Inhaled hydrogen sulfide prevents endotoxin-induced systemic inflammation and improves survival by altering sulfide metabolism in mice.
OBJECTIVE
The role of hydrogen sulfide (H(2)S) in endotoxin (lipopolysaccharide [LPS])-induced inflammation is incompletely understood. We examined the impact of H(2)S breathing on LPS-induced changes in sulfide metabolism, systemic inflammation, and survival in mice.


RESULTS
Mice that breathed air alone exhibited decreased plasma sulfide levels and poor survival rate at 72 h after LPS challenge. Endotoxemia markedly increased alanine aminotransferase (ALT) activity and nitrite/nitrate (NOx) levels in plasma and lung myeloperoxidase (MPO) activity in mice that breathed air. In contrast, breathing air supplemented with 80 ppm of H(2)S for 6 h after LPS challenge markedly improved survival rate compared to mice that breathed air alone (p<0.05). H(2)S breathing attenuated LPS-induced increase of plasma ALT activity and NOx levels and lung MPO activity. Inhaled H(2)S suppressed LPS-induced upregulation of inflammatory cytokines, while it markedly induced anti-inflammatory interleukin (IL)-10 in the liver. Beneficial effects of H(2)S inhalation after LPS challenge were associated with restored sulfide levels and markedly increased thiosulfate levels in plasma. Increased thiosulfate levels after LPS challenge were associated with upregulation of rhodanese, but not cystathionine-γ-lyase (CSE), in the liver. Administration of sodium thiosulfate dose-dependently improved survival after LPS challenge in mice.


METHODS
By measuring changes in plasma levels of sulfide and sulfide metabolites using an advanced analytical method, this study revealed a critical role of thiosulfate in the protective effects of H(2)S breathing during endotoxemia.


CONCLUSIONS
These observations suggest that H(2)S breathing prevents inflammation and improves survival after LPS challenge by altering sulfide metabolism in mice.
Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care and Pain Medicine at the Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Kentaro
K
Tokuda
Kotaro
K
Kida
Eizo
E
Marutani
Ettore
E
Crimi
Masahiko
M
Bougaki
Ashok
A
Khatri
Hideo
H
Kimura
Fumito
F
Ichinose
D000280:Administration, Inhalation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004731:Endotoxins / Q000633:toxicity*; D006862:Hydrogen Sulfide / Q000008:administration & dosage / Q000627:therapeutic use*; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013440:Sulfides / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D004731:Endotoxins; D013440:Sulfides; D006862:Hydrogen Sulfide