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Hal HAWKINS‡, Csaba SZABO†§ and Daniel L. TRABER. ∗. ∗. Department of .... Health. Female C57BL/6 mice, weighing 20–26 g (4–6 weeks of age), were ..... 12 Miskolci, V., Rollins, J., Vu, H. Y., Ghosh, C. C., Davidson,. D. and Vancurova ...

Clinical Science (2008) 115, 91–97 (Printed in Great Britain) doi:10.1042/CS20080021

A C C E L E R A T E D P U B L I C A T I O N

Protective effect of hydrogen sulfide in a murine model of acute lung injury induced by combined burn and smoke inhalation ´ Aimalohi ESECHIE∗ , Levente KISS†, Gabor OLAH†, Eszter M. HORVATH†, ∗ Hal HAWKINS‡, Csaba SZABO†§ and Daniel L. TRABER  ∗

Department of Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston, TX 77555, U.S.A., †Department of Surgery, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, U.S.A., ‡Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77555, U.S.A., §Ikaria Inc., Seattle, WA 98102, U.S.A., and Department of Anesthesiology and Intensive Care Unit, The University of Texas Medical Branch, Galveston, TX 77555, U.S.A.

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Acute lung injury results in a severe inflammatory response, which leads to priming and activation of leucocytes, release of reactive oxygen and reactive nitrogen species, destruction of pulmonary endothelium, extravasation of protein-rich fluid into the interstitium and formation of oedema. Recently, H2 S (hydrogen sulfide) has been shown to decrease the synthesis of pro-inflammatory cytokines, reduce leucocyte adherence to the endothelium and subsequent diapedesis of these cells from the microvasculature in in vivo studies, and to protect cells in culture from oxidative injury. In the present study, we hypothesized that a parenteral formulation of H2 S would reduce the lung injury induced by burn and smoke inhalation in a novel murine model. H2 S post-treatment significantly decreased mortality and increased median survival in mice. H2 S also inhibited IL (interleukin)-1β levels and significantly increased the concentration of the anti-inflammatory cytokine IL-10 in lung tissue. Additionally, H2 S administration attenuated protein oxidation following injury and improved the histological condition of the lung. In conclusion, these results suggest that H2 S exerts protective effects in acute lung injury, at least in part through the activation of anti-inflammatory and antioxidant pathways.

INTRODUCTION H2 S (hydrogen sulfide) is produced endogenously via the catalytic conversion of l-cysteine by two enzymes: CBS (cystathionine β-synthase) and CSE (cystathionine γ -lyase) [1]. Although both enzymes are required for H2 S synthesis in some tissues, CBS acts mainly in the hippocampal and cerebellar regions of the brain [2], whereas CSE is thought to be the primary enzymatic source of H2 S in the ileum [3], liver [2], vasculature

and heart [4]. Recent studies have demonstrated the anti-inflammatory and cytoprotective effects of H2 S [5]. For instance, in a study using human neuroblastoma cells, Whiteman et al. [6] reported on the ONOO− (peroxynitrite)-scavenging capabilities of H2 S, thereby decreasing intracellular tyrosine nitration as well as attenuating oxidative stress. Other groups have shown that H2 S modulates leucocyte–vascular endothelium interactions in vivo [7,8], as inhibition of CSE resulted in enhanced leucocyte adhesion and infiltration.

Key words: acute lung injury, burn and smoke inhalation, hydrogen sulfide, inflammation, interleukin-10, protein carbonylation. Abbreviations: ALI, acute lung injury; B + S, burn and smoke inhalation; CBS, cystathionine β-synthase; CSE, cystathionine γ -lyase; DNPH, 2,4-dinitrophenylhydrazine; H&E, haematoxylin and eosin; H2 S, hydrogen sulfide; IL, interleukin; LPS, lipopolysaccharide; NF-κB, nuclear factor κB; ONOO− , peroxynitrite; ROS, reactive oxygen species; s.c., subcutaneously; TBSA, total body surface area. Correspondence: Professor Daniel L. Traber (email [email protected]).  C

