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.

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.

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.].

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 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.

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.

Inhaled Anesthetics Exert Different Protective Properties in a Mouse Model of Ventilator-Induced Lung Injury.

BACKGROUND: Mechanical ventilation is an important perioperative tool in anesthesia and a lifesaving treatment for respiratory failure, but it can lead to ventilator-associated lung injury. Inhaled anesthetics have demonstrated protective properties in various models of organ damage. We compared the lung-protective potential of inhaled sevoflurane, isoflurane, and desflurane in a mouse model of ventilator-induced lung injury (VILI). METHODS: C57BL/6N mice were randomized into 5 groups (n = 8/group). One group served as a control and 4 groups were subjected to mechanical ventilation with air (12 mL/kg tidal volume) for 6 hours. Ventilated animals were anesthetized with either ketamine and acepromazine, or 1 of 3 inhaled anesthetics: isoflurane, sevoflurane, or desflurane. Lung injury was assessed by lung histology, neutrophil counts, and interleukin-1ß concentrations in bronchoalveolar lavage fluid. Antioxidant effects were explored by evaluation of production of reactive oxygen species (ROS) and glutathione content in lung tissue by immunofluorescence staining and confocal laser scanning microscopy. Changes in intercellular adhesion molecule-1 and src-protein-tyrosine-kinase levels were determined by real-time polymerase chain reaction and Western blot. RESULTS: Compared with nonventilated controls, ventilated mice anesthetized with ketamine had thickened alveolar walls, elevated VILI scores, higher polymorph neutrophil counts, and increased ROS production. Mice anesthetized with isoflurane and sevoflurane showed thinner alveolar septa, lower VILI scores, lower polymorph neutrophil counts, and lower interleukin-1ß concentrations than ketamine mice. The expression of intercellular adhesion molecule-1/src-protein-tyrosine-kinase was neither affected by mechanical ventilation nor affected by administration of inhaled anesthetics. Mice anesthetized with isoflurane and sevoflurane showed less ROS production and higher glutathione contents compared with ketamine mice. Unexpectedly, desflurane-ventilated mice showed similar signs of lung injury compared with mice ventilated with air alone and receiving ketamine anesthesia. Desflurane failed to inhibit inflammatory responses and ROS production in lung tissue and developed no antioxidant potential. CONCLUSIONS: Although isoflurane and sevoflurane prevent ventilator-associated lung injury, desflurane does not. As an underlying mechanism, both inhaled anesthetics exert major anti-inflammatory and antioxidative effects.

Genetic targets of hydrogen sulfide in ventilator-induced lung injury--a microarray study.

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.

Hydrogen sulfide prevents hyperoxia-induced lung injury by downregulating reactive oxygen species formation and angiopoietin-2 release.

Oxygen therapy is a life-sustaining treatment for patients with respiratory failure. However, prolonged exposure to high oxygen concentrations often results in hyperoxia-induced acute lung injury (HALI). At present, no effective therapeutic intervention can attenuate the development of HALI. In the present study, we investigated whether hydrogen sulfide (H2S) can confer lung protection in a mouse model of HALI. C57BL/6 mice were either exposed to room air or 90 vol% oxygen and received either the H2S donor sodium hydrosulfide (NaHS, 10 mg/kg) or vehicle. Lung injury was assessed by an HALI score in tissue sections. Bronchoalveolar lavage fluid was analyzed for protein content and cellular infiltration. Reactive oxygen species (ROS) were detected by dihydroethidium staining. Angiopoietin- 2 was detected by Western Blotting. Pulmonary epithelial, endothelial, and macrophage cells were stimulated to produce ROS either in the absence or presence of NaHS. Mice exposed to hyperoxia developed substantial lung injury, characterized by an elevated HALI score, cellular infiltration, protein leakage, ROS production, and overexpression of angiopoietin-2. NaHS treatment abolished morphological indices of HALI. Angiopoietin-2 expression was significantly reduced by NaHS in vivo. In endothelial cells and macrophages, angiopoietin-2 was released due to ROS formation and decreased in the presence of NaHS. In conclusion, H2S protects from HALI by preventing ROS production and angiopoietin-2 release.

Inhaled hydrogen sulfide protects against lipopolysaccharide-induced acute lung injury in mice.

