Hydrogen sulfide modulates sinusoidal constriction and contributes to hepatic microcirculatory dysfunction during...

The role of hydrogen sulfide (H₂S) in vascular function is well documented, but its influence on the liver's microcirculation remains unclear. It is already known that sepsis disrupts blood flow in the liver, leading to injury. However, no prior work had resolved how H₂S might contribute to this disruption. While some studies have shown H₂S can affect vascular resistance, its specific impact on hepatic sinusoids is unknown. This gap motivated researchers to explore the effects of H₂S on the liver's microcirculation. The study also aimed to determine if endogenous H₂S plays a role in the hypersensitivity of sinusoids to vasoconstrictors during sepsis. Prior research has shown that endothelin-1 (ET-1) contributes to vasoconstriction in sepsis, but the mechanism involving H₂S had not been tested. The researchers proposed to use an endotoxin model to simulate sepsis and observe H₂S's effects. This approach allowed them to isolate the role of H₂S in the liver's microcirculatory dysfunction.

The study aimed to determine how hydrogen sulfide (H₂S) affects the hepatic microcirculation and whether it contributes to microcirculatory dysfunction in sepsis. The researchers focused on the liver's sinusoids, which are critical for blood flow and oxygen delivery. They wanted to test if H₂S causes vasoconstriction in these vessels. Additionally, they sought to understand how H₂S might enhance the liver's sensitivity to vasoconstrictors like endothelin-1 (ET-1). The motivation for this study came from the observation that H₂S levels rise during sepsis, which could worsen liver injury. The researchers used a model of endotoxemia to simulate sepsis and test their hypothesis. They also aimed to determine if blocking H₂S production could reduce sinusoidal hypersensitivity to ET-1. The study's design allowed them to measure changes in portal pressure and sinusoidal diameter. By doing so, they hoped to clarify the role of H₂S in liver dysfunction during sepsis.

The researchers conducted in vivo experiments using a rat model of endotoxemia. They infused hydrogen sulfide (H₂S) into the portal vein and measured changes in portal pressure and sinusoidal diameter. Intravital microscopy was used to visualize the liver's microcirculation in real time. They also tested the effect of DL-propargylglycine (PAG), an inhibitor of cystathionine γ lyase, to block H₂S production. Endothelin-1 (ET-1) was infused to assess vasoconstriction and sinusoidal sensitivity. NADH fluorescence was measured to evaluate hepatic oxygen availability. The study compared baseline measurements with those taken after H₂S infusion and PAG treatment. They analyzed portal pressure, sinusoidal diameter, and heterogeneity to assess microcirculatory function. The use of PAG allowed them to determine if H₂S was responsible for the observed changes. This approach enabled a direct test of H₂S's role in sinusoidal constriction and ET-1 hypersensitivity.

Hydrogen sulfide (H₂S) infusion increased portal pressure from 6.8 ± 0.2 mmHg to 8.6 ± 0.8 mmHg (P < 0.05). Sinusoidal diameter decreased from 6.2 ± 0.27 μm to 5.7 ± 0.3 μm (P < 0.05) during H₂S infusion. The study also observed increased sinusoidal heterogeneity (P < 0.05), indicating uneven blood flow. PAG treatment reduced the hypersensitivity of sinusoids to endothelin-1 (ET-1) in endotoxemic animals. ET-1 infusion raised portal pressure to 175% of baseline in endotoxemic rats, but PAG reduced this to 143% (P < 0.05). PAG also reduced sinusoidal constriction after ET-1 exposure by 30.9% in LPS-treated rats compared to 11.6% in PAG/LPS rats (P < 0.05). NADH fluorescence increased by 61 grayscale units in LPS-treated rats but only 21 units in PAG/LPS rats (P < 0.05). These findings suggest that H₂S contributes to sinusoidal constriction and ET-1 hypersensitivity during sepsis.

The study is the first to show that hydrogen sulfide (H₂S) causes vasoconstriction in hepatic sinusoids. The researchers propose that H₂S may contribute to microcirculatory dysfunction during sepsis. PAG treatment reduced the hypersensitivity of sinusoids to endothelin-1 (ET-1), suggesting that H₂S plays a role in this process. The reduction in NADH fluorescence after PAG treatment indicates improved hepatic oxygen availability. These findings support the idea that H₂S modulates sinusoidal constriction in sepsis. The study provides a possible mechanism for the protective effect of PAG in endotoxemia. The authors suggest that H₂S may be a target for interventions to improve liver function during sepsis. However, further research is needed to confirm these findings in other models and clinical settings.