Anatagonizing the sympathetic nervous system in sepsis
Kofi
Antagonism of alpha(2A)-adrenoceptor: a novel approach to inhibit
inflammatory responses in sepsis.
Zhang F, Wu R, Qiang X, Zhou M, Wang P.
The Feinstein Institute for Medical Research, Manhasset, NY, 11030, USA.
Sepsis is a systemic inflammatory response syndrome (SIRS) when an
infection is the etiology of SIRS. Our previous studies have indicated
that the release of the sympathetic neurotransmitter, norepinephrine
(NE), from the gut is increased in sepsis, and that NE potentiates
endotoxin-induced tumor necrosis factor (TNF)-alpha upregulation via the
A subtype of alpha(2)-adrenoceptors (i.e., alpha(2A)-AR) expressed on
the surface of Kupffer cells. A specific antagonist for alpha(2A)-AR,
2-[(4,5-dihydro-1H-imidazol-2-yl)
methyl]-2,3-dihydro-1-methyl-1H-isoindole maleate (BRL-44408 maleate),
reduces TNF-alpha secretion in cultured Kupffer cells. We, therefore,
hypothesize that administration of BRL-44408 maleate inhibits
inflammatory responses and reduces organ injury in sepsis. To study
this, sepsis was induced in male rats by cecal ligation and puncture
(CLP). At 5 h after CLP, BRL-44408 maleate (0.3125, 0.625, 1.25, 2.5, or
5.0 mg/kg BW) or vehicle (1-ml normal saline) were administered
intravenously over a period of 30 min. Blood and intestinal samples were
collected at 20 h after CLP. Serum levels of TNF-alpha, interleukin
(IL)-6, IL-10, keratinocyte-derived chemokine (KC), macrophage
inflammatory protein-2 (MIP-2), liver enzymes (i.e., aspartate
aminotransferase (AST) and alanine aminotransferase (ALT)), and lactate
were measured. The intestinal levels of TNF-alpha, IL-6, and
myeloperoxidase (MPO) activities were also analyzed. In additional
groups of animals, the necrotic cecum was excised at 20 h post-CLP, and
the 10-day survival was recorded. Our results showed that serum levels
of proinflammatory cytokines (TNF-alpha and IL-6), anti-inflammatory
cytokine (IL-10), chemokines (KC, MIP-2), liver enzymes (AST and ALT),
lactate, and intestinal levels of TNF-alpha, IL-6, and MPO were
significantly elevated at 20 h after CLP. Administration of BRL-44408
maleate significantly reduced serum levels of proinflammatory cytokines,
chemokines, liver enzymes, and lactate, and dramatically decreased
TNF-alpha, IL-6, and MPO levels in the gut. However, it has no
statistical effects on the elevated serum levels of IL-10. Moreover,
BRL-44408 maleate at the doses of 2.5 or 5.0 mg/kg BW significantly
increased the survival rate after CLP and cecal excision. In conclusion,
modulation of the sympathetic nervous system by blocking alpha(2A)-AR
appears to be a novel treatment for inflammatory conditions such as
sepsis.
PMID: 19894027