BACKGROUND: Local pulmonary and systemic infections can lead to acute lung injury (ALI). The resulting lung damage can evoke lung failure and multiple organ dysfunction associated with increased mortality. Hydrogen sulfide (H2S) appears to represent a new therapeutic approach to ALI. The gas has been shown to mediate potent anti-inflammatory and organ protective effects in vivo. This study was designed to define its potentially protective role in sepsis-induced lung injury. METHODS: C57BL/6 N mice received lipopolysaccharide (LPS) intranasally in the absence or presence of 80 parts per million H2S. After 6 h, acute lung injury was determined by comparative histology. Bronchoalveolar lavage (BAL) fluid was analyzed for total protein content and differential cell counting. BAL and serum were further analyzed for interleukin-1ß, macrophage inflammatory protein-2, and/or myeloperoxidase glycoprotein levels by enzyme-linked immunosorbent assays. Differences between groups were analyzed by one way analysis of variance. RESULTS: Histological analysis revealed that LPS instillation led to increased alveolar wall thickening, cellular infiltration, and to an elevated ALI score. In the presence of H2S these changes were not observed despite LPS treatment. Moreover, neutrophil influx, and pro-inflammatory cytokine release were enhanced in BAL fluid of LPS-treated mice, but comparable to control levels in H2S treated mice. In addition, myeloperoxidase levels were increased in serum after LPS challenge and this was prevented by H2S inhalation. CONCLUSION: Inhalation of hydrogen sulfide protects against LPS-induced acute lung injury by attenuating pro-inflammatory responses.

Kinetic effects of carbon monoxide inhalation on tissue protection in ventilator-induced lung injury.

Mechanical ventilation causes ventilator-induced lung injury (VILI), and contributes to acute lung injury/acute respiratory distress syndrome (ALI/ARDS), a disease with high morbidity and mortality among critically ill patients. Carbon monoxide (CO) can confer lung protective effects during mechanical ventilation. This study investigates the time dependency of CO therapy with respect to lung protection in animals subjected to mechanical ventilation. For this purpose, mice were ventilated with a tidal volume of 12 ml/kg body weight for 6 h with air in the absence or presence of CO (250 parts per million). Histological analysis of lung tissue sections was used to determine alveolar wall thickening and the degree of lung damage by VILI score. Bronchoalveolar lavage fluid was analyzed for total cellular influx, neutrophil accumulation, and interleukin-1ß release. As the main results, mechanical ventilation induced pulmonary edema, cytokine release, and neutrophil recruitment. In contrast, application of CO for 6 h prevented VILI. Although CO application for 3 h followed by 3-h air ventilation failed to prevent lung injury, a further reduction of CO application time to 1 h in this setting provided sufficient protection. Pre-treatment of animals with inhaled CO for 1 h before ventilation showed no beneficial effect. Delayed application of CO beginning at 3 or 5 h after initiation of ventilation, reduced lung damage, total cell influx, and neutrophil accumulation. In conclusion, administration of CO for 6 h protected against VILI. Identical protective effects were achieved by limiting the administration of CO to the first hour of ventilation. Pre-treatment with CO had no impact on VILI. In contrast, delayed application of CO led to anti-inflammatory effects with time-dependent reduction in tissue protection.

The volatile anesthetic isoflurane prevents ventilator-induced lung injury via phosphoinositide 3-kinase/Akt signaling in mice.

BACKGROUND: Mechanical ventilation leads to ventilator-induced lung injury in animals, and can contribute to acute lung injury/acute respiratory distress syndrome in humans. Acute lung injury/acute respiratory distress syndrome currently causes an unacceptably high rate of morbidity and mortality among critically ill patients. Volatile anesthetics have been shown to exert anti-inflammatory and organ-protective effects in vivo. We investigated the effects of the volatile anesthetic isoflurane on lung injury during mechanical ventilation. METHODS: C57BL/6N mice were ventilated with a tidal volume of 12 mL/kg body weight for 6 hours in the absence or presence of isoflurane, and, in a second series, with or without the specific phosphoinositide 3-kinase/Akt inhibitor LY294002. Lung injury was determined by comparative histology, and by the isolation of bronchoalveolar lavage for differential cell counting and analysis of cytokine levels using enzyme-linked immunosorbent assays. Lung homogenates were analyzed for protein expression by Western blotting. RESULTS: Mechanical ventilation caused increases in alveolar wall thickening, cellular infiltration, and an elevated ventilator-induced lung injury score. Neutrophil influx and cytokine (i.e., interleukin-1ß, and macrophage inflammatory protein-2) release were enhanced in the bronchoalveolar lavage of ventilated mice. The expression levels of the stress proteins hemeoxygenase-1 and heat shock protein-70 were elevated in lung tissue homogenates. Isoflurane ventilation significantly reduced lung damage, inflammation, and stress protein expression. In contrast, phosphorylation of Akt protein was substantially increased during mechanical ventilation with isoflurane. Inhibition of phosphoinositide 3-kinase/Akt signaling before mechanical ventilation completely reversed the lung-protective effects of isoflurane treatment in vivo. CONCLUSIONS: Inhalation of isoflurane during mechanical ventilation protects against lung injury by preventing proinflammatory responses. This protection is mediated via phosphoinositide 3-kinase/Akt signaling.

