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

Faller S, Zimmermann KK, Strosing KM, Engelstaedter H, Buerkle H, Schmidt R, Spassov SG, Hoetzel A - Med Gas Res (2012)

Bottom Line: The resulting lung damage can evoke lung failure and multiple organ dysfunction associated with increased mortality.The gas has been shown to mediate potent anti-inflammatory and organ protective effects in vivo.In addition, myeloperoxidase levels were increased in serum after LPS challenge and this was prevented by H2S inhalation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anesthesiology and Critical Care Medicine, University Medical Center Freiburg, Hugstetter Str, 55, D-79106, Freiburg, Germany. simone.faller@uniklinik-freiburg.de.

ABSTRACT

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-1β, 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.

No MeSH data available.


Related in: MedlinePlus

Effect of LPS and hydrogen sulfide inhalation on lung inflammation. As controls, mice received phosphate buffered saline (PBS, intranasally) and were kept in room air or in 80 ppm H2S for 6 h (plus 1 h pretreatment). LPS-treated mice (LPS treatment, i.n.) were either kept in room air or in 80 ppm H2S for 6 h (plus 1 h pretreatment). Bronchoalveolar lavage was performed in the right lung. The relative amount of neutrophils (A) was determined by cytospin analysis, and the amount of IL-1β (B) and MIP-2 (C) was determined by ELISA. Graphs represent means ± SEM, n = 8/group. ANOVA on Ranks (Dunn`s posthoc test), *P < 0.05 vs. PBS + air group; #P < 0.05 vs. PBS + H2S group; §P < 0.05 vs. LPS + H2S group.
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Figure 3: Effect of LPS and hydrogen sulfide inhalation on lung inflammation. As controls, mice received phosphate buffered saline (PBS, intranasally) and were kept in room air or in 80 ppm H2S for 6 h (plus 1 h pretreatment). LPS-treated mice (LPS treatment, i.n.) were either kept in room air or in 80 ppm H2S for 6 h (plus 1 h pretreatment). Bronchoalveolar lavage was performed in the right lung. The relative amount of neutrophils (A) was determined by cytospin analysis, and the amount of IL-1β (B) and MIP-2 (C) was determined by ELISA. Graphs represent means ± SEM, n = 8/group. ANOVA on Ranks (Dunn`s posthoc test), *P < 0.05 vs. PBS + air group; #P < 0.05 vs. PBS + H2S group; §P < 0.05 vs. LPS + H2S group.

Mentions: We next investigated whether the observed H2S-mediated lung-protection was attributed to inhibition of LPS-induced inflammation. The development of lung damage in pulmonary sepsis is known to be critically dependent on the initiation of an inflammatory response, mainly characterized by neutrophil transmigration and activation and pro-inflammatory cytokine release [21,25]. Neutrophil sequestration into the bronchoalveolar space was markedly increased by LPS application as compared to the control (Figure 3A). H2S administration in LPS treated mice substantially reduced neutrophil numbers to control levels. Our data are in line with recent publications, where pulmonary neutrophil activity was found to be largely decreased in mice or rats, that had been protected from LPS-induced systemic inflammation both by inhaled H2S [23] as well as by application of the slowly releasing H2S donors S-diclofenac and GYY4137 [25,26]. The findings of these trials clearly support the notion that exogenous H2S can inhibit pro-inflammatory processes. In combination with neutrophil transmigration, the release of pro-inflammatory cytokines, e.g., IL-1β and MIP-2, is known to aggravate lung injury [21,25]. In our study, quantitative analysis of IL-1β in the BAL revealed that it was nearly absent in both control groups (PBS + air and PBS + H2S), whereas LPS instillation alone led to a vast increase of IL-1β readings (Figure 3B). In sharp contrast, H2S inhalation reduced IL-1β to control levels. Likewise, LPS treatment increased MIP-2 protein that was partially prevented by H2S (Figure 3C). The attenuation of neutrophil transmigration and pro-inflammatory cytokine release by administration of H2S has also been shown in other models of ALI, e.g., ventilator-induced lung injury [7], oleic acid-induced lung injury [9,10], caerulein-induced acute pancreatitis [27], or myocardial ischemia/reperfusion injury [28], strongly supporting our findings that gaseous H2S substantially inhibits pulmonary inflammation and thereby limits LPS-induced lung damage. Future studies using different ALI models might discover the regulatory role of H2S in each single aspect of human ALI / ARDS in order to define H2S` therapeutic potential.


