SAN ANTONIO, TEX—Although known for its lethal potential, inhaled carbon monoxide (CO) may have therapeutic value as well. At the recent annual meeting of the Society of Critical Care Medicine, Augustine Choi, MD, presented evidence from numerous animal studies of the protective effects of CO in certain conditions, including hyperoxia- or ventilator-induced lung injury, sepsis, and interstitial pulmonary fibrosis, as well as following lung transplantation.[1]

“We have known since 1968 that the body produces carbon monoxide endogenously,” said Dr. Choi, Professor of Medicine and Chief of Pulmonary, Allergy, and Critical Care Medicine at the University of Pittsburgh. By comparison, the discovery that the body produces nitric oxide occurred only in the 1980s, yet today much more is known about its effects on pathological processes, he continued.

In the body, CO is produced when heme is catabolized by the enzyme heme oxygenase (HO). Expression of HO can occur as a response to stress; the inducible isoform is termed HO-1.

A PROTECTIVE STATE

In previous studies, researchers have induced HO-1 production through exogenous gene transfer via an adenovirus. In an experiment involving hyperoxia, rats were given 100% oxygen; the rats not given the adenovirus suffered acute lung injury, hemorrhage, and edema. The rats given the adenovirus were uninjured. “HO-1 is cytoprotective through anti-inflammatory properties,” he explained. It can selectively modulate expression of both proinflammatory and anti-inflammatory cytokines.

In another study, HO-1 proved to protect against hypoxia-induced pulmonary hypertension.[2] When investigators enhanced expression of HO-1 in rat lungs, not only did it prevent pulmonary hypertension, it inhibited pulmonary vessel remodeling.

In addition, investigators have demonstrated similar protection through administration of exogenous CO itself, without HO-1 induction. In a mouse model of bacterial endotoxin, CO administered at 250 to 500 ppm inhibited the cytokines’ tumor necrosis factor (TNF) and interleukin 1ß (IL-1ß).[3] “Carbon monoxide brought down TNF in a robust way,” said Dr. Choi. Interestingly, he pointed out, “it doesn’t globally shut down all cytokines. Low concentrations of CO had selective effects, inhibiting TNF and augmenting IL-10. It brought down TNF in a dose-dependent manner.”

MODUS OPERANDI

The mechanisms behind this protective effect are unknown. As HO-1 catabolizes heme, it produces not only CO but bilirubin and ferritin as well—two potent antioxidants. Dr. Choi hypothesizes that all three may work synergistically for optimal cytoprotection depending on the stressor involved. Unlocking the biochemical processes is crucial to future research. Will HO-1 and CO ever be used as therapy in humans? “Our subclinical models give compelling evidence that we should pursue it,” noted Dr. Choi.

Because CO is a potentially deadly gas, the most obvious challenge to its clinical use is finding its optimal concentration. Determining the appropriate duration and system of delivery poses another challenge for researchers. Currently, the two methods being tested on animals are the endogenous production of CO through HO-1 expression and the exogenous administration of CO itself. It is not yet clear which method is more effective, though opinion is leaning toward the latter, according to Dr. Choi. He credited the discoveries discussed here to a collaborative effort of the team at the University of Pittsburgh School of Medicine composed of himself and colleagues Leo Otterbein, Danielle Morse, Cynthia Song, Tamas Doliny, and Jason Zhou.

POSSIBILITIES

Research to date indicates a possible place for CO in the treatment of inflammatory diseases, such as sepsis. For conditions for which other therapies have already proven successful, such as asthma, a radical treatment such as CO is probably superfluous. “In interstitial pulmonary fibrosis, where there is no competing therapy, perhaps CO has a place,” Dr. Choi speculated.

—Lisa Pallatroni

References
1. Choi A. Mechanical ventilation: unconventional approaches: role of inhaled carbon monoxide. Presented at: annual meeting of the Society of Critical Care Medicine; January 31, 2003; San Antonio, Tex.
2. Christou H, Morita T, Hsieh CM, et al. Prevention of hypoxia-induced pulmonary hypertension by enhancement of endogenous heme oxygenase-1 in the rat. Circ Res. 2001;86:1224-1229.
3. Otterbein LE, Bach FH, Alam J, et al. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med. 2000;6:422-428.

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