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Findings also suggests that H2 S may modulate cell viability. For example, significant increases in cell viability were observed in murine macrophages pretreated with H2 S and subjected to ONOO− -induced nitrosative stress [9]. Additionally, cytotoxcity was attenuated in LPS (lipopolysaccharide)-stimulated murine macrophages when they were pre-treated with H2 S. The cytoprotective effects in this case were linked to attenuated NF-κB (nuclear factor κB) activation and subsequent nuclear translocation, and decreased NF-κB-dependent gene transcription, such as iNOS (inducible nitric oxide synthase) [10]. ALI (acute lung injury) stems from a severe inflammatory response to toxic compounds such as inhaled smoke. The accumulation of inflammatory cells, such as activated neutrophils, lymphocytes and macrophages, in the lung is one of the hallmarks of ALI and results in severe tissue damage, leading to impaired pulmonary function [11]. Oxidative stress resulting from the presence of inflammatory cells contributes largely to the overall pathophysiology of ALI, causing the synthesis and secretion of inflammatory mediators, such as IL (interleukin)1α, IL-8 [12,13] and OONO− [14,15], which, in turn, may activate other pro-inflammatory signalling pathways and increase synthesis of adhesion molecules. Although the mechanisms by which H2 S functions in preventing inflammatory cell injury are incompletely understood, Zanardo et al. [8] have demonstrated that, in the presence of excess l-cysteine, the precursor of the enzymatic synthesis of H2 S, there was not only a decrease in leucocyte infiltration after an inflammatory stimulus, but there was also a decrease in paw oedema formation as a result of decreased vascular permeability. The aim of the present study was to investigate the effect of parenteral administration of an H2 S donor on B + S (burn and smoke inhalation)-induced ALI. We demonstrate that H2 S markedly improves survival in this model, and that this effect is coupled with (i) a down-regulation in IL-1β levels in the lung, (ii) an up-regulation of IL-10, a prototypical anti-inflammatory cytokine, (iii) attenuated protein oxidation, and (iv) improved lung histology.

MATERIALS AND METHODS H2 S donor Sodium sulfide was produced and formulated to pH neutrality and iso-osmolarity by Ikaria Inc. using H2 S gas (Matheson) as a starting material [16]. The H2 S formulation was diluted in normal saline to the desired concentration and used immediately thereafter. All doses were freshly made daily in a rapid fashion and sealed in sterile airtight tubes until use.

Galveston, TX, U.S.A. All the animals were handled according to the guidelines established by the American Physiology Society and the National Institutes of Health. Female C57BL/6 mice, weighing 20–26 g (4–6 weeks of age), were purchased from The Jackson Laboratory. The animals were anaesthetized using 4 % vaporized isoflurane in air in a chamber, and were intubated using a custom-made endotracheal tube (modified from a 20-gauge angiocatheter; (Baxter), allowed to breathe spontaneously under 2 % isoflurane in air. The backs and flanks of the animals were shaved and 1.0 ml of 0.9 % saline was injected s.c. (subcutaneously) to prevent deep tissue injury and spinal cord injury by flame burn under anaesthesia. The mice were randomized to three groups: (i) a sham group that received no injury, (ii) a combined B + S injury group that received both the burn [40 % TBSA (total body surface area) third-degree burn] and the smoke inhalation injury (two 30 s exposures of cool cotton smoke), and (iii) a B + S injury group treated with a sodium sulfide solution (2 mg/kg of body weight, s.c.).

B + S injury The anaesthetized mice were covered with a Zetex cloth containing a rectangular opening corresponding to 40 % of the mouse TBSA. A full-thickness flame burn was achieved by a Bunsen burner applied to exposed skin for approx. 10 s. Full-thickness injury was confirmed by loss of colouration and lack of bleeding on incision. Smoke inhalation was induced with a hand-made smoker device designed and constructed in our laboratory. The smoker, connected to tubing that provided a constant flow of air, was filled with 20 g of burning cotton towelling and then attached to the custom-made endotracheal tube via a T connection. A copper condenser coil was placed between the smoker and the endotracheal tube to cool down the hot smoke flow. Two sets of 30 s exposure of the cool cotton smoke were delivered. The animals were allowed to awaken after they were extubated and anaesthesia was discontinued. The animals were either given the vehicle or sodium sulfide (2 mg/kg of body weight, s.c.) and were resuscitated with 0.9 % saline s.c. (100 ml/kg of body weight) immediately after injury, followed by an additional injection of saline (50 ml/kg of body weight) every 24 h during the remainder of the study period. Buprenorphine (2 mg/kg of body weight, s.c.) was given for analgesia in all animals every 24 h. The animals were then returned to their cages and allowed free access to food and water.

