Critical role of P-selectin-dependent leukocyte recruitment in endotoxin-induced intestinal barrier dysfunction in mice.
OBJECTIVE
To define the importance of leukocyte recruitment in endotoxin-induced gut permeability.


METHODS
31 male C57BL/6 mice were challenged with lipopolysaccharide (LPS). Ileal permeability was measured in Ussing chambers and leukocyte-endothelium interactions studied with intravital fluorescence microscopy after 18 h.


RESULTS
LPS caused a clear-cut increase in leukocyte accumulation and intestinal permeability. Immunoneutralisation of P-selectin not only reduced leukocyte recruitment significantly (54 % reduction) but also abolished endotoxin-induced intestinal leakage. Intestinal levels of pro-inflammatory chemokines increased markedly in response to LPS but were not influenced by inhibition of P-selectin in vivo.


CONCLUSIONS
The present study shows not only that endotoxin-induced leukocyte recruitment is mediated by P-selectin but also that sepsis-associated intestinal leakage in the gut is largely regulated by leukocyte accumulation. Thus, our novel data demonstrate a critical link between P-selectin-dependent leukocyte recruitment and gut barrier failure in endotoxemia.
Mangell
P
P
Department of Surgery Malmö University Hospital, Lund University, 205 02, Malmö, Sweden.
Mihaescu
A
A
Wang
Y
Y
Schramm
R
R
Jeppsson
B
B
Thorlacius
H
H
D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism; D019446:Endotoxemia / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D004731:Endotoxins; D007082:Ileum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016209:Interleukin-8 / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007962:Leukocytes / Q000473:pathology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019007:P-Selectin / Q000502:physiology*
D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D004731:Endotoxins; D016209:Interleukin-8; D019007:P-Selectin