Abstract
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) result in high mortality, whereas effective treatments are limited. Methionine restriction (MR) has been reported to offer various benefits against multiple pathological processes of organ injuries. However, it remains unknown whether MR has any potential therapeutic value for ALI/ARDS. The current study was set to investigate the therapeutic potential of MR on lipopolysaccharide (LPS)-induced ALI and its underlying mechanisms. We found that MR attenuated LPS-induced pulmonary edema, hemorrhage, atelectasis, and alveolar epithelial cell injuries in mice. MR upregulated cystathionine-gamma-lyase (CSE) expression and enhanced the production of hydrogen sulfide (H2S). MR also inhibited the activation of Toll-like receptors 4 (TLR4)/NF-κB/NOD-like receptor protein 3 (NLRP3), then reduced IL-1β, IL-6, and TNF-α release and immune cell infiltration. Moreover, the protective effects of MR on LPS-induced ALI were abrogated by inhibiting CSE, whereas exogenous H2S treatment alone mimicked the protective effects of MR in Cse−/− mice after LPS administration. In conclusion, our findings showed that MR attenuated LPS-induced lung injury through CSE and H2S modulation. This work suggests that developing MR towards clinical use for ALI/ARDS patients may be a valuable strategy.
Highlights
Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), is a devastating condition characterized by the accumulation of inflammatory cells, injury of the epithelial/capillary interface, increase in vascular permeability and pulmonary edema, and ultimate refractory hypoxia [1,2,3,4]
Based on the previous studies showing that H2S plays a vital role in various disease models upon methionine restriction (MR) intervention, we further explored the effects of MR on H2S production Nutrients 2022, 14, x FOR PEER REaVnIdEWthe corresponding enzymes that contribute to H2S production in this model.9Wofe1f6ound that H2S levels decreased after LPS instillation at day 3 both in the plasma and lung, and MR intervention reversed these changes (p < 0.01) (Figure 5A,B)
We demonstrated that MR mitigates LPS-induced lung injury, which is characterized by a remarkably inflammatory response, inflammatory cell infiltration and alveolar epithelial cell injuries, and improves the prognosis of ALI mice
Summary
Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), is a devastating condition characterized by the accumulation of inflammatory cells, injury of the epithelial/capillary interface, increase in vascular permeability and pulmonary edema, and ultimate refractory hypoxia [1,2,3,4]. Gram-negative bacterium associated pathogenesis is one of the most common causes of ALI/ARDS [5] Patients with this syndrome are often treated with respiratory support, antibiotics, and even extracorporeal membrane oxygenation. MR has been shown to induce beneficial effects through multiple mechanisms [13] It induces autophagy by inhibiting the mechanistic target of rapamycin complex 1 (Mtorc1) and increasing polyamine, decreases reactive oxygen species (ROS) production in mitochondria, and increases the production of hydrogen sulfide (H2S), a metabolic byproduct of sulfur-containing amino acid such as methionine, which acts as a gasotransmitter and plays an important protective role in various physiological and pathological processes including inflammation, apoptosis, and functional regulation of blood vessels [14,15,16,17,18]
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