title: Treatment with Fms-like tyrosine kinase 3 ligand reverses lung dendritic cell immunoparalysis and ameliorates zymosan-induced secondary lung injury in mice.
abstract: Depletion and dysfunction of dendritic cells in the lung can induce local immunoparalysis, which often leads to multiple organ dysfunction syndrome (MODS)-associated mortality. A therapeutic strategy that reverses this immunoparalysis is required. In the present study, we examined the effects of in vivo Fms-like tyrosine kinase 3 ligand (Flt3L) treatment on zymosan (zym)-induced secondary lung injury and dendritic cell (DC) immunoparalysis. BALBc mice were divided randomly into four groups (20/group): (1) sham [intraperitoneal (i.p.) saline] + vehicle [subcutaneous (s.c.) 0·01% mouse serum albumin]; (2) sham + Flt3L (s.c.); (3) zym (i.p.) + vehicle; and (4) zym + Flt3L. Injections were for 9 consecutive days; 12 days later we examined: survival rate (monitored for 12 days); lung tissue histopathology (haematoxylin and eosin staining); plasma indices of lung function (pH, PaO(2) , PaCO(2) , HCO(3)             (-) ); DC subsets in lung tissue; and lung DCs production of interleukin (IL)-12p70 and IL-10. Zym administration resulted in increased mortality associated with significant lung histopathological changes and abnormal blood gas indices; however, these pathological changes were ameliorated by Flt3L treatment. Zym injections also resulted in significant reductions in DC subsets recovered from lungs [CD11c(+) major histocompatibility complex (MHC)-II/I-A(d+) , CD11c(+) CD11b(+)  and CD11c(+) B220(+) ]. Importantly, in-vivo Flt3L treatment reversed these trends for DC immunoparalysis by increasing the percentages of recovered DC subsets concomitant with increased DC production of IL-12 p70 and decreased IL-10 production. These results suggest that Flt3L may have therapeutic potential for reversing DC immunoparalysis and ameliorating lung injury secondary to MODS.
authors.affiliation: Department of Pathology, the First Affiliated Hospital of General Hospital of PLA, 51 Fucheng Road, Beijing 100048, China.
authors.forename: H W
authors.initials: HW
authors.lastname: Wang
authors.forename: W
authors.initials: W
authors.lastname: Yang
authors.forename: J Y
authors.initials: JY
authors.lastname: Lu
authors.forename: G
authors.initials: G
authors.lastname: Tian
authors.forename: F
authors.initials: F
authors.lastname: Li
authors.forename: X H
authors.initials: XH
authors.lastname: Wang
authors.forename: J R
authors.initials: JR
authors.lastname: Kang
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D001835:Body Weight / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D008024:Ligands; D008168:Lung / Q000187:drug effects / Q000276:immunology*; D055370:Lung Injury / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009102:Multiple Organ Failure / Q000276:immunology*; D015996:Survival Rate; D015054:Zymosan / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D008024:Ligands; D008565:Membrane Proteins; C084881:flt3 ligand protein; D016753:Interleukin-10; D018664:Interleukin-12; D015054:Zymosan; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3