Reactive oxygen or nitrogen species (ROS/RNS) generated endogenously or in response to environmental stress have long been implicated in tissue injury in the context of a variety of disease states. ...ROS/RNS can cause cell death by nonphysiological (necrotic) or regulated pathways (apoptotic). The mechanisms by which ROS/RNS cause or regulate apoptosis typically include receptor activation, caspase activation, Bcl-2 family proteins, and mitochondrial dysfunction. Various protein kinase activities, including mitogen-activated protein kinases, protein kinases-B/C, inhibitor-of-I-kappaB kinases, and their corresponding phosphatases modulate the apoptotic program depending on cellular context. Recently, lipid-derived mediators have emerged as potential intermediates in the apoptosis pathway triggered by oxidants. Cell death mechanisms have been studied across a broad spectrum of models of oxidative stress, including H2O2, nitric oxide and derivatives, endotoxin-induced inflammation, photodynamic therapy, ultraviolet-A and ionizing radiations, and cigarette smoke. Additionally ROS generated in the lung and other organs as the result of high oxygen therapy or ischemia/reperfusion can stimulate cell death pathways associated with tissue damage. Cells have evolved numerous survival pathways to counter proapoptotic stimuli, which include activation of stress-related protein responses. Among these, the heme oxygenase-1/carbon monoxide system has emerged as a major intracellular antiapoptotic mechanism.
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
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
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
S pretreatment. Moreover, H
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
S. Taken together, we provide first evidence that H
S limits lung neutrophil sequestration upon LPS challenge. As proposed underlying mechanisms, H
S prevents neutrophil transmigration through the inflamed endothelium and directly inhibits pro-inflammatory as well as oxidative signalling in neutrophils. Subsequently, H
S pretreatment ameliorates LPS-induced ALI.
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-1β, 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.
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-1β and MIP-1β 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.
Recently, we have shown that inhalation of hydrogen sulfide (H2S) protects against ventilator-induced lung injury (VILI). In the present study, we aimed to determine the underlying molecular ...mechanisms of H2S-dependent lung protection by analyzing gene expression profiles in mice. C57BL/6 mice were subjected to spontaneous breathing or mechanical ventilation in the absence or presence of H2S (80 parts per million). Gene expression profiles were determined by microarray, sqRT-PCR and Western Blot analyses. The association of Atf3 in protection against VILI was confirmed with a Vivo-Morpholino knockout model. Mechanical ventilation caused a significant lung inflammation and damage that was prevented in the presence of H2S. Mechanical ventilation favoured the expression of genes involved in inflammation, leukocyte activation and chemotaxis. In contrast, ventilation with H2S activated genes involved in extracellular matrix remodelling, angiogenesis, inhibition of apoptosis, and inflammation. Amongst others, H2S administration induced Atf3, an anti-inflammatory and anti-apoptotic regulator. Morpholino mediated reduction of Atf3 resulted in elevated lung injury despite the presence of H2S. In conclusion, lung protection by H2S during mechanical ventilation is associated with down-regulation of genes related to oxidative stress and inflammation and up-regulation of anti-apoptotic and anti-inflammatory genes. Here we show that Atf3 is clearly involved in H2S mediated protection.
Mechanical ventilation still causes an unacceptably high rate of morbidity and mortality because of ventilator-induced lung injury (VILI). Therefore, new therapeutic strategies are needed to treat ...VILI. Hydrogen sulfide can induce hypothermia and suspended animation-like states in mice. Hydrogen sulfide can also confer antiinflammatory and antiapoptotic effects. This study investigates the organ-protective effects of inhaled hydrogen sulfide during mechanical ventilation.
Mice were ventilated with a tidal volume of 12 ml/kg body weight for 6 h with synthetic air in the absence or presence of hydrogen sulfide (80 parts per million) and, in a second series, at either mild hypothermia or normothermia. Staining of lung sections determined the degree of lung damage by VILI score and apoptotic cells. Bronchoalveolar lavage fluid was analyzed for the cytokines interleukin-1beta and macrophage inflammatory protein-1beta and for neutrophil accumulation. Heme oxygenase-1 and heat shock protein 70 expression were assessed in the lung tissue by Western immunoblot analysis.
