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From the Department of Anesthesiology, the University of Alabama at Birmingham, Birmingham, Alabama.
Address correspondence to Vance G. Nielsen, MD, Department of Anesthesiology, the University of Alabama at Birmingham, 901 South 19th Street, Basic Medical Research II, Room 206, Birmingham, AL 35249-6810. Address e-mail to vnielsen{at}uab.edu.
Heme oxygenase-1 (HO-1, formerly heat shock protein 32) is the first and rate-limiting enzyme in heme catabolism, cleaving heme to form biliverdin and carbon monoxide (CO). Biliverdin is subsequently converted to bilirubin by biliverdin reductase.
Why should this enzyme and its catabolic products be of interest to clinically oriented perioperative and critical care physicians? Because the degree of attention paid by basic and clinical scientists to the protective effects of HO-1 in preclinical and in vitro models of ischemia-reperfusion and oxidative injury is rapidly approaching that observed with nitric oxide (NO) synthases in the early 1990s (1–10), with more than 2000 articles involving HO-1 published in the past 6 yr. Given the ubiquitous interest in NO and its effects on clinical outcomes, it is similarly likely that pharmacological modulation of HO-1 activity may be applied in clinical investigations if basic science findings reported in original studies and reviews (1–10) can be translated into human settings.
In particular, in this issue of Anesthesia & Analgesia Jin et al. (10) present a preclinical model of septic lung injury wherein HO-1 activity is upregulated and injury attenuated via a novel pharmacological approach. Before we address the important aspects of this investigation, however, the mechanisms by which HO-1 is posited to be protective should be briefly mentioned.
As reviewed (1,3,8) and originally reported (4–7,9), upregulation of HO-1 has been associated with decreased injury after organ transplantation in animals, exposure of various organs to ischemia-reperfusion injury, exposure to hyperoxia, and endotoxemia. The HO-1-derived product biliverdin has been posited to convey protection by inhibition of complement, whereas bilirubin is a potent antioxidant that has been shown to inhibit lymphocyte proliferation and to acutely decrease leukocyte adhesion after oxidative stress (2). With regard to CO generated by HO-1, this product stimulates cGMP production by guanylate cyclase, resulting in decreased platelet aggregation and decreased endothelin-1 production by endothelial cells. Further, HO-1 activity and NO synthases activity are somewhat coupled, with increases in NO production associated with decreases in CO production, and vice versa. Of interest, the beneficial effects of CO and bilirubin are not found in all models; for example, HO-1-derived bilirubin, but not CO, prevented leukocyte adhesion in vivo in rat mesenteric vessels after H2O2 exposure (2), whereas CO, and not bilirubin, was responsible for decreased tissue injury in a murine model of chronic colitis (6). In sum, the mechanism(s) of HO-1-mediated protection against the injurious effects of oxidant stress, sepsis, and ischemia-reperfusion injury are likely to be injury-specific, and perhaps species-specific.
With these concepts in mind, it is of particular interest to consider the investigation of Jin et al. (10), in which mice exposed to inhaled lipopolysaccharide (LPS) demonstrated lung injury, assessed histologically and biochemically. Measurements of oxidant stress/oxidant generators (malondialdehyde, nitrate, nitrite, myeloperoxidase activity), Western blot analysis/activity assays of HO-1, and immunohistochemical localization of HO-1 within the lung were performed. With this model, HO-1 activity was markedly increased after LPS exposure with a member of a new class of potent antiinflammatory drugs, the lipoxins (11). The administration of 15-epi-16-parafluoro-phenoxy lipoxin A4 (ATL) not only increased HO-1 activity in this model, but also markedly diminished all markers of lung injury. Lastly, coadministration of a specific HO-1 inhibitor with ATL abrogated ATL-mediated protection against lung injury in this model. In sum, as best as can be accomplished in vivo, Jin et al. mechanistically demonstrated protection against LPS-mediated lung injury via upregulation of HO-1 activity with ATL administration.
Should we, as clinicians, make the eclectic leap that lipoxin administration is the panacea for sepsis? The answer to this question is clearly no, given that species-specific, organ-specific and other, yet unidentified variables may be involved in the multiple organ injury associated with sepsis. Indeed, inhaled LPS is not necessarily equivalent to sepsis associated with gastrointestinal injury or ventilator-associated pneumonia. Nevertheless, the article by Jin et al. is an important and exciting first step in the pursuit of novel therapeutic interventions against a disease process as nebulous as sepsis. Lastly, the sound, methodical scientific method used by these investigators should serve as a template for those of us who pursue this and similar lines of preclinical and clinical investigation.
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No reprints will be ordered.
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