Carbon monoxide ameliorates chronic murine colitis through a heme oxygenase 1–dependent pathway

Heme oxygenase (HO)-1 and its metabolic product carbon monoxide (CO) play regulatory roles in acute inflammatory states. In this study, we demonstrate that CO administration is effective as a therapeutic modality in mice with established chronic colitis. CO administration ameliorates chronic intestinal inflammation in a T helper (Th)1-mediated model of murine colitis, interleukin (IL)-10–deficient (IL-10−/−) mice. In Th1-mediated inflammation, CO abrogates the synergistic effect of interferon (IFN)-γ on lipopolysaccharide-induced IL-12 p40 in murine macrophages and alters IFN-γ signaling by inhibiting a member of the IFN regulatory factor (IRF) family of transcription factors, IRF-8. A specific signaling pathway, not previously identified, is delineated that involves an obligatory role for HO-1 induction in the protection afforded by CO. Moreover, CO antagonizes the inhibitory effect of IFN-γ on HO-1 expression in macrophages. In macrophages and in Th1-mediated colitis, pharmacologic induction of HO-1 recapitulates the immunosuppressive effects of CO. In conclusion, this study begins to elucidate potential etiologic and therapeutic implications of CO and the HO-1 pathway in chronic inflammatory bowel diseases.

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An Anti-Inflammatory Role for Carbon Monoxide and Heme Oxygenase-1 in Chronic Th2-Mediated Murine Colitis

The Journal of Immunology ◽

10.4049/jimmunol.1002433 ◽

2011 ◽

Vol 186 (9) ◽

pp. 5506-5513 ◽

Cited By ~ 85

Author(s):

Shehzad Z. Sheikh ◽

Refaat A. Hegazi ◽

Taku Kobayashi ◽

Joseph C. Onyiah ◽

Steven M. Russo ◽

...

Keyword(s):

Carbon Monoxide ◽

Heme Oxygenase ◽

Heme Oxygenase 1 ◽

Murine Colitis ◽

Anti Inflammatory

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Carbon Monoxide and Heme Oxygenase-1 Prevent Intestinal Inflammation in Mice by Promoting Bacterial Clearance

Gastroenterology ◽

10.1053/j.gastro.2012.12.025 ◽

2013 ◽

Vol 144 (4) ◽

pp. 789-798 ◽

Cited By ~ 67

Author(s):

Joseph C. Onyiah ◽

Shehzad Z. Sheikh ◽

Nitsan Maharshak ◽

Erin C. Steinbach ◽

Steven M. Russo ◽

...

Keyword(s):

Carbon Monoxide ◽

Heme Oxygenase ◽

Intestinal Inflammation ◽

Heme Oxygenase 1 ◽

Bacterial Clearance

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Faculty Opinions recommendation of Galantamine and carbon monoxide protect brain microvascular endothelial cells by heme oxygenase-1 induction.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1122912.580012 ◽

2008 ◽

Author(s):

George Perry

Keyword(s):

Carbon Monoxide ◽

Endothelial Cells ◽

Heme Oxygenase ◽

Microvascular Endothelial Cells ◽

Heme Oxygenase 1 ◽

Brain Microvascular Endothelial Cells ◽

Microvascular Endothelial

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Heme Oxygenase-1/Carbon Monoxide: Novel Therapeutic Strategies in Critical Care Medicine

Current Drug Targets ◽

10.2174/1389450111009011485 ◽

2010 ◽

Vol 11 (12) ◽

pp. 1485-1494 ◽

Cited By ~ 73

Author(s):

Stefan W. Ryter ◽

Augustine M.K. Choi

Keyword(s):

Carbon Monoxide ◽

Critical Care ◽

Heme Oxygenase ◽

Therapeutic Strategies ◽

Critical Care Medicine ◽

Heme Oxygenase 1 ◽

Novel Therapeutic Strategies ◽

Novel Therapeutic

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Pharmacological Targeting of Heme Oxygenase-1 in Osteoarthritis

Antioxidants ◽

10.3390/antiox10030419 ◽

2021 ◽

Vol 10 (3) ◽

pp. 419

Author(s):

Yohei Sanada ◽

Sho Joseph Ozaki Tan ◽

Nobuo Adachi ◽

Shigeru Miyaki

Keyword(s):

Heme Oxygenase ◽

Redox Homeostasis ◽

Synovial Fibroblasts ◽

Protective Role ◽

Joint Disease ◽

Heme Oxygenase 1 ◽

Transcriptional Level ◽

Related Factor ◽

Mobility Limitations ◽

Therapeutic Implications

Osteoarthritis (OA) is a common aging-associated disease that clinically manifests as joint pain, mobility limitations, and compromised quality of life. Today, OA treatment is limited to pain management and joint arthroplasty at the later stages of disease progression. OA pathogenesis is predominantly mediated by oxidative damage to joint cartilage extracellular matrix and local cells such as chondrocytes, osteoclasts, osteoblasts, and synovial fibroblasts. Under normal conditions, cells prevent the accumulation of reactive oxygen species (ROS) under oxidatively stressful conditions through their adaptive cytoprotective mechanisms. Heme oxygenase-1 (HO-1) is an iron-dependent cytoprotective enzyme that functions as the inducible form of HO. HO-1 and its metabolites carbon monoxide and biliverdin contribute towards the maintenance of redox homeostasis. HO-1 expression is primarily regulated at the transcriptional level through transcriptional factor nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), specificity protein 1 (Sp1), transcriptional repressor BTB-and-CNC homology 1 (Bach1), and epigenetic regulation. Several studies report that HO-1 expression can be regulated using various antioxidative factors and chemical compounds, suggesting therapeutic implications in OA pathogenesis as well as in the wider context of joint disease. Here, we review the protective role of HO-1 in OA with a focus on the regulatory mechanisms that mediate HO-1 activity.

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