Intravenous controlled-release hydrogen sulfide protects against ventilator-induced lung injury

<p><b>Background</b>: Despite its critical utility in providing life support to patients with impaired respiratory functions, prolonged mechanical ventilation has been found to cause a series of pathological changes in the lung that are collectively referred to as ventilator-induced lung injury (VILI). This study aims to investigate the therapeutic effects of mesoporous silica nanoparticles (DATS-MSN), which is capable of releasing H<sub>2</sub>S in a slow and controlled manner, on VILI. <b>Methods</b>: A murine VILI model was generated. Rats were randomly divided to three equal groups, the DATS-MSN group, the ventilation group and the nonventilated control group. The animals in both the DATS-MSN group and the ventilation group were surgically connected to rodent ventilators. Meanwhile, the DATS-MSN group and the ventilation group were administered intravenously with 50 mg/kg DATS-MSN and physiological saline, respectively. Animal mortality and various physiological parameters of the lung were recorded throughout the experiment period. Upon completion, the rats were sacrificed and lung tissues were collected for histological examination. The levels of various pro- and anti-inflammatory cytokines in the bronchoalveolar lavage fluid were quantified. The protein levels of NF-κB, total and phosphorylated IκB-α in lung tissues were determined by Western blotting. <b>Results</b>: The rats in the ventilation group showed severe lung injuries and impaired respiratory functions as evidenced by decreased tension of oxygen in arterial blood. However, the injection of DATS-MSN was found to significantly mitigate these abnormalities. In addition, DATS-MSN could significantly alleviate ventilator-induced up-regulation of several pro-inflammatory proteins, such as TNF-α, IL-1α/β and IL-2, in the murine lung tissues, while stimulating the expression of IL-4, an anti-inflammatory cytokine. Lastly, the nanoparticles were demonstrated to decrease NF-κB activity in lung tissues by inhibiting IκB-α phosphorylation and degradation. <b>Conclusion</b>: The current study provided preliminary evidence that intravenous administration of DATS-MSN, a controlled-release H<sub>2</sub>S donor, led to prolonged survival, improved lung function and alleviated the inflammatory response to mechanical ventilation in a murine model.</p>