Carbon monoxide in acute lung injury.

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.

Lophotrochozoan neuroanatomy: An analysis of the brain and nervous system of Lineus viridis(Nemertea) using different staining techniques.

BACKGROUND: The now thriving field of neurophylogeny that links the morphology of the nervous system to early evolutionary events relies heavily on detailed descriptions of the neuronal architecture of taxa under scrutiny. While recent accounts on the nervous system of a number of animal clades such as arthropods, annelids, and molluscs are abundant, in depth studies of the neuroanatomy of nemerteans are still wanting. In this study, we used different staining techniques and confocal laser scanning microscopy to reveal the architecture of the nervous system of Lineus viridis with high anatomical resolution. RESULTS: In L. viridis, the peripheral nervous system comprises four distinct but interconnected nerve plexus. The central nervous system consists of a pair of medullary cords and a brain. The brain surrounds the proboscis and is subdivided into four voluminous lobes and a ring of commissural tracts. The brain is well developed and contains thousands of neurons. It does not reveal compartmentalized neuropils found in other animal groups with elaborate cerebral ganglia. CONCLUSIONS: The detailed analysis of the nemertean nervous system presented in this study does not support any hypothesis on the phylogenetic position of Nemertea within Lophotrochozoa. Neuroanatomical characters that are described here are either common in other lophotrochozoan taxa or are seemingly restricted to nemerteans. Since detailed descriptions of the nervous system of adults in other nemertean species have not been available so far, this study may serve as a basis for future studies that might add data to the unsettled question of the nemertean ground pattern and the position of this taxon within the phylogenetic tree.

Major histocompatibility complex-dependent cytotoxic T lymphocyte repertoire and functional avidity contribute to strain-specific disease susceptibility after murine respiratory syncytial virus infection.

Susceptibility to respiratory syncytial virus (RSV) infection in mice is genetically determined. While RSV causes little pathology in C57BL/6 mice, pulmonary inflammation and weight loss occur in BALB/c mice. Using major histocompatibility complex (MHC)-congenic mice, we observed that the H-2(d) allele can partially transfer disease susceptibility to C57BL/6 mice. This was not explained by altered viral elimination or differences in the magnitude of the overall virus-specific cytotoxic T lymphocyte (CTL) response. However, H-2(d) mice showed a more focused response, with 70% of virus-specific CTL representing Vß8.2(+) CTL directed against the immunodominant epitope M2-1 82, while in H-2(b) mice only 20% of antiviral CTL were Vß9(+) CTL specific for the immunodominant epitope M187. The immunodominant H-2(d)-restricted CTL lysed target cells less efficiently than the immunodominant H-2(b) CTL, probably contributing to prolonged CTL stimulation and cytokine-mediated immunopathology. Accordingly, reduction of dominance of the M2-1 82-specific CTL population by introduction of an M187 response in the F1 generation of a C57BL/6N × C57BL/6-H-2(d) mating (C57BL/6-H-2(dxb) mice) attenuated disease. Moreover, disease in H-2(d) mice was less pronounced after infection with an RSV mutant failing to activate M2-1 82-specific CTL or after depletion of Vß8.2(+) cells. These data illustrate how the MHC-determined diversity and functional avidity of CTL responses contribute to disease susceptibility after viral infection.

Invertebrate neurophylogeny: suggested terms and definitions for a neuroanatomical glossary.

BACKGROUND: Invertebrate nervous systems are highly disparate between different taxa. This is reflected in the terminology used to describe them, which is very rich and often confusing. Even very general terms such as 'brain', 'nerve', and 'eye' have been used in various ways in the different animal groups, but no consensus on the exact meaning exists. This impedes our understanding of the architecture of the invertebrate nervous system in general and of evolutionary transformations of nervous system characters between different taxa. RESULTS: We provide a glossary of invertebrate neuroanatomical terms with a precise and consistent terminology, taxon-independent and free of homology assumptions. This terminology is intended to form a basis for new morphological descriptions. A total of 47 terms are defined. Each entry consists of a definition, discouraged terms, and a background/comment section. CONCLUSIONS: The use of our revised neuroanatomical terminology in any new descriptions of the anatomy of invertebrate nervous systems will improve the comparability of this organ system and its substructures between the various taxa, and finally even lead to better and more robust homology hypotheses.

Inhaled hydrogen sulfide protects against ventilator-induced lung injury.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.