Establishment and validation of intravenous anesthesia with dexmedetomidine for pigs under assisted spontaneous breathing: A preclinical model of intensive care conditions.

Large animal models are frequently used to investigate new medical approaches. In most cases, animals are kept under general anesthesia and mandatory mechanical ventilation during the experiments. However, in some situations assisted spontaneous breathing is essential, e.g. when simulating conditions in a modern intensive care unit. Therefore, we established an anesthesia regime with dexmedetomidine and midazolam/ketamine in porcine models of assisted spontaneous breathing. The total intravenous anesthesia was used in lung healthy pigs, in pigs with oleic acid induced acute respiratory distress syndrome and in pigs with methacholine induced bronchopulmonary obstruction. We were able to maintain stable conditions of assisted spontaneous breathing without impairment of hemodynamic, respiratory or blood gas variables in lung healthy pigs and pigs with induced acute respiratory distress syndrome for a period of five hours and in pigs with induced bronchopulmonary obstruction for three hours. Total intravenous anesthesia containing dexmedetomidine enables stable conditions of assisted spontaneous breathing in healthy pigs, in pigs with induced acute respiratory distress syndrome and in pigs induced bronchopulmonary obstruction as models of intensive care unit conditions.

Lung area estimation using functional tidal electrical impedance variation images and active contouring.

Objective.Electrical impedance tomography is a valuable tool for monitoring global and regional lung mechanics. To evaluate the recorded data, an accurate estimate of the lung area is crucial.Approach.We present two novel methods for estimating the lung area using functional tidal images or active contouring methods. A convolutional neural network was trained to determine, whether or not the heart region was visible within tidal images. In addition, the effects of lung area mirroring were investigated. The performance of the methods and the effects of mirroring were evaluated via a score based on the impedance magnitudes and their standard deviations in functional tidal images.Main results.Our analyses showed that the method based on functional tidal images provided the best estimate of the lung area. Mirroring of the lung area had an impact on the accuracy of area estimation for both methods. The achieved accuracy of the neural network's classification was 94%. For images without a visible heart area, the subtraction of a heart template proved to be a pragmatic approach with good results.Significance.In summary, we developed a routine for estimation of the lung area combined with estimation of the heart area in electrical impedance tomography images.

Profiling Distinctive Inflammatory and Redox Responses to Hydrogen Sulfide in Stretched and Stimulated Lung Cells.

Hydrogen sulfide (H2S) protects against stretch-induced lung injury. However, the impact of H2S on individual cells or their crosstalk upon stretch remains unclear. Therefore, we addressed this issue in vitro using relevant lung cells. We have explored (i) the anti-inflammatory properties of H2S on epithelial (A549 and BEAS-2B), macrophage (RAW264.7) and endothelial (HUVEC) cells subjected to cycling mechanical stretch; (ii) the intercellular transduction of inflammation by co-culturing epithelial cells and macrophages (A549 and RAW264.7); (iii) the effect of H2S on neutrophils (Hoxb8) in transmigration (co-culture setup with HUVECs) and chemotaxis experiments. In stretched epithelial cells (A549, BEAS-2B), the release of interleukin-8 was not prevented by H2S treatment. However, H2S reduced macrophage inflammatory protein-2 (MIP-2) release from unstretched macrophages (RAW264.7) co-cultured with stretched epithelial cells. In stretched macrophages, H2S prevented MIP-2 release by limiting nicotinamide adenine dinucleotide phosphate oxidase-derived superoxide radicals (ROS). In endothelial cells (HUVEC), H2S inhibited interleukin-8 release and preserved endothelial integrity. In neutrophils (Hoxb8), H2S limited MIP-2-induced transmigration through endothelial monolayers, ROS formation and their chemotactic movement. H2S induces anti-inflammatory effects in a cell-type specific manner. H2S limits stretch- and/or paracrine-induced inflammatory response in endothelial, macrophage, and neutrophil cells by maintaining redox homeostasis as underlying mechanism.

Biosensor-Enabled Multiplexed On-Site Therapeutic Drug Monitoring of Antibiotics.

