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Efficacy and safety of inhaled carbon monoxide during pulmonary inflammation in mice.

Wilson MR, O'Dea KP, Dorr AD, Yamamoto H, Goddard ME, Takata M - PLoS ONE (2010)

Bottom Line: Here we investigate the efficacy, safety and mechanism of action of low dose inhaled carbon monoxide (CO) using a mouse model of lipopolysaccharide (LPS)-induced pulmonary inflammation.In contrast to such apparently beneficial effects, 100 ppm inhaled CO induced an increase in pulmonary barrier permeability as determined by lavage fluid protein content and translocation of labelled albumin from blood to the alveolar space.Overall, these data confirm some protective role for inhaled CO during pulmonary inflammation, although this required a dose that produced carboxyhemoglobin values close to potentially toxic levels for humans, and increased lung permeability.

View Article: PubMed Central - PubMed

Affiliation: Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, Chelsea and Westminster Hospital, London, UK. michael.wilson@imperial.ac.uk

ABSTRACT

Background: Pulmonary inflammation is a major contributor to morbidity in a variety of respiratory disorders, but treatment options are limited. Here we investigate the efficacy, safety and mechanism of action of low dose inhaled carbon monoxide (CO) using a mouse model of lipopolysaccharide (LPS)-induced pulmonary inflammation.

Methodology: Mice were exposed to 0-500 ppm inhaled CO for periods of up to 24 hours prior to and following intratracheal instillation of 10 ng LPS. Animals were sacrificed and assessed for intraalveolar neutrophil influx and cytokine levels, flow cytometric determination of neutrophil number and activation in blood, lung and lavage fluid samples, or neutrophil mobilisation from bone marrow.

Principal findings: When administered for 24 hours both before and after LPS, inhaled CO of 100 ppm or more reduced intraalveolar neutrophil infiltration by 40-50%, although doses above 100 ppm were associated with either high carboxyhemoglobin, weight loss or reduced physical activity. This anti-inflammatory effect of CO did not require pre-exposure before induction of injury. 100 ppm CO exposure attenuated neutrophil sequestration within the pulmonary vasculature as well as LPS-induced neutrophilia at 6 hours after LPS, likely due to abrogation of neutrophil mobilisation from bone marrow. In contrast to such apparently beneficial effects, 100 ppm inhaled CO induced an increase in pulmonary barrier permeability as determined by lavage fluid protein content and translocation of labelled albumin from blood to the alveolar space.

Conclusions: Overall, these data confirm some protective role for inhaled CO during pulmonary inflammation, although this required a dose that produced carboxyhemoglobin values close to potentially toxic levels for humans, and increased lung permeability.

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Related in: MedlinePlus

Lavage fluid cytokine concentrations 6 hours after LPS challenge.Concentration of cytokines IL-6 (A), MIP-2 (B), and KC (C) in lung lavage fluid of untreated mice (no LPS or CO), and mice exposed to 0 or 100 ppm carbon monoxide (CO) for 6 hours after LPS instillation. *p<0.05, **p<0.01 ***p<0.001 vs LPS +0 ppm CO; n = 7–8/group for IL-6 and MIP-2; n = 14–15/group for KC.
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pone-0011565-g005: Lavage fluid cytokine concentrations 6 hours after LPS challenge.Concentration of cytokines IL-6 (A), MIP-2 (B), and KC (C) in lung lavage fluid of untreated mice (no LPS or CO), and mice exposed to 0 or 100 ppm carbon monoxide (CO) for 6 hours after LPS instillation. *p<0.05, **p<0.01 ***p<0.001 vs LPS +0 ppm CO; n = 7–8/group for IL-6 and MIP-2; n = 14–15/group for KC.

Mentions: To examine whether the observed decrease in neutrophil infiltration into the alveolar space following inhaled CO was related to local production of inflammatory mediators, levels of the proinflammatory cytokines IL-6 and MIP-2, and the anti-inflammatory cytokine IL-10 were assessed in lavage fluid of mice exposed to 100 ppm CO for 24 hours after LPS instillation. The level of each of these mediators, with or without CO, was effectively negligible, suggesting that inflammatory mediator response within the alveoli had passed its peak and already returned to baseline by this point in the model. We therefore studied lavage fluid levels of cytokines in mice exposed to 100 ppm CO at 6 hours after LPS instillation. At this earlier time point in the progression of pulmonary inflammation, much higher levels of the proinflammatory mediators (including the addition of KC) were detected, although IL-10 levels were again negligible. There was however no effect of CO exposure on any of the mediators studied (fig. 5).


