Carbon Monoxide and Human Disease

Morse, Danielle; Sethi, Jigme M.

doi:10.1089/152308602753666389

Cited by 22 publications

(19 citation statements)

References 80 publications

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“…Carbon monoxide (CO), an endogenous messenger generated by heme oxygenase-1 (HO-1) [1], has cytoprotective [2], [3], anti-proliferative [4]–[6], and anti-inflammatory effects [7]–[10] that indicate a potential for clinical applications. In animal models, CO itself or CO-releasing molecules (CORMs) have demonstrated benefits in ischemia/reperfusion injury [11]–[13], pulmonary inflammation [8], [14], [15], and sepsis [10], [16].…”

Section: Introductionmentioning

confidence: 99%

Carbon Monoxide Blocks Lipopolysaccharide-Induced Gene Expression by Interfering with Proximal TLR4 to NF-κB Signal Transduction in Human Monocytes

et al. 2009

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Carbon monoxide (CO) is an endogenous messenger that suppresses inflammation, modulates apoptosis and promotes vascular remodeling. Here, microarrays were employed to globally characterize the CO (250 ppm) suppression of early (1 h) LPS-induced inflammation in human monocytic THP-1 cells. CO suppressed 79 of 101 immediate-early genes induced by LPS; 19% (15/79) were transcription factors and most others were cytokines, chemokines and immune response genes. The prototypic effects of CO on transcription and protein production occurred early but decreased rapidly. CO activated p38 MAPK, ERK1/2 and Akt and caused an early and transitory delay in LPS-induced JNK activation. However, selective inhibitors of these kinases failed to block CO suppression of LPS-induced IL-1β, an inflammation marker. Of CO-suppressed genes, 81% (64/79) were found to have promoters with putative NF-κB binding sites. CO was subsequently shown to block LPS-induced phosphorylation and degradation of IκBα in human monocytes, thereby inhibiting NF-κB signal transduction. CO broadly suppresses the initial inflammatory response of human monocytes to LPS by reshaping proximal events in TLR4 signal transduction such as stress kinase responses and early NF-κB activation. These rapid, but transient effects of CO may have therapeutic applications in acute pulmonary and vascular injury.

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Section: Introductionmentioning

confidence: 99%

Carbon Monoxide Blocks Lipopolysaccharide-Induced Gene Expression by Interfering with Proximal TLR4 to NF-κB Signal Transduction in Human Monocytes

et al. 2009

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“…HO-1 has been shown to be upregulated following exposure to UV irradiation, endotoxin, heavy metals, hydrogen peroxide, and prostaglandins (4; reviewed in Refs. 19,20,32). HO-1 knockout mice rarely survive to term but those that do exhibit growth retardation and chronic inflammation, as shown by hepatosplenomegaly, leukocytosis, and glomerulonephritis.…”

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confidence: 99%

Evaluation of inhaled carbon monoxide as an anti-inflammatory therapy in a nonhuman primate model of lung inflammation

Mitchell

Channell

Royer

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Carbon monoxide (CO) confers anti-inflammatory protection in rodent models of lung injury when applied at low concentration. Translation of these findings to clinical therapies for pulmonary inflammation requires validation in higher mammals. We have evaluated the efficacy of inhaled CO in reducing LPS-induced lung inflammation in cynomolgus macaques. LPS inhalation resulted in profound neutrophil influx and moderate increases in airway lymphocytes, which returned to baseline levels within 2 wk following exposure. CO exposure (500 ppm, 6 h) following LPS inhalation decreased TNF-α release in bronchoalveolar lavage fluid but did not affect IL-6 or IL-8 release. Lower concentrations of CO (250 ppm, 6 h) did not reduce pulmonary neutrophilia. Pretreatment with budesonide, a currently used inhaled corticosteroid, decreased LPS-induced expression of TNF-α, IL-6, and IL-8, and reduced LPS-induced neutrophilia by ∼84%. In comparison, CO inhalation (500 ppm, for 6 h after LPS exposure) reduced neutrophilia by ∼67%. Thus, inhaled CO was nearly as efficacious as pretreatment with an inhaled corticosteroid at reducing airway neutrophil influx in cynomolgus macaques. However, the therapeutic efficacy of CO required relatively high doses (500 ppm) that resulted in high carboxyhemoglobin (COHb) levels (>30%). Lower CO concentrations (250 ppm), associated with anti-inflammatory protection in rodents, were ineffective in cynomolgus macaques and also yielded relatively high COHb levels. These studies highlight the complexity of interspecies variation of dose-response relationships of CO to COHb levels and to the anti-inflammatory functions of CO. The findings of this study warrant further investigations for assessing the therapeutic application of CO in nonhuman primate models of tissue injury and in human diseases. The study also suggests that akin to many new therapies in human diseases, the translation of CO therapy to human disease will require additional extensive and rigorous proof-of-concept studies in humans in the future.

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“…The enzyme HO-1 is inducible and HO-2 is constitutive; heme oxygenase degrades heme into CO and biliverdin, and the latter is rapidly converted into bilirubin (Coburn et al, 1963(Coburn et al, , 1967Coburn, 1979;Mores and Sethi, 2002). Current literature emphasizes only a physiological role for endogenously generated CO Boehning and Snyder, 2003;Ryter and Otterben, 2004;Wu and Wang, 2005;Mannaioni et al, 2006), although it is quite likely that it could add to the toxicity of inhaled CO.…”

Section: Endogenous Sources Of Comentioning

confidence: 99%