Personalized antibiotherapy ensures that the antibiotic concentration remains in the optimal therapeutic window to maximize efficacy, minimize side effects, and avoid the emergence of drug resistance due to insufficient dosing. However, such individualized schemes need frequent sampling to tailor the blood antibiotic concentrations. To optimally integrate therapeutic drug monitoring (TDM) into the clinical workflow, antibiotic levels can either be measured in blood using point-of-care testing (POCT), or can rely on noninvasive sampling. Here, a versatile biosensor with an antibody-free assay for on-site TDM is presented. The platform is evaluated with an animal study, where antibiotic concentrations are quantified in different matrices including whole blood, plasma, urine, saliva, and exhaled breath condensate (EBC). The clearance and the temporal evaluation of antibiotic levels in EBC and plasma are demonstrated. Influence of matrix effects on measured drug concentrations is determined by comparing the plasma levels with those in noninvasive samples. The system's potential for blood-based POCT is further illustrated by tracking ß-lactam concentrations in untreated blood samples. Finally, multiplexing capabilities are explored successfully for multianalyte/sample analysis. By enabling a rapid, low-cost, sample-independent, and multiplexed on-site TDM, this system can shift the paradigm of "one-size-fits-all" strategy.

Argon reduces microglial activation and inflammatory cytokine expression in retinal ischemia/reperfusion injury.

We previously found that argon exerts its neuroprotective effect in part by inhibition of the toll-like receptors (TLR) 2 and 4. The downstream transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB) are also affected by argon and may play a role in neuroprotection. It also has been demonstrated that argon treatment could mitigate brain damage, reduce excessive microglial activation, and subsequently attenuate brain inflammation. Despite intensive research, the further exact mechanism remains unclear. In this study, human neuroblastoma cells were damaged in vitro with rotenone over a period of 4 hours (to mimic cerebral ischemia and reperfusion damage), followed by a 2-hour post-conditioning with argon (75%). In a separate in vivo experiment, retinal ischemia/reperfusion injury was induced in rats by increasing intraocular pressure for 1 hour. Upon reperfusion, argon was administered by inhalation for 2 hours. Argon reduced the binding of the transcription factors signal transducer and activator of transcription 3, nuclear factor kappa B, activator protein 1, and nuclear factor erythroid 2-related factor 2, which are involved in regulation of neuronal damage. Flow cytometry analysis showed that argon downregulated the Fas ligand. Some transcription factors were regulated by toll-like receptors; therefore, their effects could be eliminated, at least in part, by the TLR2 and TLR4 inhibitor oxidized phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC). Argon treatment reduced microglial activation after retinal ischemia/reperfusion injury. Subsequent quantitative polymerase chain reaction analysis revealed a reduction in the pro-inflammatory cytokines interleukin (IL-1α), IL-1ß, IL-6, tumor necrosis factor α, and inducible nitric oxide synthase. Our results suggest that argon reduced the extent of inflammation in retinal neurons after ischemia/reperfusion injury by suppression of transcription factors crucial for microglial activation. Argon has no known side effects or narcotic properties; therefore, therapeutic use of this noble gas appears ideal for treatment of patients with neuronal damage in retinal ischemia/reperfusion injury. The animal experiments were approved by the Commission for Animal Care of the University of Freiburg (approval No. 35-9185.81/G14-122) on October 19, 2012.

Mechanical ventilation restores blood gas homeostasis and diaphragm muscle strength in ketamine/medetomidine-anaesthetized rats.

