• Sashko G Spassov, Simone Faller, Matthias Hummel, Khaled Helo, Andreas Ihle, Stefan W Ryter, Karl M Strosing, and Alexander Hoetzel.
• 1Department of Anaesthesiology and Critical Care Medicine, University Medical Center Freiburg, Freiburg, Germany.2Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY.
• Crit. Care Med. 2017 Aug 1; 45 (8): e849-e857.

ObjectivesHydrogen sulfide reduces ventilator-induced lung injury in mice. Here, we have examined the underlying mechanisms of hydrogen sulfide-mediated lung protection and determined the involvement of cyclooxygenase 2, 15-deoxy Δ-prostaglandin J2, and peroxisome proliferator-activated receptor gamma in this response.DesignRandomized, experimental study.SettingUniversity medical center research laboratory.SubjectsC57BL/6 mice and in vitro cell catheters.InterventionsThe effects of hydrogen sulfide were analyzed in a mouse ventilator-induced lung injury model in vivo as well as in a cell stretch model in vitro in the absence or presence of hydrogen sulfide. The physiologic relevance of our findings was confirmed using pharmacologic inhibitors of cyclooxygenase 2 and peroxisome proliferator-activated receptor gamma.Measurements And Main ResultsMechanical ventilation caused significant lung inflammation and injury that was prevented in the presence of hydrogen sulfide. Hydrogen sulfide-mediated protection was associated with induction of cyclooxygenase 2 and increases of its product 15-deoxy Δ-prostaglandin J2 as well as cyclooxygenase 2/15-deoxy Δ-prostaglandin J2-dependent activation of peroxisome proliferator-activated receptor gamma. Hydrogen sulfide-dependent effects were mainly observed in macrophages. Applied mechanical stretch to RAW 264.7 macrophages resulted in increased expression of interleukin receptor 1 messenger RNA and release of macrophage inflammatory protein-2. In contrast, incubation of stretched macrophages with sodium hydrosulfide prevented the inflammatory response dependent on peroxisome proliferator-activated receptor gamma activity. Finally, application of a specific peroxisome proliferator-activated receptor gamma inhibitor abolished hydrogen sulfide-mediated protection in ventilated animals.ConclusionsOne hydrogen sulfide-triggered mechanism in the protection against ventilator-induced lung injury involves cyclooxygenase 2/15-deoxy Δ-prostaglandin J2-dependent activation of peroxisome proliferator-activated receptor gamma and macrophage activity.

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