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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

Alveolar neutrophil recruitment 24 hours after LPS.Impact of carbon monoxide (CO) exposure on neutrophil (PMN) percentage (A) and number/ml (B) in lung lavage fluid of untreated animals (no LPS or CO), or mice treated with 10 ng intratracheal LPS. LPS-challenged mice were exposed to either 0 (air), 50, 100, 200, or 500 ppm CO for 24 hours both before and after LPS. *p<0.05, **p<0.01 ***p<0.001 vs LPS +0 ppm CO; n = 19 for LPS +0 ppm CO, and 8–12 for all other groups (numbers are higher in the LPS+0 ppm CO group because, as our primary control, we ran 1–2 of these animals alongside the experiments for each of the other groups).
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pone-0011565-g001: Alveolar neutrophil recruitment 24 hours after LPS.Impact of carbon monoxide (CO) exposure on neutrophil (PMN) percentage (A) and number/ml (B) in lung lavage fluid of untreated animals (no LPS or CO), or mice treated with 10 ng intratracheal LPS. LPS-challenged mice were exposed to either 0 (air), 50, 100, 200, or 500 ppm CO for 24 hours both before and after LPS. *p<0.05, **p<0.01 ***p<0.001 vs LPS +0 ppm CO; n = 19 for LPS +0 ppm CO, and 8–12 for all other groups (numbers are higher in the LPS+0 ppm CO group because, as our primary control, we ran 1–2 of these animals alongside the experiments for each of the other groups).

Mentions: No animals died after randomisation to treatment groups in any of the experimental protocols. Initial experiments were carried out using prolonged exposure to CO, to determine the maximal impact of CO both in terms of anti-inflammatory consequences and potential side-effects. Recruitment of neutrophils into the alveolar space was determined in animals exposed to 0–500 ppm CO for 24 hours both before and after LPS (fig. 1). LPS induced a substantial intra-alveolar neutrophil infiltration compared to untreated mice, while inhaled CO of 100 ppm or more significantly reduced this by ∼40–50%.


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)

Alveolar neutrophil recruitment 24 hours after LPS.Impact of carbon monoxide (CO) exposure on neutrophil (PMN) percentage (A) and number/ml (B) in lung lavage fluid of untreated animals (no LPS or CO), or mice treated with 10 ng intratracheal LPS. LPS-challenged mice were exposed to either 0 (air), 50, 100, 200, or 500 ppm CO for 24 hours both before and after LPS. *p<0.05, **p<0.01 ***p<0.001 vs LPS +0 ppm CO; n = 19 for LPS +0 ppm CO, and 8–12 for all other groups (numbers are higher in the LPS+0 ppm CO group because, as our primary control, we ran 1–2 of these animals alongside the experiments for each of the other groups).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0011565-g001: Alveolar neutrophil recruitment 24 hours after LPS.Impact of carbon monoxide (CO) exposure on neutrophil (PMN) percentage (A) and number/ml (B) in lung lavage fluid of untreated animals (no LPS or CO), or mice treated with 10 ng intratracheal LPS. LPS-challenged mice were exposed to either 0 (air), 50, 100, 200, or 500 ppm CO for 24 hours both before and after LPS. *p<0.05, **p<0.01 ***p<0.001 vs LPS +0 ppm CO; n = 19 for LPS +0 ppm CO, and 8–12 for all other groups (numbers are higher in the LPS+0 ppm CO group because, as our primary control, we ran 1–2 of these animals alongside the experiments for each of the other groups).
Mentions: No animals died after randomisation to treatment groups in any of the experimental protocols. Initial experiments were carried out using prolonged exposure to CO, to determine the maximal impact of CO both in terms of anti-inflammatory consequences and potential side-effects. Recruitment of neutrophils into the alveolar space was determined in animals exposed to 0–500 ppm CO for 24 hours both before and after LPS (fig. 1). LPS induced a substantial intra-alveolar neutrophil infiltration compared to untreated mice, while inhaled CO of 100 ppm or more significantly reduced this by ∼40–50%.

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