Page 98 - 73_01

JUAN SANDOVAL Y COLS. AN. R. ACAD. NAC. FARM.

de la pentoxifilina en las fases iniciales de la PA, o como tratamiento preventivo,
al bloquear los estímulos pro-inflamatorios característicos de la PA.

Palabras clave: ChIP.—HAT/HDAC.—Cromatina.—Modificación de histonas.—
Inflamación.

ABSTRACT

Epigenetic regulation during acute necrotic pancreatitis.

The acute necrotic pancreatitis (AP) produces, in serious clinical cases, a severe
local necrosis, develops several systemic complications and elevate mortality. In
the present work we analysed the complex and ordered temporal profile of gene
expression of the most important genes related with the initiation of AP induced
by taurocholate in rat. They include genes coding for transcriptional factors (f.i.
egr-1), intracellular signalling network, adhesion molecules (f.i. icam-1), cytokines
(f.i. tnfa) and oxidative stress genes. The analysis of regulation epigenetic
mechanisms in three model genes (egr-1, icam-1y tnfa) showed the involvement of
different pro-inflammatory transcriptional factors (EGR-1, ATF-2, NF-?B, C/EBPß
or SP1), binding of HAT complexes (CBP) and release of HDAC complexes (HDAC1/
2-Sin3A-) and site-specific histone modification (H3K9ac, H3K14ac, H4K5ac y
H3K4me3). Furthermore, the study of the mechanism of action of the potentially
pharmacological agent pentoxyfiline showed that beneficial effect may be produced,
at least partially, by repression of different genes, specially egr-1, icam-1 and tnfa,
throughout regulation of pro-inflammatory transcriptional factors binding (NF-?B,
SP1, C/EBPß or EGR-1) and inhibition of signalling network ERK1/2 and JNK1/2
involved in the activation of those genes. The results support the potential
therapeutic use of pentoxyfilline in the initial phases of AP, or as preventive
treatment, since it blocks the pro-inflammatory stimulus generated in AP.

Key words: ChIP.—HAT/HDAC.—Chromatin.—Histone modification.—
Inflammation.

INTRODUCCIÓN

La pancreatitis aguda (PA) es una enfermedad cuya incidencia se
ha incrementado notablemente durante las últimas décadas. Hoy en
día implica alrededor del 3% de los pacientes ingresados en los gran-
des hospitales, presentando una importante tasa de complicacio-
nes y, lo que es más importante, una mortalidad considerable (1). A
pesar de que existen diferentes hipótesis acerca de los sucesos tem-
pranos en la PA, hoy en día se acepta que el principal desencadenan-

48