obliteration in a mouse model of BO and decreased ERK expression.


CONCLUSIONS
Blockade of chemokine receptors by Met-RANTES ameliorated airway obliteration and decreased ERK expression. These findings suggest that chemokine receptors CCR1 and CCR5 play significant roles in the development of chronic rejection and ERK may be a new molecular target for chronic rejection.
Uchida
Osamu
O
Department of Thoracic Surgery, Tokyo Medical University, Tokyo, Japan.
Kajiwara
Naohiro
N
Hayashi
Aeru
A
Miyajima
Kuniharu
K
Nagatsuka
Takayoshi
T
Hayashi
Hiroki
H
Taira
Masahiro
M
Kimura
Masakazu
M
Tsuboi
Masahiro
M
Kato
Harubumi
H
D000818:Animals; D015153:Blotting, Western; D001989:Bronchiolitis Obliterans / Q000378:metabolism / Q000503:physiopathology*; D018946:Chemokine CCL5; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D006084:Graft Rejection / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D054389:Receptors, CCR1; D019713:Receptors, CCR5 / Q000502:physiology*; D019707:Receptors, Chemokine / Q000502:physiology*; D014132:Trachea / Q000637:transplantation*; D014183:Transplantation, Heterologous
C515301:Ccr1 protein, mouse; D018946:Chemokine CCL5; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D048049:Extracellular Signal-Regulated MAP Kinases