NEW FINDINGS: What is the central question of the study? Does respiratory support ensure blood gas homeostasis and the relevance of experimental outcomes? What is the main finding and its importance? Spontaneous breathing during surgical intervention under anaesthesia results in impaired gas exchange and loss of diaphragm muscle strength in rats. Subsequent short-term mechanical ventilation restored blood gas homeostasis and diaphragm muscle strength. Blood gas homeostasis interferes substantially with experimental conditions and may alter study results. Monitoring and maintenance of blood gas balance is required to ensure quality and relevance of physiological animal experiments. ABSTRACT: In pre-clinical small animal studies with surgical interventions under general anaesthesia, animals are often left to breathe spontaneously. However, anaesthesia may impair respiratory functions and result in disturbed blood gas homeostasis. In turn, the disturbed blood gas homeostasis can affect physiological functions and thus unintentionally impact the experimental results. We hypothesized that short-term mechanical ventilation restores blood gas balance and physiological functions despite anaesthesia and surgical interventions. Therefore, we investigated variables of blood gas analyses and diaphragm muscle strength in rats anaesthetized with ketamine/medetomidine after tracheotomy and catheterization of the carotid artery under spontaneous breathing and after 20 min of mechanical ventilation following the same surgical intervention. Spontaneous breathing during general anaesthesia and surgical intervention resulted in unphysiological blood oxygen partial pressure (<65 mmHg) and carbon dioxide partial pressure (>55 mmHg). After subsequent short-term mechanical ventilation, blood gas partial pressures were restored to their physiological ranges. Additionally, diaphragm muscle strength of animals breathing spontaneously was lower compared to animals that received subsequent mechanical ventilation (P = 0.0063). We conclude that spontaneous breathing of rats under ketamine/medetomidine anaesthesia is not sufficient to maintain a physiological blood gas balance. Disturbed blood gas balance is related to reduced diaphragm muscle strength. Mechanical ventilation for only 20 min restores blood gas homeostasis and muscle strength. Therefore, monitoring and maintenance of blood gas balance should be conducted to ensure quality and relevance of small animal experiments.

Sine ventilation in lung injury models: a new perspective for lung protective ventilation.

Mechanical ventilation is associated with the risk of ventilator induced lung injury. For reducing lung injury in mechanically ventilated patients, the application of small tidal volumes and positive end-expiratory pressures has become clinical standard. Recently, an approach based on linear airway pressure decline and decelerated expiratory flow during expiration implied lung protective capacities. We assumed that ventilation with a smoothed, i.e. sinusoidal airway pressure profile may further improve ventilation efficiency and lung protection. We compared the effects of mechanical ventilation with sinusoidal airway pressure profile (SINE) regarding gas exchange, respiratory system compliance and histology to conventional volume and pressure controlled ventilation (VCV and PCV) and to VCV with flow-controlled expiration (FLEX) in two rat models of lung injury, tween induced surfactant depletion and high tidal volume mechanical ventilation. In both lung injury models ventilation with SINE showed more efficient CO2 elimination and blood oxygenation, improved respiratory system compliance and resulted in lower alveolar wall thickness, compared to VCV, PCV and FLEX. Optimization of the airway pressure profile may provide a novel means of lung protective mechanical ventilation.

A novel mechanical ventilator providing flow-controlled expiration for small animals.

For investigating the effects of mechanical ventilation on the respiratory system, experiments in small mammal models are used. However, conventional ventilators for small animals are usually limited to a specific ventilation mode, and in particular to passive expiration. Here, we present a computer-controlled research ventilator for small animals which provides conventional mechanical ventilation as well as new type ventilation profiles. Typical profiles of conventional mechanical ventilation, as well as flow-controlled expiration and sinusoidal ventilation profiles can be generated with our new ventilator. Flow control during expiration reduced the expiratory peak flow rate by 73% and increased the mean airway pressure by up to 1 mbar compared with conventional ventilation without increasing peak pressure and end-expiratory pressure. Our new ventilator for small animals allows for the application of various ventilation profiles. We could analyse the effects of applying conventional ventilation profiles, pressure-controlled ventilation and volume-controlled ventilation, as well as the novel flow-controlled ventilation profile. This new approach enables studying the mechanical properties of the respiratory system with an increased freedom for choosing independent ventilation parameters.

Flow-Controlled Ventilation Attenuates Lung Injury in a Porcine Model of Acute Respiratory Distress Syndrome: A Preclinical Randomized Controlled Study.

