Molecular hydrogen ameliorates lipopolysaccharide-induced acute lung injury in mice through reducing inflammation and aopotosis

Abstract

Acute lung injury (ALI) is still a leading cause of morbidity and mortality in critically ill patients. Recently, our and other studies have found that hydrogen gas (H2) treatment can ameliorate the lung injury induced by sepsis, ventilator, hyperoxia, and ischemia-reperfusion. However, the molecular mechanisms by which H2 ameliorates lung injury remain unclear. In the current study, we investigated whether H2 or hydrogen-rich saline (HS) could exert protective effects in a mouse model of ALI induced by intratracheal administration of lipopolysaccharide (LPS) via inhibiting the nuclear factor .B (NF-.B) signaling pathwayYmediated inflammation and apoptosis. Two percent of H2 was inhaled for 1 h beginning at 1 and 6 h after LPS administration, respectively. We found that LPS-challenged mice exhibited significant lung injury characterized by the deterioration of histopathology and histologic scores, wet-to-dry weight ratio, and oxygenation index (PaO2/FIO2), as well as total protein in the bronchoalveolar lavage fluid (BALF), which was attenuated by H2 treatment. Hy- drogen gas treatment inhibited LPS-induced pulmonary early and late NF-.B activation. Moreover, H2 treatment dra- matically prevented the LPS-induced pulmonary cell apoptosis in LPS-challenged mice, as reflected by the decrease in TUNEL (deoxynucleotidyl transferase dUTP nick end labeling) stainingYpositive cells and caspase 3 activity. Furthermore, H2 treatment markedly attenuated LPS-induced lung neutrophil recruitment and inflammation, as evidenced by down- regulation of lung myeloperoxidase activity, total cells, and polymorphonuclear neutrophils in BALF, as well as proin- flammatory cytokines (tumor necrosis factor !, interleukin 1", interleukin 6, and high-mobility group box 1) and chemokines (keratinocyte-derived chemokine, macrophage inflammatory protein [MIP] 1!, MIP-2, and monocyte chemoattractant pro- tein 1) in BALF. In addition, i.p. injection of 10 mL/kg hydrogen-rich saline also significantly attenuated the LPS-induced ALI. Collectively, these results demonstrate that molecular hydrogen treatment ameliorates LPS-induced ALI through reducing lung inflammation and apoptosis, which may be associated with the decreased NF-.B activity. Hydrogen gas may be useful as a novel therapy to treat ALI.

Study details

Article type

Original Research

Disease / injury model

Lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice

Duration

24 hours

Dose comparison

Only one concentration of H2 (2% for inhalation, 0.85 mmol/L for HS) was used; no dose-response comparison was performed.

Dose-dependent effect

No

Outcome

Positive

Findings

Molecular hydrogen (H2) treatment significantly ameliorates lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice by reducing lung inflammation and apoptosis, likely through inhibition of NF-κB activation. Both inhaled H2 and hydrogen-rich saline (HS) improved lung histopathology, reduced edema, improved oxygenation, decreased neutrophil infiltration, and lowered proinflammatory cytokine and chemokine levels.