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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online October 13, 2005 as doi:10.1096/fj.05-3782fje. |
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* Dipartimento di Patologia Animale, Igiene e Sanità Pubblica Veterinaria, Sezione di Biochimica e Fisiologia Veterinaria, Università degli Studi di Milano, Milan, Italy;
Dipartimento di Morfofisiologia Veterinaria e Produzioni Animali, Università di Bologna, Bologna, Italy;
Dipartimento di Scienze Chirurgiche e Terapia Intensiva, Università Milano-Bicocca, Milan, Italy;
Dipartimento Clinico Veterinario, Università di Bologna, Bologna, Italy; and
|| Immunobiology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
1Correspondence: E-mail: silvia.mazzola{at}unimi.it
SPECIFIC AIMS
Endotoxic shock is one of the most prominent causes of mortality in intensive care units. Humans share the same symptoms as pigs, including fever, metabolic dysfunctions, systemic hypotension, pulmonary hypertension, vascular leakage resulting in lung edema, and increased proinflammatory cytokines, including IL-1ß and TNF
. Likewise, disseminated intravascular coagulation (DIC) and similar end-organ failure are observed in the pig and in humans.
We studied the effects of CO administration in a model of endotoxic shock in pigs because this shock model bears close resemblance to the human clinical entity.
Carbon monoxide (CO), a product of the degradation of heme by heme oxygenases (HO), has long been regarded solely as a toxic gas. Recent evidence, however, shows that CO is a molecule that regulates cellular processes and has other salutary functions. A growing number of studies in rodents support the hypothesis that expression of heme oxygenase-1 (HO-1) or administration of CO can exert potent therapeutic effects in a variety of diseases/disorders. The doses of CO used in the therapeutic studies are well below concentrations that have been shown to have toxic consequences. Both in vivo and in vitro anti-inflammatory and antiapoptotic effects in rodent models of endotoxic shock have been described. However, the beneficial effects of CO have been demonstrated only in rodents, with a single exception described in a study that appeared while this paper was being prepared. Of the reports in the literature, only a few have probed the physiological and functional processes afforded by CO. We studied the effects of CO in a LPS-induced acute lung injury in pigs that closely mimics that observed in human ARDS patients.
PRINCIPAL FINDINGS
1. In the CO-treated pigs, the percent carboxyhemoglobin rose to 14.08 ± 1.34 after 1 h of CO inhalation.
COHb levels were 8.7 ± 0.42% 30 min after discontinuing CO and starting 100% O2 inhalation and returned to baseline (4.63±0.64%) after 90’.
2. CO pretreatment completely prevented the increase in respiratory resistance (Rrs) induced by LPS.
The Rrs values at 120 and 150 min in the CO+LPS group were lower than the values at time zero (P<0.03).
3. CO pretreatment completely prevented the LPS induced decrease in respiratory compliance (Crs).
Crs values did not vary over the experimental time in the CO+LPS group and showed significant differences at each time point compared with the control group (P<0.001).
4. CO pretreatment significantly ameliorated the degree of acidosis ensued during the LPS infusion (P<0.05).
5. CO pretreatment improved heart function, preventing the progressive and continuing decreases in stroke volume (SV) induced by LPS in the control group (P<0.05).
6. CO pretreatment significantly suppressed the up-regulation of IL-1ß to undetectable levels (P<0.001).
7. CO augmented LPS-induced IL-10 levels in the serum, which was maintained until the end of the experiment.
8. CO pretreatment improved the coagulation status, with fewer signs of disseminated intravascular coagulation precipitated by LPS, reflected by a significant reduction in fibrinogen consumption and D-dimer formation (P<0.05).
9. The loss of organ function with LPS was also improved by CO pretreatment in the kidney and in the liver.
10. As previously shown, CO pretreatment blocked LPS-induced ICAM expression (Fig. 1
).
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11. CO pretreatment ameliorated the lung inflammatory response LPS-induced, reducing thrombosis and neutrophilic margination in alveolar capillaries and the thickening of the alveolar septa.
CONCLUSIONS AND SIGNIFICANCE
The observation that in rodents CO can be a therapeutic gas when used at appropriate concentrations begged the question of whether CO would have similar effects in a larger animal species such as the pig. The therapeutic effects of CO have been studied primarily in rodents, with only one other report in pigs. We tested the effect of CO in a well-known model of continuous LPS infusion in pigs that allowed us to evaluate pathophysiologic functional readouts, including pulmonary wedge pressures. CO diminished the adverse effects of LPS on pigs at several levels.
The principal findings of studies in this porcine model of endotoxic shock were that pretreatment with inhaled CO significantly ameliorated several acute pathological changes induced by LPS. Perhaps more important, these effects occurred when CO was administered only as a pretreatment. Moreover, the CO was stopped just before LPS administration, at which point the animals were placed on 100% O2, which would remove the CO at a much faster rate; thus CO was present systemically for an even shorter period, especially in the lung.
During LPS-induced endotoxic shock, a major disturbance is in lung mechanics, as shown by derangement of resistance and compliance of the respiratory system. As a result of the infusion of LPS, resistance (Rrs) increases and compliance (Crs) decreases, making respiration more difficult. There is exudation of fluid into the lung, measured as extravascular lung water (EVLW), as well as a worsening of gas exchange leading to increased PCO2 (acidosis). CO benefited most of these processes, resulting in an overall improvement in lung function and respiratory distress. Pretreatment with CO improved both Rrs and Crs. The Rrs decreased and Crs increased significantly, leading to an underpinning for good respiratory mechanics. These results lead us to believe that the protective role exerted by CO is due to an improvement in alveolar-capillary water trafficking, typically altered during acute lung injury. This beneficial effect of CO on the development of lung edema, not been seen before in studies of lung injury in rodents, will assist potential clinical use of CO. In humans, administration of substances able to block IL-1ß activity ameliorated the effects of chronic inflammation but not acute effects. Anti-TNF therapy has shown mixed results in limiting end-organ failure. We posit that perhaps TNF- is not the best predictor of outcome in the shock state.
Our work also demonstrates that administration of CO exerts beneficial effects on disseminated intravascular coagulation (DIC). CO pretreatment reduced the development of DIC, as supported by less consumption of fibrinogen and lower levels of D-dimers in the CO pretreated group, which most likely contributes to less microthrombi as confirmed by the lung tissue histological analysis, and improved vascular tone. The less severe DIC in the CO pretreated group could contribute to decreased organ dysfunction as evidenced by the creatinine plasma levels, a specific index of kidney function, and by plasma AST levels, a measure of liver damage; both are significantly ameliorated by CO administration.
These results extend previous work in rodents where CO exposure resulted in the generation of an anti-inflammatory phenotype. These studies lacked relevance in terms of organ physiology. Critical data in terms of overall interpretation of efficacy and the effects on end-organ dysfunction in the septic state, which until now had not been shown, contribute to understanding the effects on respiratory mechanics.
Our studies suggest that CO pretreatment may be beneficial in endotoxic shock in humans. However, the exact concentrations to be used, the length of exposure as well as the timing at which point should CO be first administered vis-à-vis the stage of the endotoxic shock, clearly requires further studies as does intense toxicological profiling in large animal models that result in a good model for human use.
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FOOTNOTES
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.05-3782fje;
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