OBJECTIVES: Lung-protective ventilation for acute respiratory distress syndrome aims for providing sufficient oxygenation and carbon dioxide clearance, while limiting the harmful effects of mechanical ventilation. "Flow-controlled ventilation", providing a constant expiratory flow, has been suggested as a new lung-protective ventilation strategy. The aim of this study was to test whether flow-controlled ventilation attenuates lung injury in an animal model of acute respiratory distress syndrome. DESIGN: Preclinical, randomized controlled animal study. SETTING: Animal research facility. SUBJECTS: Nineteen German landrace hybrid pigs. INTERVENTION: Flow-controlled ventilation (intervention group) or volume-controlled ventilation (control group) with identical tidal volume (7 mL/kg) and positive end-expiratory pressure (9 cm H2O) after inducing acute respiratory distress syndrome with oleic acid. MEASUREMENTS AND MAIN RESULTS: PaO2 and PaCO2, minute volume, tracheal pressure, lung aeration measured via CT, alveolar wall thickness, cell infiltration, and surfactant protein A concentration in bronchoalveolar lavage fluid. Five pigs were excluded leaving n equals to 7 for each group. Compared with control, flow-controlled ventilation elevated PaO2 (154 ± 21 vs 105 ± 9 torr; 20.5 ± 2.8 vs 14.0 ± 1.2 kPa; p = 0.035) and achieved comparable PaCO2 (57 ± 3 vs 54 ± 1 torr; 7.6 ± 0.4 vs 7.1 ± 0.1 kPa; p = 0.37) with a lower minute volume (6.4 ± 0.5 vs 8.7 ± 0.4 L/min; p < 0.001). Inspiratory plateau pressure was comparable in both groups (31 ± 2 vs 34 ± 2 cm H2O; p = 0.16). Flow-controlled ventilation increased normally aerated (24% ± 4% vs 10% ± 2%; p = 0.004) and decreased nonaerated lung volume (23% ± 6% vs 38% ± 5%; p = 0.033) in the dependent lung region. Alveolar walls were thinner (5.5 ± 0.1 vs 7.8 ± 0.2 µm; p < 0.0001), cell infiltration was lower (20 ± 2 vs 32 ± 2 n/field; p < 0.0001), and normalized surfactant protein A concentration was higher with flow-controlled ventilation (1.1 ± 0.04 vs 1.0 ± 0.03; p = 0.039). CONCLUSIONS: Flow-controlled ventilation enhances lung aeration in the dependent lung region and consequently improves gas exchange and attenuates lung injury. Control of the expiratory flow may provide a novel option for lung-protective ventilation.

Ventilation-Like Mechanical Strain Modulates the Inflammatory Response of BEAS2B Epithelial Cells.

Protective mechanical ventilation is aimed at preventing ventilator-induced lung injury while ensuring sufficient gas exchange. A new approach focuses on the temporal profile of the mechanical ventilation. We hypothesized that the temporal mechanical strain profile modulates inflammatory signalling. We applied cyclic strain with various temporal profiles to human bronchial epithelial cells (BEAS2B) and assessed proinflammatory response. The cells were subjected to sinusoidal, rectangular, or triangular strain profile and rectangular strain profile with prestrain set to 0, 25, 50, or 75% of the maximum stain, static strain, and strain resembling a mechanical ventilation-like profile with or without flow-controlled expiration. The BEAS2B response to mechanical load included altered mitochondrial activity, increased superoxide radical levels, NF-kappaB translocation, and release of interleukin-8. The response to strain was substantially modulated by the dynamics of the stimulation pattern. The rate of dynamic changes of the strain profile correlates with the degree of mechanical stress-induced cell response.

Hydrogen sulfide limits neutrophil transmigration, inflammation, and oxidative burst in lipopolysaccharide-induced acute lung injury.

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 (H2S) 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 H2S 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 H2S pretreatment. Moreover, H2S 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-1ß 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 H2S. Taken together, we provide first evidence that H2S limits lung neutrophil sequestration upon LPS challenge. As proposed underlying mechanisms, H2S prevents neutrophil transmigration through the inflamed endothelium and directly inhibits pro-inflammatory as well as oxidative signalling in neutrophils. Subsequently, H2S pretreatment ameliorates LPS-induced ALI.

Improved lung recruitment and oxygenation during mandatory ventilation with a new expiratory ventilation assistance device: A controlled interventional trial in healthy pigs.

