Modulation of FLT3 signaling targets conventional dendritic cells to attenuate acute lung injury.
APMIS
; 120(10): 808-18, 2012 Oct.
Article
en En
| MEDLINE
| ID: mdl-22958289
ABSTRACT
Conventional dendritic cells (cDCs) have been reported to participate in the pathophysiology of acute lung injury (ALI). Fms-like tyrosine kinase 3 (FLT3) signaling represents a highly specific pathway for the manipulation of cDCs in vivo. The purpose of this study was to clarify the effect of FLT3 signaling on the accumulation and maturation of pulmonary cDCs, and whether inhibition of FLT3 signaling may attenuate acute lung inflammation and lung injury. C57BL/6 mice were pretreated with FLT3-ligand (FLT3L) and lestaurtinib separately for five consecutive days. A murine model of ALI was subsequently generated by intra-tracheal instillation of lipopolysaccharide (LPS) and lung specimens were harvested 24 h later. Flow cytometry was conducted to measure the accumulation and maturation of pulmonary cDCs. IL-6, IFN-γ, IL-4, MPO activity and transcription factor T-bet/GATA-3 mRNA ratio were quantified to evaluate lung inflammation. Lung injury was estimated by lung wet weight/body weight ratio (LWW/BW) and histopathological analysis. LPS challenge resulted in rapid accumulation and maturation of pulmonary cDCs. FLT3L pretreatment further stimulated the accumulation and maturation of pulmonary cDCs, leading to a markedly increased LWW/BW and aggravated lung histopathology. Meanwhile, lung MPO activity, T-bet/GATA-3 mRNA ratio and concentrations of IL-6 and IFN-γ were elevated by FLT3L administration. In contrast, lestaurtinib pretreatment inhibited the accumulation and maturation of pulmonary cDCs, leading to a significantly decreased LWW/BW and improved lung histopathology. Lestaurtinib administration also suppressed lung MPO activity, T-bet/GATA-3 mRNA ratio and production of IL-6 and IFN-γ. Our findings show that FLT3 signaling ameliorates ALI by regulating the accumulation and maturation of pulmonary cDCs, suggesting an innovative pharmacotherapy for ALI.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Células Dendríticas
/
Carbazoles
/
Inhibidores de Proteínas Quinasas
/
Lesión Pulmonar Aguda
/
Pulmón
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
APMIS
Asunto de la revista:
ALERGIA E IMUNOLOGIA
/
MICROBIOLOGIA
/
PATOLOGIA
Año:
2012
Tipo del documento:
Article
País de afiliación:
China