Mechanical ventilation at both hypothermia and normothermia led to a profound development of VILI, characterized by pulmonary edema, increased apoptosis, cytokine release, neutrophil recruitment, and up-regulation of the stress proteins such as heme oxygenase-1 and heat shock protein 70. In contrast, the application of hydrogen sulfide during ventilation at either mild hypothermia or normothermia prevented edema formation, apoptosis, proinflammatory cytokine production, neutrophil accumulation, and inhibited heme oxygenase-1 expression.
Inhalation of hydrogen sulfide during mechanical ventilation protects against VILI by the inhibition of inflammatory and apoptotic responses. Hydrogen sulfide confers lung protection independently of its ability to induce mild hypothermia during ventilation.
As an enzyme, heme oxygenase (HO) can provide substantial cellular protection. By eliminating free heme and generating iron, biliverdin, as well as carbon monoxide, HO exerts anti-inflammatory, ...anti-proliferative, antioxidative, and vasodilatory effects. The inducible form of HO, heme oxygenase-1 (HO-1) can be upregulated by harmful stimuli in most human cell types. In such a way, cells utilize HO-1 as a mechanism of self-protection. Many studies have shown that upregulation of HO-1 prior to injurious stimuli conferred protection to cells and organs against subsequent injury. Therefore, manipulation of HO-1 gene expression might represent a valuable strategy for the prevention of organ dysfunction. In recent studies, intravenous and inhaled anesthetics (e.g., ketamine, propofol, opioids, isoflurane, sevoflurane, desflurane, etc.) not only upregulate HO-1 to varying extents, but account for organ protection via the HO pathway. The major advantage of anesthetics over other HO-inducing agents is related to their clinically proven safety. Another important issue is that patients receiving anesthetics in anesthesia or intensive care medicine are often suffering from pathological conditions involving pro-oxidative or pro-inflammatory states. Therefore, it would be interesting to know whether the impact of anesthetics on HO-1 regulation might influence outcome of these patients. This overview summarizes the effects of different anesthetics on HO-1 regulation and function in disease models.
Carbon monoxide in acute lung injury Faller, Simone; Hoetzel, Alexander
Current pharmaceutical biotechnology,
05/2012, Letnik:
13, Številka:
6
Journal Article
Recenzirano
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.
Proliferation of pancreatic stellate cells (PSCs) plays a cardinal role during fibrosis development. Therefore, the suppression of PSC growth represents a therapeutic option for the treatment of ...pancreatic fibrosis. It has been shown that up-regulation of the enzyme heme oxygenase-1 (HO-1) could exert antiproliferative effects on PSCs, but no information is available on the possible role of carbon monoxide (CO), a catalytic byproduct of the HO metabolism, in this process. In the present study, we have examined the effect of CO releasing molecule-2 (CORM-2) liberated CO on PSC proliferation and have elucidated the mechanisms involved. Using primary rat PSCs, we found that CORM-2 inhibited PSC proliferation at nontoxic concentrations by arresting cells at the G(0)/G(1) phase of the cell cycle. This effect was associated with activation of p38 mitogen-activated protein kinase (MAPK) signaling, induction of HO-1 protein, and up-regulation of the cell cycle inhibitor p21(Waf1/Cip1). The p38 MAPK inhibitor 4-(4-flurophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)imidazole (SB203580) abolished the inhibitory effect of CORM-2 on PSC proliferation and prevented both CORM-2-induced HO-1 and p21(Waf1/Cip1) up-regulation. Treatment with tin protoporphyrin IX, an HO inhibitor, or transfection of HO-1 small interfering RNA abolished the inductive effect of CORM-2 on p21(Waf1/Cip1) and reversed the suppressive effect of CORM-2 on PSC growth. The ability of CORM-2 to induce cell cycle arrest was abrogated in p21(Waf1/Cip1)-silenced cells. Taken together, our results suggest that CORM-2 inhibits PSC proliferation by activation of the p38/HO-1 pathway. These findings may indicate a therapeutic potential of CO carriers in the treatment of pancreatic fibrosis.
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