Mortality study Animal model The study was approved by the Animal Care and Use Committee of the University Texas Medical Branch,  C

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Mice in all groups (n = 12) were observed every 12 h for 120 h after the injury. No other parameters were measured in these mice.

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ELISA In a separate set of experiments, 18 mice were studied for 12 h after injury. Lung samples from the groups (sham, B + S control and B + S + treatment; n = 6 in each group) were collected and frozen immediately in liquid nitrogen. The tissue was homogenized using Tissue-Tearor (BioSpec Products) in 30 s bursts on ice and the homogenate was centrifuged at 2655 g for 30 min at 4 ◦ C. The supernatant was collected, and ELISA kits (R&D Systems) were used to quantify IL-10 and IL-1β following the manufacturer’s instructions. The Bradford assay (BioRad Laboratories) was used to measure protein content in the homogenate.

OxyBlotTM detection of protein carbonylation Lung samples were homogenized in 10 vols of homogenization buffer [50 mmol/l Tris/HCl (pH 7.4), 1 mmol/l EDTA, 1 % (v/v) Nonidet P40, 150 mmol/l NaCl, 0.25 % sodium deoxycholate and 1:100 dilution of Protease Inhibitor Cocktail (Sigma–Aldrich)]. The protein concentration in the samples was determined by the Bradford assay with BSA as a standard. For detection of protein oxidation, an OxyBlotTM kit (Millipore) was used. The carbonyl groups in proteins were first derivatized with DNPH (2,4-dinitrophenylhydrazine) in the presence of 6 % (w/v) SDS. The kit used is sensitive to detect as little as 10 fmols of dinitrophenyl residues. To determine the specificity, the oxidized proteins provided by the kit were included as a positive control. Treatment of samples with a control solution served as a negative control for the DNPH treatment. The reaction was stopped after incubation for 15 min at room temperature (21 ◦ C).

Western blotting and quantification Samples were loaded on to 4–12 % gradient NuPAGE Novex Bis-Tris SDS/PAGE gels (Invitrogen) and run for 60 min at 200 V. Following electroblotting of proteins on to 0.2 μm nitrocellulose for 1 h at 100 V, the membrane was blocked and stained using OxyBlotTM kit reagents, according to the manufacturer’s instructions. Bands were visualized with chemiluminescence and captured on film. The total protein carbonylated was measured by reviewing all of the bands in each sample by densitometry. Densitometry was performed on scanned films using an Alpha ImagerTM 3400 system with AlphaEaseFCTM software. To quantify the amount of oxidation and to allow the comparison between the various samples, the oxidative index was defined as the ratio between densitometric values of the total OxyBlotTM bands and those stained for actin.

Figure 1 Effect of H2 S treatment on mortality after injury

Both groups received 40 % third-degree burn followed by cotton smoke inhalation injury. Compared with the untreated control animals (solid line), treatment with the H2 S (2 mg/kg of body weight) significantly increased median survival (22 h in the control group compared with 76 h in the H2 S treatment group; ∗ P = 0.0248). Animals were observed every 12 h for 120 h. Results were analysed using the Mantel–Haenszel test. Experiments were repeated at least twice. were paraffin-embedded, sectioned at a thickness of 5 μm and stained with H&E (haematoxylin and eosin). Masked slides were examined by two observers, and the patterns of morphological changes were determined by a pathologist who was blinded to the treatment protocol.

Statistical analysis Results was analysed using GraphPad Prism version 4, and values are presented as means + − S.E.M. The survival curve was analysed using the Mantel–Haenszel test. Other results were compared using ANOVA with a post-hoc Tukey test. A value of P < 0.05 was considered significant.

RESULTS Mortality Study Figure 1 shows the results of experiments on the survival rate of mice after being subjected to B + S injury. All animals in the sham group survived for 120 h (results not shown). Animals in the control group received saline vehicle alone and the observed median survival was 22 h after injury. After the first 24 h, only 33.3 % of the control animals were alive. There was a significant increase in median survival (75 h) in the mice that received H2 S treatment (2 mg/kg of body weight, s.c.) after injury (P < 0.05). In the same group, eight out of 12 of the animals were alive during the first 24 h.