BACKGROUND: In contrast to conventional mandatory ventilation, a new ventilation mode, expiratory ventilation assistance (EVA), linearises the expiratory tracheal pressure decline. OBJECTIVE: We hypothesised that due to a recruiting effect, linearised expiration oxygenates better than volume controlled ventilation (VCV). We compared the EVA with VCV mode with regard to gas exchange, ventilation volumes and pressures and lung aeration in a model of peri-operative mandatory ventilation in healthy pigs. DESIGN: Controlled interventional trial. SETTING: Animal operating facility at a university medical centre. ANIMALS: A total of 16 German Landrace hybrid pigs. INTERVENTION: The lungs of anaesthetised pigs were ventilated with the EVA mode (n=9) or VCV (control, n=7) for 5 h with positive end-expiratory pressure of 5 cmH2O and tidal volume of 8 ml kg. The respiratory rate was adjusted for a target end-tidal CO2 of 4.7 to 6 kPa. MAIN OUTCOME MEASURES: Tracheal pressure, minute volume and arterial blood gases were recorded repeatedly. Computed thoracic tomography was performed to quantify the percentages of normally and poorly aerated lung tissue. RESULTS: Two animals in the EVA group were excluded due to unstable ventilation (n=1) or unstable FiO2 delivery (n=1). Mean tracheal pressure and PaO2 were higher in the EVA group compared with control (mean tracheal pressure: 11.6 ±â€Š0.4 versus 9.0 ±â€Š0.3 cmH2O, P < 0.001 and PaO2: 19.2 ±â€Š0.7 versus 17.5 ±â€Š0.4 kPa, P = 0.002) with comparable peak inspiratory tracheal pressure (18.3 ±â€Š0.9 versus 18.0 ±â€Š1.2 cmH2O, P > 0.99). Minute volume was lower in the EVA group compared with control (5.5 ±â€Š0.2 versus 7.0 ±â€Š1.0 l min, P = 0.02) with normoventilation in both groups (PaCO2 5.4 ±â€Š0.3 versus 5.5 ±â€Š0.3 kPa, P > 0.99). In the EVA group, the percentage of normally aerated lung tissue was higher (81.0 ±â€Š3.6 versus 75.8 ±â€Š3.0%, P = 0.017) and of poorly aerated lung tissue lower (9.5 ±â€Š3.3 versus 15.7 ±â€Š3.5%, P = 0.002) compared with control. CONCLUSION: EVA ventilation improves lung aeration via elevated mean tracheal pressure and consequently improves arterial oxygenation at unaltered positive end-expiratory pressure (PEEP) and peak inspiratory pressure (PIP). These findings suggest the EVA mode is a new approach for protective lung ventilation.

Sevoflurane posttreatment prevents oxidative and inflammatory injury in ventilator-induced lung injury.

Mechanical ventilation is a life-saving clinical treatment but it can induce or aggravate lung injury. New therapeutic strategies, aimed at reducing the negative effects of mechanical ventilation such as excessive production of reactive oxygen species, release of pro-inflammatory cytokines, and transmigration as well as activation of neutrophil cells, are needed to improve the clinical outcome of ventilated patients. Though the inhaled anesthetic sevoflurane is known to exert organ-protective effects, little is known about the potential of sevoflurane therapy in ventilator-induced lung injury. This study focused on the effects of delayed sevoflurane application in mechanically ventilated C57BL/6N mice. Lung function, lung injury, oxidative stress, and inflammatory parameters were analyzed and compared between non-ventilated and ventilated groups with or without sevoflurane anesthesia. Mechanical ventilation led to a substantial induction of lung injury, reactive oxygen species production, pro-inflammatory cytokine release, and neutrophil influx. In contrast, sevoflurane posttreatment time dependently reduced histological signs of lung injury. Most interestingly, increased production of reactive oxygen species was clearly inhibited in all sevoflurane posttreatment groups. Likewise, the release of the pro-inflammatory cytokines interleukin-1ß and MIP-1ß and neutrophil transmigration were completely prevented by sevoflurane independent of the onset of sevoflurane administration. In conclusion, sevoflurane posttreatment time dependently limits lung injury, and oxidative and pro-inflammatory responses are clearly prevented by sevoflurane irrespective of the onset of posttreatment. These findings underline the therapeutic potential of sevoflurane treatment in ventilator-induced lung injury.

Hydrogen Sulfide Exerts Anti-oxidative and Anti-inflammatory Effects in Acute Lung Injury.

