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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

Neutrophil adhesion molecule expression, determined by flow cytometry.Surface expression of L-selectin (A–C) and CD11b (D–F) on neutrophils from lavage (A,D), lung tissue (B,E) and blood (C,F) from untreated animals (no LPS or CO), or mice exposed to 0 or 100 ppm carbon monoxide (CO) for 6 hours after LPS instillation. Data are expressed as mean fluorescence intensity (MFI). The data of lavage neutrophils in untreated animals were not included because the numbers of cells recovered were too small to allow for accurate analysis. *p<0.05 vs LPS +0 ppm CO; n = 9–10/group.
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pone-0011565-g008: Neutrophil adhesion molecule expression, determined by flow cytometry.Surface expression of L-selectin (A–C) and CD11b (D–F) on neutrophils from lavage (A,D), lung tissue (B,E) and blood (C,F) from untreated animals (no LPS or CO), or mice exposed to 0 or 100 ppm carbon monoxide (CO) for 6 hours after LPS instillation. Data are expressed as mean fluorescence intensity (MFI). The data of lavage neutrophils in untreated animals were not included because the numbers of cells recovered were too small to allow for accurate analysis. *p<0.05 vs LPS +0 ppm CO; n = 9–10/group.

Mentions: We also investigated potential changes in the levels of neutrophil activation in terms of surface expression of L-selectin and CD11b (fig. 8). LPS induced a significant activation of lung-marginated neutrophils, promoting shedding of L-selectin (i.e. reduced expression), and upregulation of CD11b. CO had no impact on L-selectin expression, but tended to reduce CD11b expression on lung-marginated neutrophils. Neither LPS nor CO had a significant impact on activation of circulating neutrophils.


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)

Neutrophil adhesion molecule expression, determined by flow cytometry.Surface expression of L-selectin (A–C) and CD11b (D–F) on neutrophils from lavage (A,D), lung tissue (B,E) and blood (C,F) from untreated animals (no LPS or CO), or mice exposed to 0 or 100 ppm carbon monoxide (CO) for 6 hours after LPS instillation. Data are expressed as mean fluorescence intensity (MFI). The data of lavage neutrophils in untreated animals were not included because the numbers of cells recovered were too small to allow for accurate analysis. *p<0.05 vs LPS +0 ppm CO; n = 9–10/group.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0011565-g008: Neutrophil adhesion molecule expression, determined by flow cytometry.Surface expression of L-selectin (A–C) and CD11b (D–F) on neutrophils from lavage (A,D), lung tissue (B,E) and blood (C,F) from untreated animals (no LPS or CO), or mice exposed to 0 or 100 ppm carbon monoxide (CO) for 6 hours after LPS instillation. Data are expressed as mean fluorescence intensity (MFI). The data of lavage neutrophils in untreated animals were not included because the numbers of cells recovered were too small to allow for accurate analysis. *p<0.05 vs LPS +0 ppm CO; n = 9–10/group.
Mentions: We also investigated potential changes in the levels of neutrophil activation in terms of surface expression of L-selectin and CD11b (fig. 8). LPS induced a significant activation of lung-marginated neutrophils, promoting shedding of L-selectin (i.e. reduced expression), and upregulation of CD11b. CO had no impact on L-selectin expression, but tended to reduce CD11b expression on lung-marginated neutrophils. Neither LPS nor CO had a significant impact on activation of circulating neutrophils.

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