Fructose 1,6-bisphosphate prevented endotoxemia, macrophage activation, and liver injury induced by D-galactosamine in rats.
OBJECTIVE
Fructose 1,6-bisphosphate (F1,6BP) protects organs against a wide range of challenges involving inflammation. We hypothesized that the primary action of F1,6BP is to prevent macrophage activation and cytokine release. Our aim was to determine the tissue and cellular targets for this bisphosphorylated sugar and to provide new insights into its mechanisms of action.


METHODS
Prospective, controlled laboratory study.


METHODS
Animal resource facilities and research laboratory.


METHODS
Male Sprague-Dawley rats (200-250 g body weight).


METHODS
The protective action of F1,6BP was analyzed in galactosamine (GalN)-induced hepatitis in rats. The in vivo effects of F1,6BP were evaluated by changes in transaminase activities, blood endotoxins, and tumor necrosis factor (TNF)-alpha production in GalN-challenged rats. The targets of F1,6BP to reduce macrophage response to lipopolysaccharide (LPS) were determined by correlation between changes in TNF-alpha production and K+ fluxes through cell membrane in primary cultures of Kupffer cells.


RESULTS
The in vivo results indicate that F1,6BP treatment prevented GalN-induced injury in liver parenchymal cells. This protection was mainly associated with a reduction of the inflammatory response. F1,6BP prevention of GalN-induced endotoxemia correlated with preclusion of mast cell degranulation and histamine release that preceded the increased plasma endotoxins and liver production of TNF-alpha. In addition, F1,6BP treatment decreased sensitivity to LPS, which reduced the GalN-induced increase in TNF-alpha. The in vitro results show that F1,6BP inhibited Kupffer cell response and reduced TNF-alpha production by preventing LPS-induced K+ channel activation.


CONCLUSIONS
The role of exogenous F1,6BP as a K+ channel modulator underlies its antihistaminic and anti-inflammatory action and increases its interest as a protective compound.
Cuesta
Eduardo
E
Unitat de Biofísica, Departament de Ciències Fisiològiques II, IDIBELL, Universitat de Barcelona, Spain.
Boada
Jordi
J
Calafell
Roser
R
Perales
Jose C
JC
Roig
Teresa
T
Bermudez
Jordi
J
D000704:Analysis of Variance; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy; D004195:Disease Models, Animal; D005635:Fructosediphosphates / Q000494:pharmacology*; D005688:Galactosamine; D022781:Hepatocytes / Q000187:drug effects; D006636:Histamine Release / Q000187:drug effects; D007155:Immunologic Factors / Q000494:pharmacology*; D007249:Inflammation / Q000517:prevention & control; D007728:Kupffer Cells / Q000187:drug effects; D017114:Liver Failure, Acute / Q000517:prevention & control*; D008262:Macrophage Activation / Q000187:drug effects*; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects
D005635:Fructosediphosphates; D007155:Immunologic Factors; D015221:Potassium Channels; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; C029063:fructose-1,6-diphosphate