Supplemental Digital Content 2 The subarachnoid space and adjacent brain is depicted Bacteria blue cocci take up cysteine Cys from cerebrospinal or interstitial fluid which is further enriched by phagocytes ID: 593394
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Slide1
Hydrogen sulfide and meningitis
Supplemental Digital Content 2. The subarachnoid space and adjacent brain is depicted. Bacteria (blue
cocci
) take up
cysteine
(
Cys
) from cerebrospinal or interstitial fluid, which is further enriched by phagocytes (
polymorphonuclear
neutrophils
(PMN),
monocytes
, microglia) exporting
Cys
into their extracellular environment when activated. Bacteria metabolize
Cys
through one of 3 metabolic pathways (CBS, CSE, 3MST – see discussion) to elaborate H
2
S, a toxicant gas that diffuses freely. A gradient of H
2
S gas (green) is depicted permeating CSF, brain tissue and blood vessels. H
2
S inactivates the oxidative burst of
polymorphonuclear
(PMN) cells and kills all cells (phagocytes,
glia
, neurons) within a defined radius. Within neuronal mitochondria, the terminal
cytochrome
c
oxidase
complex (E) uses H
2
S as a poor substrate. H
2
S also binds the intermediate state (E*) to inhibit electron transport non-competitively and reversibly. Sites of action of other gases (HCN, CO, NO and O
2
) are also depicted, with kind permission from Springer
Science+Business
Media from reference 6, Figure 1. Within the radius of high concentrations of H
2
S, mitochondrial respiration ceases in all resident cells and necrosis ensues. Within vessels, H
2
S acts similarly to NO on vascular smooth muscle, causing dilatation. At high levels of H
2
S, refractory dilatation occurs. During treatment for H
2
S intoxication, hyperbaric oxygen directly oxidizes H
2
S and also boosts
cytochrome
c
oxidase
activity, restoring mitochondrial function and also consuming H
2
S as substrate.
Dipyridamole
potentiates production of nitric oxide (NO), which spontaneously, and through interaction with hemoglobin, decomposes to nitrite (NO
2
-
) and nitrate. Nitrite, generated endogenously or administered, interacts with H
2
S to form NO, and also causes
methemoglobin
(
metHb
) formation.
MetHb
actively scavenges H
2
S to form
sulfmethemoglobin
.Slide2
Cys
Cys
Cys
H
2
S
H
2
S
Activated microglia
Activated monocyte
Activated PMN
NO
metHb
S-metHb
Vascular smooth muscle
Arachnoid mater
Pia
mater
NO
2
-
Endothelial cell
Neuron: E
E*ER
H
2
S
HCN
H
2
S producing
bacteria
NO
CO
H
2
0 0
2
H
2
S
S
Hyperbaric oxygen
Dipyridamole, or
Nitrite (NO
2
-
)