Limits...
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.

Show MeSH

Related in: MedlinePlus

Impact of CO on pulmonary barrier permeability.A. Lung lavage fluid total protein concentration from untreated animals (no LPS or CO), or mice exposed to 0 or 100 ppm carbon monoxide (CO) for 6 hours after LPS instillation. *p<0.05 vs LPS +0 ppm CO; n = 8 for untreated animals and 15–16 for LPS treated groups. B. Lung lavage fluid total protein concentration from untreated animals or mice exposed to 0 or 100 ppm CO for 24 hours after LPS instillation. ***p<0.001 vs LPS +0 ppm CO; n = 7–8/group. C. Permeability was also assessed in both untreated mice (no LPS or CO) and animals receiving 100 ppm CO alone for 6 hours (no LPS) by determining translocation of a fluorescence-labelled albumin from plasma to alveolar space over a 1 hour period. Data are expressed as a ratio of fluorescence between lavage fluid and plasma. *p<0.05 vs untreated group; n = 6–7.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2903490&req=5

pone-0011565-g009: Impact of CO on pulmonary barrier permeability.A. Lung lavage fluid total protein concentration from untreated animals (no LPS or CO), or mice exposed to 0 or 100 ppm carbon monoxide (CO) for 6 hours after LPS instillation. *p<0.05 vs LPS +0 ppm CO; n = 8 for untreated animals and 15–16 for LPS treated groups. B. Lung lavage fluid total protein concentration from untreated animals or mice exposed to 0 or 100 ppm CO for 24 hours after LPS instillation. ***p<0.001 vs LPS +0 ppm CO; n = 7–8/group. C. Permeability was also assessed in both untreated mice (no LPS or CO) and animals receiving 100 ppm CO alone for 6 hours (no LPS) by determining translocation of a fluorescence-labelled albumin from plasma to alveolar space over a 1 hour period. Data are expressed as a ratio of fluorescence between lavage fluid and plasma. *p<0.05 vs untreated group; n = 6–7.

Mentions: To assess whether the attenuated pulmonary inflammation following CO exposure was associated with a corresponding improvement in pulmonary barrier permeability, we initially determined lavage fluid total protein concentration at 6 and 24 hours after LPS (fig. 9A, B). Lavage fluid protein was significantly increased at both time points after LPS compared to untreated control mice. Somewhat unexpectedly, mice exposed to 100 ppm CO for 24 hours after LPS showed a further increase in total protein. To clarify that this was an effect of CO on barrier dysfunction, permeability was directly assessed in animals exposed to CO alone (i.e. no LPS) for 6 hours. Permeability, in terms of the lavage fluid to plasma ratio of fluorescence-labelled albumin, was significantly enhanced by CO inhalation (fig. 9C).


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)

Impact of CO on pulmonary barrier permeability.A. Lung lavage fluid total protein concentration from untreated animals (no LPS or CO), or mice exposed to 0 or 100 ppm carbon monoxide (CO) for 6 hours after LPS instillation. *p<0.05 vs LPS +0 ppm CO; n = 8 for untreated animals and 15–16 for LPS treated groups. B. Lung lavage fluid total protein concentration from untreated animals or mice exposed to 0 or 100 ppm CO for 24 hours after LPS instillation. ***p<0.001 vs LPS +0 ppm CO; n = 7–8/group. C. Permeability was also assessed in both untreated mice (no LPS or CO) and animals receiving 100 ppm CO alone for 6 hours (no LPS) by determining translocation of a fluorescence-labelled albumin from plasma to alveolar space over a 1 hour period. Data are expressed as a ratio of fluorescence between lavage fluid and plasma. *p<0.05 vs untreated group; n = 6–7.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2903490&req=5

pone-0011565-g009: Impact of CO on pulmonary barrier permeability.A. Lung lavage fluid total protein concentration from untreated animals (no LPS or CO), or mice exposed to 0 or 100 ppm carbon monoxide (CO) for 6 hours after LPS instillation. *p<0.05 vs LPS +0 ppm CO; n = 8 for untreated animals and 15–16 for LPS treated groups. B. Lung lavage fluid total protein concentration from untreated animals or mice exposed to 0 or 100 ppm CO for 24 hours after LPS instillation. ***p<0.001 vs LPS +0 ppm CO; n = 7–8/group. C. Permeability was also assessed in both untreated mice (no LPS or CO) and animals receiving 100 ppm CO alone for 6 hours (no LPS) by determining translocation of a fluorescence-labelled albumin from plasma to alveolar space over a 1 hour period. Data are expressed as a ratio of fluorescence between lavage fluid and plasma. *p<0.05 vs untreated group; n = 6–7.
Mentions: To assess whether the attenuated pulmonary inflammation following CO exposure was associated with a corresponding improvement in pulmonary barrier permeability, we initially determined lavage fluid total protein concentration at 6 and 24 hours after LPS (fig. 9A, B). Lavage fluid protein was significantly increased at both time points after LPS compared to untreated control mice. Somewhat unexpectedly, mice exposed to 100 ppm CO for 24 hours after LPS showed a further increase in total protein. To clarify that this was an effect of CO on barrier dysfunction, permeability was directly assessed in animals exposed to CO alone (i.e. no LPS) for 6 hours. Permeability, in terms of the lavage fluid to plasma ratio of fluorescence-labelled albumin, was significantly enhanced by CO inhalation (fig. 9C).

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