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Cell-cell interactions and bronchoconstrictor eicosanoid reduction with inhaled carbon monoxide and resolvin D1
Masakazu Shinohara1, Megumi Kibi1, Ian R Riley1
1Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts;
Abstract:
Polymorphonuclear leukocyte (PMN)-mediated acute lung injury from ischemia/reperfusion (I/R) remains a major cause of morbidity and mortality in critical care medicine. Here, we report that inhaled low-dose carbon monoxide (CO) and intravenous resolvin D1 (RvD1) in mice each reduced PMN-mediated acute lung injury from I/R. Inhaled CO (125-250 ppm) and RvD1 (250-500 ng) each reduced PMN lung infiltration and gave additive lung protection. In mouse whole blood, CO and RvD1 attenuated PMN-platelet aggregates, reducing leukotrienes (LTs) and thromboxane B2 (TxB2) in I/R lungs. With human whole blood, CO (125-250 ppm) decreased PMN-platelet aggregates, expression of adhesion molecules, and cysteinyl LTs, as well as TxB2. RvD1 (1-100 nM) also dose dependently reduced platelet activating factor-stimulated PMN-platelet aggregates in human whole blood. In nonhuman primate (baboon) lung infection with Streptococcus pneumoniae, inhaled CO reduced urinary cysteinyl LTs. These results demonstrate lung protection by low-dose inhaled CO as well as RvD1 that each reduced PMN-mediated acute tissue injury, PMN-platelet interactions, and production of both cysteinyl LTs and TxB2. Together they suggest a potential therapeutic role of low-dose inhaled CO in organ protection, as demonstrated using mouse I/R-initiated lung injury, baboon infections, and human whole blood.
Insights
Inhaled low-dose carbon monoxide (CO) and resolvin D1 (RvD1) protect against acute lung injury by reducing inflammatory cell aggregation and mediators. These findings suggest a therapeutic role for CO in organ protection.
Area of Science:
- Critical care medicine
- Pulmonary medicine
- Inflammation research
Background:
- Polymorphonuclear leukocyte (PMN)-mediated acute lung injury from ischemia/reperfusion (I/R) is a significant cause of morbidity and mortality.
- Current treatments for I/R-induced lung injury have limitations.
Purpose of the Study:
- To investigate the protective effects of inhaled low-dose carbon monoxide (CO) and intravenous resolvin D1 (RvD1) on PMN-mediated acute lung injury.
- To elucidate the mechanisms underlying the protective effects of CO and RvD1.
Main Methods:
- Studies were conducted in mouse models of I/R-induced lung injury, human whole blood assays, and baboon models of lung infection.
- Measurements included PMN lung infiltration, PMN-platelet aggregates, leukotrienes (LTs), thromboxane B2 (TxB2), and adhesion molecule expression.
Main Results:
- Both inhaled CO and RvD1 reduced PMN lung infiltration and provided additive lung protection in mice.
- CO and RvD1 attenuated PMN-platelet aggregates and reduced LTs and TxB2 in I/R lungs.
- In human whole blood, CO and RvD1 decreased PMN-platelet aggregates, adhesion molecules, and cysteinyl LTs.
Conclusions:
- Low-dose inhaled CO and RvD1 demonstrate significant lung protection by reducing PMN-mediated injury, PMN-platelet interactions, and inflammatory mediators.
- These findings support a potential therapeutic role for low-dose inhaled CO in organ protection, particularly in I/R injury and infection models.
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