Inhaled carbon monoxide accelerates resolution of inflammation via unique proresolving mediator-heme oxygenase-1 circuits.

Resolution of acute inflammation is an active event accompanied by biosynthesis of specialized proresolving mediators (SPM). We employed a systems approach to determine the impact of CO in resolution active programs during self-limited inflammation in mice. Compared with ambient air, inhaled CO gas (250 ppm) significantly limited PMN infiltration (∼44%, 6 h) into peritoneum and shortened resolution interval from 4 to 2 h. We profiled exudate lipid mediators (LM) via metabololipidomics, CO reduced leukotriene B4 (21 ± 11 versus 59 ± 24 pg/mouse, 6 h), and elevated SPM including resolvin (Rv) D1 (27 ± 4 versus 16 ± 5 pg/mouse) and maresin 1 (26 ± 9 versus 15 ± 3 pg/mouse). With human macrophages, SPM (10 pM-10 nM) elevated heme oxygenase (HO)-1 (∼50%, 8 h). CO also enhanced HO-1 expression and accumulation of RvD1 and RvD5, an action reversed by blockage of a key SPM biosynthesis enzyme 15-lipoxygenase type 1. Compared with normoxia, CO increased ∼30% phagocytosis of opsonized zymosan with human macrophage, which was further enhanced by SPM (∼100%). This CO increased phagocytosis was blocked by 15-lipoxygenase inhibition, and SPM stimulated phagocytosis was diminished by HO-1 inhibition. In murine peritonitis, both pre- and posttreatment with CO inhalation significantly increased macrophages carrying ingested apoptotic PMN in exudates and enhanced PMN apoptosis. Taken together, these results indicate that CO accelerates resolution of acute inflammation, shortens resolution intervals, enhances macrophage efferocytosis, and temporally regulates local levels of lipid mediator/SPM. Moreover, they provide proresolving mechanisms for HO-1/CO, which is part of the SPM-initiated resolution circuit.

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

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.

[A case of Cronkhite-Canada syndrome with multiple colon adenomas and early colon cancers].

A 60-year-old man presented with diarrhea and weight loss. Colonoscopy revealed multiple reddish polypoid lesions throughout the gastrointestinal tract and was diagnosed as Cronkhite-Canada syndrome (CCS). Prednisolone therapy caused regression of polyps. Some of them were suspected to be early colon cancers and adenomas. We endoscopically performed mucosal resection for 15 polyps after prednisolone therapy. Histological examination of one of polyps showed invasion of the submucosal layer and colon resection was performed. This case suggests that diagnosis and treatment are important in polyps of CCS.

GC/MS and LC/MS-based Tissue Metabolomic Analysis Detected Increased Levels of Antioxidant Metabolites in Colorectal Cancer.

Late-stage colorectal cancer is resistant to current treatments. Understanding the biological processes responsible for the development and progression of colorectal cancer could aid the development of new diagnostic and treatment approaches. We used gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry-based metabolomic analysis to measure metabolite levels in pairs of colorectal cancer tissue samples and samples of the adjacent macroscopically normal mucosal tissue from 10 colon cancer patients. Regarding nucleotide metabolomic intermediates, the colorectal cancer tissue contained lower levels of ribulose 5-phosphate and higher levels of xanthine, adenine, and hypoxanthine than the normal tissue. The levels of antioxidant metabolites, such as sulfur-containing amino acids, were also significantly higher in the colorectal cancer tissue. The level of tryptophan was decreased, and the levels of molecules downstream of the tryptophan pathway, such as kynurenine and quinolinic acid, which protect colorectal cancer against the host's immune system and function in de novo nicotinamide adenine dinucleotide synthesis, were increased in the colorectal cancer tissue. The colorectal cancer tissue samples also contained higher levels of lysophospholipids and fatty acids, especially stearic acid and polyunsaturated fatty acids, including arachidonic acid and docosahexaenoic acid. Thus, understanding these cancer-specific alterations could make it possible to detect colorectal cancer early and aid the development of additional treatments for the disease, leading to improvements in colorectal cancer patients' quality of life.

A novel serum metabolomics-based diagnostic approach for colorectal cancer.

BACKGROUND: To improve the quality of life of colorectal cancer patients, it is important to establish new screening methods for early diagnosis of colorectal cancer. METHODOLOGY/PRINCIPAL FINDINGS: We performed serum metabolome analysis using gas-chromatography/mass-spectrometry (GC/MS). First, the accuracy of our GC/MS-based serum metabolomic analytical method was evaluated by calculating the RSD% values of serum levels of various metabolites. Second, the intra-day (morning, daytime, and night) and inter-day (among 3 days) variances of serum metabolite levels were examined. Then, serum metabolite levels were compared between colorectal cancer patients (N = 60; N = 12 for each stage from 0 to 4) and age- and sex-matched healthy volunteers (N = 60) as a training set. The metabolites whose levels displayed significant changes were subjected to multiple logistic regression analysis using the stepwise variable selection method, and a colorectal cancer prediction model was established. The prediction model was composed of 2-hydroxybutyrate, aspartic acid, kynurenine, and cystamine, and its AUC, sensitivity, specificity, and accuracy were 0.9097, 85.0%, 85.0%, and 85.0%, respectively, according to the training set data. In contrast, the sensitivity, specificity, and accuracy of CEA were 35.0%, 96.7%, and 65.8%, respectively, and those of CA19-9 were 16.7%, 100%, and 58.3%, respectively. The validity of the prediction model was confirmed using colorectal cancer patients (N = 59) and healthy volunteers (N = 63) as a validation set. At the validation set, the sensitivity, specificity, and accuracy of the prediction model were 83.1%, 81.0%, and 82.0%, respectively, and these values were almost the same as those obtained with the training set. In addition, the model displayed high sensitivity for detecting stage 0-2 colorectal cancer (82.8%). CONCLUSIONS/SIGNIFICANCE: Our prediction model established via GC/MS-based serum metabolomic analysis is valuable for early detection of colorectal cancer and has the potential to become a novel screening test for colorectal cancer.