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Editorial Views  |   April 2005
Brain Cell Damage and S-100B Increase after Acute Lung Injury
Author Affiliations & Notes
  • Andreas Raabe, M.D., Ph.D.
    *
  • * Johann Wolfgang Goethe Uni-versity, Frankfurt am Main, Germany.
Article Information
Editorial Views / Respiratory System
Editorial Views   |   April 2005
Brain Cell Damage and S-100B Increase after Acute Lung Injury
Anesthesiology 4 2005, Vol.102, 713-714. doi:
Anesthesiology 4 2005, Vol.102, 713-714. doi:
ACUTE respiratory distress syndrome  (ARDS) is a severe, inflammatory disease of the lung with a high mortality rate. It is characterized by the sudden onset of pulmonary edema and respiratory failure, usually in the setting of other acute medical conditions resulting from local (e.g.  , pneumonia) or distant (e.g.  , multiple trauma) injury. Previous outcome studies of ARDS have mainly focused on survival, pulmonary function, or both as the primary outcome measures. However, there is increasing evidence that patients with ARDS are at risk for brain injury through hypoxemia or other mechanisms. In this issue of Anesthesiology, Fries et al.  1 demonstrate histopathologic findings of neuronal cell damage in the vulnerable CA1 subregion of the hippocampus and serum S-100B protein increases in a porcine acute lung injury model. Hippocampal damage is a major cause of cognitive impairment and a substantial portion of ARDS survivors exhibit impaired health status and long-term cognitive sequelae.2,3 
The article delivers two important messages. First, acute lung injury in an animal model may cause brain cell damage. However, the observed time course of changes of serum S-100B protein concentrations and the significant differences between the two experimental groups do not allow us to draw conclusions about neuronal damage. S-100B is not specific for the brain, it is believed to originate from glial cells (that are more resistant to hypoxemia than neurons), and increases may also be caused by extracranial injuries,4–6 such as in the setting of an acute lung injury model. Likewise, the differences in S-100B between the two experimental groups may simply reflect the use of two different experimental models. However, the histopathologic finding of argyrophilic dark neurons is considered a reliable and early sign of damaged neurons. The CA1 subregion of the hippocampus is an established model often used to investigate brain damage in the experimental setting. This region of the brain is especially vulnerable to a variety of pathologic conditions, such as ischemia, inflammation, and hypoxia. The study of Fries et al.  1 was designed in a way that both experimental groups, the acute lung injury group and the hypoxia-only group, had nearly the same time course of changes in pulse oxymetry saturation. Therefore, the degree of hypoxemia was comparable between the two groups. The observation of argyrophilic dark neurons in the CA1 subregion of the hippocampus in both groups as a result of hypoxemia was not unexpected but until now unproven. However, there is a difference between the two groups in terms of the degree of brain cell damage. In the lung injury group, the relative percentage of damaged neurons was three times higher compared with the hypoxia group.
This leads us to the second message, which is the intriguing hypothesis that acute lung injury may result in brain cell damage independent of the level of hypoxemia. The authors speculate that the inflammatory response induced by the lavage model of the acute lung injury group but not in the hypoxia-only group is accountable for the difference in neuronal injury.
Repetitive lung lavage leads to lung injury similar to ARDS, resulting in poor gas exchange, protein leakage, infiltration of polymorphonuclear neutrophils into the alveolar spaces, and other local and systemic inflammatory responses.7–11 Conversely, in acute lung injury or ARDS, lung-protective ventilation strategies reduce both hypoxemia and sustained mediator release12–14 with effect on multiorgan failure15 and further mediator production.16 
The brain is believed to be an immunologically privileged organ, normally sheltered from the systemic immunologic defense by the blood–brain barrier. However, there is increasing evidence for a marked inflammatory response in the brain after traumatic brain injury17 and after remote organ injury.18 Using a rodent cecal ligation and puncture model of sepsis, measurements of the proinflammatory cytokine tumor necrosis factor α were increased threefold in septic rat brain (P  < 0.02), and electron microscopic examination revealed scattered injury in approximately 0.25% of glial cells.19 Within minutes after acute myocardial infarction, proinflammatory cytokines increase in the brain, heart, and plasma. It was demonstrated recently that the appearance of proinflammatory cytokines in the brain after myocardial infarction was independent of blood-borne cytokines, suggesting that cardiac sympathetic afferent nerves activated by myocardial ischemia signal the brain to increase cytokine production.18 In turn, local activation of cellular inflammatory responses may exacerbate hypoxic or ischemic brain injury.
It is tempting to see the findings of the study by Fries et al.  1 in the light of inflammation. Unfortunately, this remains speculative, because there were no measurements of cytokines in this study and, hence, there is no evidence that the lung injury and hypoxia-only groups were different in this aspect. We are left with hard evidence of histopathologically proven neuronal cell damage and the feeling that in the clinical setting, a presumably safe arterial partial pressure of oxygen may not be safe enough to protect the vulnerable neurons in the brain from damage during ARDS. The data presented by Fries et al.  1 challenge the clinician because they suggest that in patients with ARDS, we treat not only the lung but also the brain.
This is an important article that provides answers, raises new questions, and should stimulate further research about the cause and prevention of neuronal cell damage after ARDS.
* Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
References
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