Lung histological assessment

H2 S attenuates the concentration of the pro-inflammatory cytokine IL-1β in lung tissue

Lung samples were fixed by complete immersion in 10 % (v/v) formalin for 3–5 days. Following fixation, samples

Table 1 shows the results from experiments using lung tissue to quantify IL-1β concentrations after B + S  C

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Table 1 Changes in IL-1β and IL-10 concentrations in lung tissue following B + S injury

Results are means + − S.E.M. for all groups of mice. The sham group did not receive any injury; the control group received B + S injury and were given saline vehicle; the H2 S treatment group were given the H2 S donor compound diluted in saline after being subjected to B + S injury. Experiments were repeated at least twice. ∗ P < 0.05 compared with the control group. Cytokine Group

IL-1β (pg/ml)

IL-10 (pg/ml)

Sham Control H2 S treatment

124 + − 27 187 + − 35 ∗ 88 + − 14

232 + − 69 238 + − 47 ∗ 480 + − 48

injury. At 12 h after injury, the H2 S donor compound significantly decreased the level of the pro-inflammatory cytokine in the lung by 50 % when compared with the control animals (P < 0.05).

Treatment with H2 S increases the concentration of IL-10 in lung tissue Following B + S injury and saline vehicle treatment, the IL-10 concentration was unaffected compared with the sham group (Table 1). However, there was a 2fold increase in IL-10 concentration in the lung after injury and treatment with the H2 S donor compound compared with both sham and B + S-injured animals (P < 0.05).

H2 S attenuates oxidative stress following B + S injury

B + S injury significantly increased the presence of protein carbonyl formation in the lung, whereas administration of H2 S reversed this effect and decreased protein carbonyl formation, indicative of an overall antioxidant effect (Figure 2).

Lung histology Animals in the control group that received B + S injury and saline vehicle had a pattern of increased epithelial disorganization, increased presence of airway exudates and oedema, whereas treatment with the H2 S donor significantly attenuated this lung injury (Figure 3), as shown by the histology score (1.0 + − 0.10 in S treatment; controls compared with 0.71 + 0.08 with H 2 − P < 0.05).

DISCUSSION The present study has examined the effect of parenteral administration of an H2 S donor in a murine model of B + S-induced ALI. As demonstrated in the present and previous studies [17,18], B + S resulted in increased  C

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Figure 2 Effect of H2 S treatment on the formation of protein carbonyl following B + S injury

(A) Representative Western blots of lung homogenate using rabbit anti-DNP (dinitrophenol) after protein derivatization with DNPH. Each lane represents samples obtained from separate animals in each group. Arrows indicate protein molecular masses. (B) Quantification of the densitometric analysis of the expressed protein carbonyl bands. Results are means + − S.E.M for all groups of mice. The change in immunoreactivity was expressed by comparing the integrated intensities obtained with at least five different samples from each group. ∗ P < 0.05 compared with the control group.

mortality and synthesis of pro-inflammatory cytokines. However, treatment with H2 S improved mortality and decreased the lung tissue concentration of IL-1β, while the anti-inflammatory cytokine IL-10 was up-regulated. Additionally, we have demonstrated that protein oxidation due to B + S injury is increased markedly and this effect is attenuated by H2 S administration. H2 S has been shown previously to exert a cytoprotective effect in several animal models of inflammation and to trigger the production of anti-inflammatory molecules [8,19,20]. In the present study, we found that mice exposed to B + S injury had early and high mortality, whereas H2 S treatment significantly improved mortality. Relevant to our findings may be a study where H2 S was shown to ‘scavenge’ ONOO− , decrease cytotoxicity and improve cell viability in a manner comparable with GSH, a known inhibitor of ONOO− [6]. H2 S supplementation has also been shown to potentiate cellular GSH + GSSG levels [21]. Additionally, on exposure to H2 S, LPSstimulated murine macrophages have been shown

Hydrogen sulfide in acute lung injury

Figure 3 Representative light micrographs of H&E-stained lung sections from the control (A) and H2 S treatment (B) groups

