TRENDS in Molecular Medicine
Carbon monoxide: from the origin of life to molecular medicine
Fritz H. Bach
Lewis Thomas Distinguished Professor, Harvard Medical School, Boston, MA 02215, USA
Carbon monoxide, long considered only as a toxic gas, has recently been shown to mediate potent anti-inﬂammatory and other salutary effects in rodents when it is used atlow doses. Carbon monoxide is one of the products of the degradation of heme by heme oxygenase 1. Until recently, these beneﬁcial effects of carbon monoxide were shown only when it was given before a stress stimulus. Hagazi and colleagues have recently shown that this substance is effective even when it is given after a disease process has started. The effects of low doses of carbon monoxide arecomplemented by the production of biliverdin and probably also by ferritin, which are additional products of heme degradation.
The heme oxygenase 1 system
Treatment of an inﬂammatory disorder
A friend proudly recounted at a recent dinner party that he had installed carbon monoxide (CO) detectors in his house that detect CO at much lower concentrations than commercially available detectors.Having become a ﬁrm devotee of the salutary effects of exogenous CO at low nontoxic concentrations for the prevention of a wide variety of inﬂammation-based diseases in rodents, I warned my friend that he might be denying his family the potential beneﬁt of a low-concentration CO environment. I also pointed out that CO might even have participated in the origin of life , based on demonstrationsthat a CO-containing atmosphere can yield various bio-organic compounds, which might render such an atmosphere conducive to prebiotic synthesis and perhaps the origin of life. Although the toxicity of high-concentration exposure to CO is well known, what is new and exciting is the extensive evidence that ‘pretreatment’ of animals with low concentrations of CO, sometimes administered for as littleas one hour by inhalation, can ameliorate the severe consequences of endotoxic shock and subdue the level of the inﬂammatory response to a xenograft . CO is one of the three products of heme degradation by heme oxygenase 1 (HO-1), the other two being Fe2+ and biliverdin. Fe2+ stimulates the upregulation of the ironbinding protein ferritin, whereas biliverdin is rapidly converted to bilirubin bybiliverdin reductase (Figure 1). Induced expression of HO-1 and administration of CO, ferritin and biliverdin or bilirubin have been shown to provide potent anti-inﬂammatory effects and to modulate apoptosis and cell proliferation to maintain homeostasis .
Corresponding author: Bach, F.H. (Fritz_bach@hms.harvard.edu) Available online 10 July 2006.
It now appears thatCO can be administered during an ongoing disease process and can still provide salutary effects. Hegazi and his co-workers from the University of Pittsburgh and the Beth Israel Deaconess Medical Center at Harvard Medical School have shown that CO at low concentration mitigates chronic intestinal inﬂammation in a T helper-type-1 cell-mediated mouse model of murine colitis in interleukin (IL)10-deﬁcient mice, even when CO therapy is begun after the disease has already been established . Administration of CO after the onset of colitis suppressed the inﬂammatory responses that mediate disease progression. CO abrogated the effect of interferon-g (IFN-g) on lipopolysaccharide (LPS)-induced IL-12 p40, which is involved in T helper-type-1 cell responses such as that causing colitis in thismodel and in chronic inﬂammation, and modulated IFN regulatory factor-8. Anti-IL-12 p40 antibodies have been shown to ameliorate colitis and are being tested clinically [5–7]. Hegazi’s studies raise other issues related to CO therapy in ﬁnding that the modulation of IFN-g signaling by CO depends on the expression of HO-1. The effects of CO are lost in hmox1À/À macrophages, suggesting the need for...