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Cell-cell interactions and bronchoconstrictor eicosanoid reduction with inhaled carbon monoxide and resolvin D1.

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.

SUBMITTER: Shinohara M

PROVIDER: S-EPMC4233292 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Cell-cell interactions and bronchoconstrictor eicosanoid reduction with inhaled carbon monoxide and resolvin D1.

Shinohara Masakazu M Kibi Megumi M Riley Ian R IR Chiang Nan N Dalli Jesmond J Kraft Bryan D BD Piantadosi Claude A CA Choi Augustine M K AM Serhan Charles N CN

American journal of physiology. Lung cellular and molecular physiology 20140912 10

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 ...[more]

PMID: 25217660

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Project description:PurposeIschemia and reperfusion injury (I/R) of neuronal structures and organs is associated with increased morbidity and mortality due to neuronal cell death. We hypothesized that inhalation of carbon monoxide (CO) after I/R injury ('postconditioning') would protect retinal ganglion cells (RGC).MethodsRetinal I/R injury was performed in Sprague-Dawley rats (n = 8) by increasing ocular pressure (120 mmHg, 1 h). Rats inhaled room air or CO (250 ppm) for 1 h immediately following ischemia or with 1.5 and 3 h latency. Retinal tissue was harvested to analyze Bcl-2, Bax, Caspase-3, HO-1 expression and phosphorylation of the nuclear transcription factor (NF)-κB, p38 and ERK-1/2 MAPK. NF-κB activation was determined and inhibition of ERK-1/2 was performed using PD98059 (2 mg/kg). Densities of fluorogold prelabeled RGC were analyzed 7 days after injury. Microglia, macrophage and Müller cell activation and proliferation were evaluated by Iba-1, GFAP and Ki-67 staining.ResultsInhalation of CO after I/R inhibited Bax and Caspase-3 expression (Bax: 1.9 ± 0.3 vs. 1.4 ± 0.2, p = 0.028; caspase-3: 2.0 ± 0.2 vs. 1.5 ± 0.1, p = 0.007; mean ± S.D., fold induction at 12 h), while expression of Bcl-2 was induced (1.2 ± 0.2 vs. 1.6 ± 0.2, p = 0.001; mean ± S.D., fold induction at 12 h). CO postconditioning suppressed retinal p38 phosphorylation (p = 0.023 at 24 h) and induced the phosphorylation of ERK-1/2 (p<0.001 at 24 h). CO postconditioning inhibited the expression of HO-1. The activation of NF-κB, microglia and Müller cells was potently inhibited by CO as well as immigration of proliferative microglia and macrophages into the retina. CO protected I/R-injured RGC with a therapeutic window at least up to 3 h (n = 8; RGC/mm(2); mean ± S.D.: 1255 ± 327 I/R only vs. 1956 ± 157 immediate CO treatment, vs. 1830 ± 109 1.5 h time lag and vs. 1626 ± 122 3 h time lag; p<0.001). Inhibition of ERK-1/2 did not counteract the CO effects (RGC/mm(2): 1956 ± 157 vs. 1931 ± 124, mean ± S.D., p = 0.799).ConclusionInhaled CO, administered after retinal ischemic injury, protects RGC through its strong anti-apoptotic and anti-inflammatory effects.

Dataset Information

Cell-cell interactions and bronchoconstrictor eicosanoid reduction with inhaled carbon monoxide and resolvin D1.

Publications

Cell-cell interactions and bronchoconstrictor eicosanoid reduction with inhaled carbon monoxide and resolvin D1.

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