to not only decrease cytotoxicity, but also inhibit transcriptional activity [10]. In light of this, it is possible that exogenous H2 S exerts its protective effects through de novo synthesis of cytoprotective proteins and/or through activation of anti-inflammatory pathways. Understanding the mechanism by which H2 S regulates key cytokines in the presence of ALI is considerably important, as increased synthesis and secretion of inflammatory mediators is thought to contribute to the overall pathology of the injury. In large animal studies, it has been reported previously that B + S injury triggers the transcriptional activation of several inflammatory genes, which led to increased cellular levels of ROS (reactive oxygen species) and reactive nitrogen species, and a large numbers of inflammatory mediators such as cytokines, chemokines and enzymes [22,23]. In particular, extensive lung parenchymal damage was observed in animals subjected to smoke inhalation. In our present study, mice were insufflated with cooled cotton smoke in order to minimize upper airway injury, thus mimicking the injury observed in human victims of house fires. Impaired oxygenation, as evidenced by attenuated Pao2 /Fio2 (partial pressure of arterial oxygen/fraction of inspired oxygen) ratios, is characteristic of this injury [24]. A marked decrease in the pro-inflammatory cytokine IL-1β occurred in lung tissue of H2 S-treated mice after B + S injury, suggesting the efficacy of H2 S in regulating neutrophil diapedesis and gene expression of adhesion proteins. A recent study [20] has demonstrated similar findings in that slow release of H2 S from a

donor compound decreased inflammatory damage to the lung associated with LPS stimulation. In addition, the same H2 S donor formulation used in the present study has recently been shown to decrease myocardial IL-1β levels in the heart after myocardial ischaemia and reperfusion in a murine model in vivo [16]. Although the mechanistic details of how H2 S attenuates IL-1β is currently unknown, it will be interesting to investigate in future studies how various concentrations of H2 S in vivo alter the proteolytic cleavage of IL-1β from its ‘pro-form’ and, therefore, activity. The tissue concentration of IL-10 was dramatically increased in mice treated with H2 S compared with the untreated group. Although IL-10 signalling is less well understood it is, however, widely accepted that it can inhibit immune function by suppressing adhesion molecules, inflammatory cells, such as macrophages and neutrophils, as well as pro-inflammatory mediators that are transcriptionally controlled by NF-κB [25]. It is therefore plausible that H2 S controls a central ‘switch’ in the inflammatory pathways which are simultaneously responsible for both the down-regulation of IL-1β and the up-regulation of IL-10. A similar pattern of response has been reported previously with a number of anti-inflammatory agents, including glucocorticoids, β-receptor agonists [26] and anti-inflammatory adenosine receptor ligands [27]. The generation of ROS is a consistent observation following smoke inhalation injury [28,29]. Because of the potential for ROS, such as hydroxyl radicals, to induce significant damage in vivo, cells and tissues possess antioxidant systems to scavenge and eliminate ROS. However, in ALI, this system is significantly overwhelmed by ROS-generating cells to the extent that antioxidants, such as GSH, are decreased in the lung [30]. Oxidative stress ensues and can lead to a state of altered cellular metabolism [31] or disruption of relevant function and systems. The physiological consequences of oxidative modification is seen where the protease–antiprotease system may become imbalanced or lung function compromised by surfactant or mucous dysfunction. The extent of pulmonary protein oxidation in patients with ARDS (acute respiratory distress syndrome) has been shown to be five times the level of oxidized proteins in control patients [30]. In the present study, we demonstrated that the H2 S donor compound is able to rescue smokeexposed lungs from oxidative stress by decreasing protein oxidation and, thereby, improving survival. Histological changes in mice that underwent smoke exposure without treatment had deterioration of airway epithelial organization. Previous studies by Abdi et al. [32] and Hubbard et al. [33] have demonstrated significant sloughing of airway epithelium as early as 15 min after smoke insufflation and increased mucus production by 12 h. In the sham animals, there was evidence of damage due to intubation; however, the treated groups had a markedly  C

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lower mean histology score, thus supporting our finding of the cytoprotective effect of H2 S in lung tissue after smoke exposure. In summary, these findings in the present study demonstrate the H2 S exerts a protective effect in B + Sinduced lung injury by attenuating the tissue concentration of pro-inflammatory cytokine and up-regulating anti-inflammatory cytokines. To our knowledge, this is the first study to demonstrate the protective effects of H2 S in trauma-induced ALI. The present study, in combination with an emerging body of results ([7,8,16,34,35]; and overviewed in [5]), indicates that H2 S-releasing compounds may represent a novel pharmacological intervention in the treatment of critical illness.

ACKNOWLEDGMENTS This study was supported by a grant from Shriners of North America SBI 8450, and by a grant from Ikaria Inc. We thank Mr Paul Hill (Ikaria, Seattle, WA, U.S.A.) for formulating the H2 S donor compound used in the present study, and Dr Don Deyo for the design and construction of the smoker device.

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Received 18 January 2008/12 February 2008; accepted 3 March 2008 Published as Immediate Publication 3 March 2008, doi:10.1042/CS20080021

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