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Transmigration and activation of neutrophils in the lung reflect key steps in the progression of acute lung injury (ALI). It is known that hydrogen sulfide (H 2 S) can limit neutrophil activation, but the respective mechanisms remain elusive. Here, we aimed to examine the underlying pathways in pulmonary inflammation. In vivo, C57BL/6N mice received the H 2 S slow releasing compound GYY4137 prior to lipopolysaccharide (LPS) inhalation. LPS challenge led to pulmonary injury, inflammation, and neutrophil transmigration that were inhibited in response to H 2 S pretreatment. Moreover, H 2 S reduced mRNA expression of macrophage inflammatory protein-2 (MIP-2) and its receptor in lung tissue, as well as the accumulation of MIP-2 and interleukin-1β in the alveolar space. In vitro, GYY4137 did not exert toxic effects on Hoxb8 neutrophils, but prevented their transmigration through an endothelial barrier in the presence and absence of MIP-2. In addition, the release of MIP-2 and reactive oxygen species from LPS-stimulated Hoxb8 neutrophils were directly inhibited by H 2 S. Taken together, we provide first evidence that H 2 S limits lung neutrophil sequestration upon LPS challenge. As proposed underlying mechanisms, H 2 S prevents neutrophil transmigration through the inflamed endothelium and directly inhibits pro-inflammatory as well as oxidative signalling in neutrophils. Subsequently, H 2 S pretreatment ameliorates LPS-induced ALI.

Acute lung injury (ALI) caused by septic stimuli is still a major problem in critical care patients. We have shown previously that hydrogen sulfide (H 2 S) mediates anti-inflammatory and lung protective effects. In the present study, we aimed to investigate the underlying mechanisms. C57BL/6N mice were instilled with lipopolysaccharide (LPS) intranasally in the absence or presence of inhaled H 2 S for 6 h. LPS instillation led to alveolar wall thickening, an elevated ALI score, increased neutrophil transmigration, and elevated interleukin-1β cytokine release into the bronchoalveolar lavage fluid. In contrast, H 2 S inhalation prevented lung injury and inflammation despite LPS treatment. Moreover, H 2 S inhalation significantly inhibited protein expression of cystathionine-β-synthetase, heat shock protein 70, phosphorylated p38 MAP kinase, NADPH oxidase 2, and the formation of reactive oxygen species (ROS) in LPS-challenged animals. In conclusion, H 2 S prevents LPS-induced ALI by inhibition of pro-inflammatory and oxidative responses via the concerted attenuation of stress protein, MAP kinase, and ROS signaling pathways.

Despite modern clinical practice in critical care medicine, acute lung injury still causes unacceptably high rates of morbidity and mortality. Therefore, the challenge today is to identify new and effective strategies in order to improve the outcome of these patients. Carbon monoxide, endogenously produced by the heme oxygenase enzyme system, has emerged as promising gaseous therapeutic that exerts protective effects against inflammation, oxidative and mechanical stress, and apoptosis, thus potentially limiting acute lung injury. In this review we discuss the effects of inhaled carbon monoxide on acute lung injury that results from ischemia-reperfusion, transplantation, sepsis, hyperoxia, or mechanical ventilation, the latter referred to as ventilator-induced lung injury. Multiple investigations using in vivo and in vitro models have demonstrated anti-inflammatory, anti-apoptotic, and anti-proliferative properties of carbon monoxide in the lung when applied at low dose prior to or during stressful stimuli. The molecular mechanisms that are modulated by carbon monoxide exposure are still not fully understood. Carbon monoxide mediated lung protection involves several signaling pathways including mitogen activated protein kinases, nuclear factor-κB, activator protein-1, Akt, peroxisome proliferating- activated receptor-γ, early growth response-1, caveolin-1, hypoxia-inducible factor-1α, caspases, Bcl-2-family members, heat shock proteins, or molecules of the fibrinolytic axis. At present, clinical trials on the efficacy and safety of CO investigate whether the promising laboratory findings might be translatable to humans.

Objectives: Carbon monoxide (CO) can confer anti-inflammatory protection in rodent models of ventilator-induced lung injury (VILI). Caveolin-1 exerts a critical role in cellular responses to mechanical stress and has been shown to mediate cytoprotective effects of CO in vitro. We sought to determine the role of caveolin-1 in lung susceptibility to VILI in mice. Furthermore, we assessed the role of caveolin-1 in the tissue-protective effects of CO in the VILI model., Design: Prospective experimental study., Setting: University laboratory., Subjects: Wild type (wt) and caveolin-1 deficient (cav-1) mice., Interventions: Mice were subjected to tracheostomy and arterial cannulation. Wt and cav-1 mice were ventilated with a tidal volume of 12 mL/kg body weight and a frequency of 80/minute for 5 minutes as control or for 8 hours with air in the absence or presence of CO (250 parts per million). Bronchoalveolar lavage and histology were used to determine lung injury. Lung sections or homogenates were analyzed for caveolin-1 expression by immunohistochemical staining or Western blotting, respectively., Measurements and Main Results: Ventilation led to an increase in bronchoalveolar lavage protein concentration, cell count, neutrophil recruitment, and edema formation, which was prevented in the presence of CO. Although ventilation alone slightly induced caveolin-1 expression in epithelial cells, the application of CO during the ventilation significantly increased the expression of caveolin-1. In comparison with wt mice, mechanical ventilation of cav-1 mice led to a significantly higher degree of lung injury when compared with wt mice. In contrast to its effectiveness in wt mice, CO administration failed to reduce lung-injury markers in cav-1 mice., Conclusions: Caveolin-1 null mice are more susceptible to VILI. CO executes lung-protective effects during mechanical ventilation that are dependent, in part, on caveolin-1 expression.