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

Faller S, Zimmermann KK, Strosing KM, Engelstaedter H, Buerkle H, Schmidt R, Spassov SG, Hoetzel A - Med Gas Res (2012)

Effect of LPS and hydrogen sulfide inhalation on lung inflammation. As controls, mice received phosphate buffered saline (PBS, intranasally) and were kept in room air or in 80 ppm H2S for 6 h (plus 1 h pretreatment). LPS-treated mice (LPS treatment, i.n.) were either kept in room air or in 80 ppm H2S for 6 h (plus 1 h pretreatment). Bronchoalveolar lavage was performed in the right lung. The relative amount of neutrophils (A) was determined by cytospin analysis, and the amount of IL-1β (B) and MIP-2 (C) was determined by ELISA. Graphs represent means ± SEM, n = 8/group. ANOVA on Ranks (Dunn`s posthoc test), *P < 0.05 vs. PBS + air group; #P < 0.05 vs. PBS + H2S group; §P < 0.05 vs. LPS + H2S group.
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Figure 3: Effect of LPS and hydrogen sulfide inhalation on lung inflammation. As controls, mice received phosphate buffered saline (PBS, intranasally) and were kept in room air or in 80 ppm H2S for 6 h (plus 1 h pretreatment). LPS-treated mice (LPS treatment, i.n.) were either kept in room air or in 80 ppm H2S for 6 h (plus 1 h pretreatment). Bronchoalveolar lavage was performed in the right lung. The relative amount of neutrophils (A) was determined by cytospin analysis, and the amount of IL-1β (B) and MIP-2 (C) was determined by ELISA. Graphs represent means ± SEM, n = 8/group. ANOVA on Ranks (Dunn`s posthoc test), *P < 0.05 vs. PBS + air group; #P < 0.05 vs. PBS + H2S group; §P < 0.05 vs. LPS + H2S group.
Mentions: We next investigated whether the observed H2S-mediated lung-protection was attributed to inhibition of LPS-induced inflammation. The development of lung damage in pulmonary sepsis is known to be critically dependent on the initiation of an inflammatory response, mainly characterized by neutrophil transmigration and activation and pro-inflammatory cytokine release [21,25]. Neutrophil sequestration into the bronchoalveolar space was markedly increased by LPS application as compared to the control (Figure 3A). H2S administration in LPS treated mice substantially reduced neutrophil numbers to control levels. Our data are in line with recent publications, where pulmonary neutrophil activity was found to be largely decreased in mice or rats, that had been protected from LPS-induced systemic inflammation both by inhaled H2S [23] as well as by application of the slowly releasing H2S donors S-diclofenac and GYY4137 [25,26]. The findings of these trials clearly support the notion that exogenous H2S can inhibit pro-inflammatory processes. In combination with neutrophil transmigration, the release of pro-inflammatory cytokines, e.g., IL-1β and MIP-2, is known to aggravate lung injury [21,25]. In our study, quantitative analysis of IL-1β in the BAL revealed that it was nearly absent in both control groups (PBS + air and PBS + H2S), whereas LPS instillation alone led to a vast increase of IL-1β readings (Figure 3B). In sharp contrast, H2S inhalation reduced IL-1β to control levels. Likewise, LPS treatment increased MIP-2 protein that was partially prevented by H2S (Figure 3C). The attenuation of neutrophil transmigration and pro-inflammatory cytokine release by administration of H2S has also been shown in other models of ALI, e.g., ventilator-induced lung injury [7], oleic acid-induced lung injury [9,10], caerulein-induced acute pancreatitis [27], or myocardial ischemia/reperfusion injury [28], strongly supporting our findings that gaseous H2S substantially inhibits pulmonary inflammation and thereby limits LPS-induced lung damage. Future studies using different ALI models might discover the regulatory role of H2S in each single aspect of human ALI / ARDS in order to define H2S` therapeutic potential.

Bottom Line: The resulting lung damage can evoke lung failure and multiple organ dysfunction associated with increased mortality.The gas has been shown to mediate potent anti-inflammatory and organ protective effects in vivo.In addition, myeloperoxidase levels were increased in serum after LPS challenge and this was prevented by H2S inhalation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anesthesiology and Critical Care Medicine, University Medical Center Freiburg, Hugstetter Str, 55, D-79106, Freiburg, Germany. simone.faller@uniklinik-freiburg.de.

ABSTRACT

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-1β, 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.

No MeSH data available.


Related in: MedlinePlus