An analysis of signaling mechanisms triggered by toll receptor 4 (TLR4) in macrophages, as well as of pertinent cell-culture and rodent studies, suggests that various nutraceuticals may have clinical potential for preventing and treating Gram-negative
sepsis.
Endotoxin activation of TLR4 results in induction of
nitric oxide synthase (iNOS);
cyclooxygenase 2 (COX-2);
tissue factor (TF); and a range of proinflammatory
cytokines, such as
tumor necrosis factor α (TNF-α),
interleukin-1 β (IL-1β), and
interleukin 6 (IL-6), that collaborate to generate the clinical picture of
sepsis. Upstream activation of
nicotinamide adenine dinucleotide phosphate (
NADPH) oxidase contributes importantly to those effects by inducing
superoxide production that promotes activation of p38
mitogen-activated
protein (MAP)
kinase and nuclear factor (NF) κΒ.
Bilirubin generated intracellularly by activation of
heme oxygenase 1 (HO-1) functions to provide feedback inhibition of NAPDH-
oxidase complexes. Exogenous
bilirubin, or its precursor,
biliverdin, is protective in rodent models of
sepsis. One nutraceutical,
phycocyanobilin (PhyCB), is a
biliverdin derivative that functions as a light-gathering chromophore in cyanobacteria such as spirulina and can be converted intracellularly to a compound structurally homologous to
bilirubin that likewise inhibits
NADPH-oxidase complexes. In rodent studies, administration of
phycocyanin, to which PhyCB is covalently attached, has likewise been shown to be protective in rodent models of
sepsis. Other nutraceuticals provide benefits in counteracting the effects of TLR4. Phase 2-inductive nutraceuticals, such as
lipoic acid, have the potential to induce HO-1 activity in macrophages, promoting
bilirubin production. They may also antagonize the upregulatory impact of
reactive oxygen species (ROS) on macrophage signaling by boosting
glutathione synthesis. Another nutraceutical,
glycine, helps counter the TLR4-triggered
calcium influx that occurs through voltage-sensitive
calcium channels and contributes to
NADPH-oxidase activation, and, via activation of Ca+2/
calmodulin-dependent
kinase 2, also promotes induction of proinflammatory
cytokines and
cyclo-oxygenase 2 (COX-2). Elevations of serum
glycine that are achievable through supplementation can block that
calcium influx by activating membrane
chloride channels in macrophages, inducing membrane hyperpolarization. Use of high-dose
folate, another nutraceutical, has been shown to antagonize activation of
endotoxin-mediated macrophages in cell cultures and in rodents. That result likely reflects the versatile, radical-scavenging activity of reduced intracellular folates, which in particular scavenge radicals derived from
peroxynitrite, a key mediator of tissue damage in
sepsis. Activators of
adenosine monophosphate (
AMP)-activated kinase (AMPK), such as the
drug metformin or the nutraceutical
berberine, have been shown to antagonize TLR4-mediated activation of extracellular-signal-regulated kinase1/2 (ERK1/2), which contributes to the induction of TF and TNF-α. In rodent models of
sepsis,
lipoic acid,
glycine, high-dose
folate,
metformin,
berberine, and
phycocyanin have all shown protective utility, yet none of those substances has been evaluated clinically in that regard. Because those agents are all well tolerated individually, complex nutraceuticals featuring several of those agents can be envisioned as possibly aiding prevention and control of
sepsis. Clinical evaluation of such a strategy should be a high priority. That approach may also have the potential for aiding survival in
Ebola infection, the lethality of which is mediated by mechanisms quite analogous to those involved in
sepsis.