Acute lung injury (ALI) caused by septic stimuli is still a major problem in critical care patients. We have shown previously that hydrogen sulfide (H2S) 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 H2S for 6 h. LPS instillation led to alveolar wall thickening, an elevated ALI score, increased neutrophil transmigration, and elevated interleukin-1ß cytokine release into the bronchoalveolar lavage fluid. In contrast, H2S inhalation prevented lung injury and inflammation despite LPS treatment. Moreover, H2S inhalation significantly inhibited protein expression of cystathionine-ß-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, H2S 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.

Corrigendum to "Hydrogen Sulfide Prevents Formation of Reactive Oxygen Species through PI3K/Akt Signaling and Limits Ventilator-Induced Lung Injury".

[This corrects the article DOI: 10.1155/2017/3715037.].

Correction: Pre- and posttreatment with hydrogen sulfide prevents ventilator-induced lung injury by limiting inflammation and oxidation.

[This corrects the article DOI: 10.1371/journal.pone.0176649.].

Hydrogen Sulfide Confers Lung Protection During Mechanical Ventilation via Cyclooxygenase 2, 15-deoxy Δ12,14-Prostaglandin J2, and Peroxisome Proliferator-Activated Receptor Gamma.

OBJECTIVES: Hydrogen 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. DESIGN: Randomized, experimental study. SETTING: University medical center research laboratory. SUBJECTS: C57BL/6 mice and in vitro cell catheters. INTERVENTIONS: The 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 RESULTS: Mechanical 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. CONCLUSIONS: One 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.

Pre- and posttreatment with hydrogen sulfide prevents ventilator-induced lung injury by limiting inflammation and oxidation.

Although essential in critical care medicine, mechanical ventilation often results in ventilator-induced lung injury. Low concentrations of hydrogen sulfide have been proven to have anti-inflammatory and anti-oxidative effects in the lung. The aim of this study was to analyze the kinetic effects of pre- and posttreatment with hydrogen sulfide in order to prevent lung injury as well as inflammatory and oxidative stress upon mechanical ventilation. Mice were either non-ventilated or mechanically ventilated with a tidal volume of 12 ml/kg for 6 h. Pretreated mice inhaled hydrogen sulfide in low dose for 1, 3, or 5 h prior to mechanical ventilation. Posttreated mice were ventilated with air followed by ventilation with hydrogen sulfide in various combinations. In addition, mice were ventilated with air for 10 h, or with air for 5 h and subsequently with hydrogen sulfide for 5 h. Histology, interleukin-1ß, neutrophil counts, and reactive oxygen species formation were examined in the lungs. Both pre-and posttreatment with hydrogen sulfide time-dependently reduced or even prevented edema formation, gross histological damage, neutrophil influx and reactive oxygen species production in the lung. These results were also observed in posttreatment, when the experimental time was extended and hydrogen sulfide administration started as late as after 5 h air ventilation. In conclusion, hydrogen sulfide exerts lung protection even when its application is limited to a short or delayed period. The observed lung protection is mediated by inhibition of inflammatory and oxidative signaling.

Hydrogen Sulfide Prevents Formation of Reactive Oxygen Species through PI3K/Akt Signaling and Limits Ventilator-Induced Lung Injury.

The development of ventilator-induced lung injury (VILI) is still a major problem in mechanically ventilated patients. Low dose inhalation of hydrogen sulfide (H2S) during mechanical ventilation has been proven to prevent lung damage by limiting inflammatory responses in rodent models. However, the capacity of H2S to affect oxidative processes in VILI and its underlying molecular signaling pathways remains elusive. In the present study we show that ventilation with moderate tidal volumes of 12 ml/kg for 6 h led to an excessive formation of reactive oxygen species (ROS) in mice lungs which was prevented by supplemental inhalation of 80 parts per million of H2S. In addition, phosphorylation of the signaling protein Akt was induced by H2S. In contrast, inhibition of Akt by LY294002 during ventilation reestablished lung damage, neutrophil influx, and proinflammatory cytokine release despite the presence of H2S. Moreover, the ability of H2S to induce the antioxidant glutathione and to prevent ROS production was reversed in the presence of the Akt inhibitor. Here, we provide the first evidence that H2S-mediated Akt activation is a key step in protection against VILI, suggesting that Akt signaling limits not only inflammatory but also detrimental oxidative processes that promote the development of lung injury.