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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

Impact of CO exposure either pre- or post- LPS challenge on alveolar neutrophil recruitment.Neutrophil (PMN) % (A) and number/ml (B) in lung lavage fluid of mice exposed to 100 ppm carbon monoxide (CO) for 24 hours either before or after lipopolysaccharide (LPS) instillation. *p<0.05, **p<0.01 vs 100 ppm CO pre-LPS; n = 8/group. For comparison, data from Figure 1 of the animals exposed either to 0 ppm or 100 ppm CO for 24 hours both pre- and post-LPS are shown (but not included in statistical analysis).
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pone-0011565-g004: Impact of CO exposure either pre- or post- LPS challenge on alveolar neutrophil recruitment.Neutrophil (PMN) % (A) and number/ml (B) in lung lavage fluid of mice exposed to 100 ppm carbon monoxide (CO) for 24 hours either before or after lipopolysaccharide (LPS) instillation. *p<0.05, **p<0.01 vs 100 ppm CO pre-LPS; n = 8/group. For comparison, data from Figure 1 of the animals exposed either to 0 ppm or 100 ppm CO for 24 hours both pre- and post-LPS are shown (but not included in statistical analysis).

Mentions: To determine whether efficacy of inhaled CO required pre-exposure, mice were exposed to 100 ppm CO (as the lowest dose which produced consistent attenuation of neutrophil infiltration) for 24 hours either before or after LPS challenge, and sacrificed for analysis at 24 hours after LPS. The beneficial effect of CO could be attributed entirely to the period following LPS, demonstrating that pre-exposure was unnecessary (fig. 4). Thus, exposure to CO after LPS challenge was utilised for the subsequent experiments.


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 exposure either pre- or post- LPS challenge on alveolar neutrophil recruitment.Neutrophil (PMN) % (A) and number/ml (B) in lung lavage fluid of mice exposed to 100 ppm carbon monoxide (CO) for 24 hours either before or after lipopolysaccharide (LPS) instillation. *p<0.05, **p<0.01 vs 100 ppm CO pre-LPS; n = 8/group. For comparison, data from Figure 1 of the animals exposed either to 0 ppm or 100 ppm CO for 24 hours both pre- and post-LPS are shown (but not included in statistical analysis).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2903490&req=5

pone-0011565-g004: Impact of CO exposure either pre- or post- LPS challenge on alveolar neutrophil recruitment.Neutrophil (PMN) % (A) and number/ml (B) in lung lavage fluid of mice exposed to 100 ppm carbon monoxide (CO) for 24 hours either before or after lipopolysaccharide (LPS) instillation. *p<0.05, **p<0.01 vs 100 ppm CO pre-LPS; n = 8/group. For comparison, data from Figure 1 of the animals exposed either to 0 ppm or 100 ppm CO for 24 hours both pre- and post-LPS are shown (but not included in statistical analysis).
Mentions: To determine whether efficacy of inhaled CO required pre-exposure, mice were exposed to 100 ppm CO (as the lowest dose which produced consistent attenuation of neutrophil infiltration) for 24 hours either before or after LPS challenge, and sacrificed for analysis at 24 hours after LPS. The beneficial effect of CO could be attributed entirely to the period following LPS, demonstrating that pre-exposure was unnecessary (fig. 4). Thus, exposure to CO after LPS challenge was utilised for the subsequent experiments.

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