Efficacy and safety of inhaled carbon monoxide during pulmonary inflammation in mice.

Wilson MR, O'Dea KP, Dorr AD, Yamamoto H, Goddard ME, Takata M - PLoS ONE (2010)

Lavage fluid cytokine concentrations 6 hours after LPS challenge.Concentration of cytokines IL-6 (A), MIP-2 (B), and KC (C) in lung lavage fluid of untreated mice (no LPS or CO), and mice exposed to 0 or 100 ppm carbon monoxide (CO) for 6 hours after LPS instillation. *p<0.05, **p<0.01 ***p<0.001 vs LPS +0 ppm CO; n = 7–8/group for IL-6 and MIP-2; n = 14–15/group for KC.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2903490&req=5

pone-0011565-g005: Lavage fluid cytokine concentrations 6 hours after LPS challenge.Concentration of cytokines IL-6 (A), MIP-2 (B), and KC (C) in lung lavage fluid of untreated mice (no LPS or CO), and mice exposed to 0 or 100 ppm carbon monoxide (CO) for 6 hours after LPS instillation. *p<0.05, **p<0.01 ***p<0.001 vs LPS +0 ppm CO; n = 7–8/group for IL-6 and MIP-2; n = 14–15/group for KC.
Mentions: To examine whether the observed decrease in neutrophil infiltration into the alveolar space following inhaled CO was related to local production of inflammatory mediators, levels of the proinflammatory cytokines IL-6 and MIP-2, and the anti-inflammatory cytokine IL-10 were assessed in lavage fluid of mice exposed to 100 ppm CO for 24 hours after LPS instillation. The level of each of these mediators, with or without CO, was effectively negligible, suggesting that inflammatory mediator response within the alveoli had passed its peak and already returned to baseline by this point in the model. We therefore studied lavage fluid levels of cytokines in mice exposed to 100 ppm CO at 6 hours after LPS instillation. At this earlier time point in the progression of pulmonary inflammation, much higher levels of the proinflammatory mediators (including the addition of KC) were detected, although IL-10 levels were again negligible. There was however no effect of CO exposure on any of the mediators studied (fig. 5).

Bottom Line: Here we investigate the efficacy, safety and mechanism of action of low dose inhaled carbon monoxide (CO) using a mouse model of lipopolysaccharide (LPS)-induced pulmonary inflammation.In contrast to such apparently beneficial effects, 100 ppm inhaled CO induced an increase in pulmonary barrier permeability as determined by lavage fluid protein content and translocation of labelled albumin from blood to the alveolar space.Overall, these data confirm some protective role for inhaled CO during pulmonary inflammation, although this required a dose that produced carboxyhemoglobin values close to potentially toxic levels for humans, and increased lung permeability.

View Article: PubMed Central - PubMed

Affiliation: Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, Chelsea and Westminster Hospital, London, UK. michael.wilson@imperial.ac.uk

ABSTRACT

Background: Pulmonary inflammation is a major contributor to morbidity in a variety of respiratory disorders, but treatment options are limited. Here we investigate the efficacy, safety and mechanism of action of low dose inhaled carbon monoxide (CO) using a mouse model of lipopolysaccharide (LPS)-induced pulmonary inflammation.

Methodology: Mice were exposed to 0-500 ppm inhaled CO for periods of up to 24 hours prior to and following intratracheal instillation of 10 ng LPS. Animals were sacrificed and assessed for intraalveolar neutrophil influx and cytokine levels, flow cytometric determination of neutrophil number and activation in blood, lung and lavage fluid samples, or neutrophil mobilisation from bone marrow.

Principal findings: When administered for 24 hours both before and after LPS, inhaled CO of 100 ppm or more reduced intraalveolar neutrophil infiltration by 40-50%, although doses above 100 ppm were associated with either high carboxyhemoglobin, weight loss or reduced physical activity. This anti-inflammatory effect of CO did not require pre-exposure before induction of injury. 100 ppm CO exposure attenuated neutrophil sequestration within the pulmonary vasculature as well as LPS-induced neutrophilia at 6 hours after LPS, likely due to abrogation of neutrophil mobilisation from bone marrow. In contrast to such apparently beneficial effects, 100 ppm inhaled CO induced an increase in pulmonary barrier permeability as determined by lavage fluid protein content and translocation of labelled albumin from blood to the alveolar space.

Conclusions: Overall, these data confirm some protective role for inhaled CO during pulmonary inflammation, although this required a dose that produced carboxyhemoglobin values close to potentially toxic levels for humans, and increased lung permeability.

Show MeSH
Related in: MedlinePlus