Letters to the Editor

	ABSTRACT

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The following is the abstract of the article discussed in the subsequent letter:

Worrall, Neil K., Kathy Chang, Wanda S. LeJeune, Thomas P. Misko, Patrick M. Sullivan, T. Bruce Ferguson, Jr., and Joseph R. Williamson. TNF- causes reversible in vivo systemic vascular barrier dysfunction via NO-dependent and -independent mechanisms. Am. J. Physiol. 273 (Heart Circ. Physiol. 42): H2565-H2574, 1997.Tumor necrosis factor (TNF-) and nitric oxide (NO) are important vasoactive mediators of septic shock. This study used a well-characterized quantitative permeation method to examine the effect of TNF- and NO on systemic vascular barrier function in vivo, without confounding endotoxemia, hypotension, or organ damage. Our results showed 1) TNF- reversibly increased albumin permeation in the systemic vasculature (e.g., lung, liver, brain, etc.); 2) TNF- did not affect hemodynamics or blood flow or cause significant tissue injury; 3) pulmonary vascular barrier dysfunction was associated with increased lung water content and impaired oxygenation; 4) TNF- caused inducible nitric oxide synthase (iNOS) mRNA expression in the lung and increased in vivo NO production; 5) selective inhibition of iNOS with aminoguanidine prevented TNF--induced lung and liver vascular barrier dysfunction; 6) aminoguanidine prevented increased tissue water content in TNF--treated lungs and improved oxygenation; and 7) nonselective inhibition of NOS with N^G-monomethyl-L-arginine increased vascular permeation in control lungs and caused severe lung injury in TNF--treated animals. We conclude that 1) TNF- reversibly impairs vascular barrier integrity through NO-dependent and -independent mechanisms; 2) nonselective NOS inhibition increased vascular barrier dysfunction and caused severe lung injury, whereas selective inhibition of iNOS prevented impaired endothelial barrier integrity and pulmonary dysfunction; and 3) selective inhibition of iNOS may be beneficial in treating increased vascular permeability that complicates endotoxemia and cytokine immunotherapy.

	LETTER

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TNF--induced selective cerebral endothelial leakage and increased mortality risk in postmyocardial infarction depression

To the Editor: The paper of Worrall and co-workers (11) describes a vascular barrier dysfunction in various organs, including the brain, after intraperitoneal injections of recombinant murine tumor necrosis factor- (TNF-) in the rat. This extravasation was characterized quantitatively by isotope-dilution techniques, employing sequential injections of ¹²⁵I- and ¹³¹I-labeled bovine serum albumin. It could be demonstrated that both nitric oxide (NO)-dependent and -independent mechanisms generate the TNF--induced vascular barrier dysfunction. An additional important observation was the reversibility of the TNF--induced leakage, starting ~12 h and ending ~36 h after the intraperitoneal injection. Unfortunately, the paper does not give a description of the anatomic location of the vascular barrier dysfunction in the various organs, and thus it remains unclear whether TNF--induced leakage is a generalized or regional effect. Previously, we presented evidence of a selective cerebral endothelial leakage after acute myocardial infarction (MI) and intravenous injections of murine recombinant TNF-, but not interleukin-1, in the rat, using immunocytochemical methods (8, 10) that showed the same time span of development. Both MI and recombinant TNF- generated a selective neuronal IgG and albumin immunoreactivity in some limbic forebrain areas, particularly in the anterior cingulate gyrus (10).

These observations may have clinical relevance with respect to development of neuropsychiatric diseases, for example, after MI. A consistent finding in post-MI patients is that ~15-20% will develop major depression and that occurrence of this mood disorder is associated with a significantly increased risk of mortality (3). The relation between MI and the occurrence of major depression is not clear, but it may be related to derangement of higher limbic function, because these regions participate in both cardiovascular activity control (7, 9) and emotional responses (4). Anatomic and functional neuroimaging studies have implicated, among other forebrain regions, the anterior cingulate cortex in primary depression (1, 2). Moreover, metabolism in the rostral anterior cingulate of depressed patients uniquely differentiated responders and nonresponders to antidepressant treatment at baseline (6). MI is accompanied by significantly increased levels of cytokines including TNF- for at least several hours to days after occurrence of the event (5). Therefore, endothelial leakage, as shown by Worrall et al. (11) and by us could be long lasting in these patients, creating opportunities for potentially neurotoxic substances, including cytokines and macrophages, to penetrate the brain. Considering our observations on locations of such leakage in the brain, this would imply that, in particular, neuronal functioning and integrity in limbic forebrain areas participating in cardiovascular control and emotional responses are being challenged. Therefore, we hypothesize that TNF--mediated cerebral vascular dysfunction in the limbic forebrain predisposes MI patients for both occurrence of post-MI depression and associated increased risk of mortality.

	REFERENCES

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1.   Devinsky, O., M. J. Morrell, and B. A. Vogt. Contributions of anterior cingulate cortex to behaviour. Brain 118: 279-306, 1995[Abstract/Free Full Text].

2.   Drevets, W. C., T. O. Videen, J. L. Price, S. H. Preskom, S. T. Carmichael, and M. E. Raichle. A functional anatomical study of unipolar depression. J. Neurosci. 12: 3628-3641, 1992[Abstract].

3.   Glassman, A. H., and P. A. Shapiro. Depression and the course of coronary artery disease. Am. J. Psychiatry 155: 4-11, 1998[Abstract/Free Full Text].

4.   LeDoux, J. E. The Emotional Brain. New York: Simon and Schuster, 1996.

5.   Lissoni, P., F. Pelizzoni, O. Mauri, M. Perego, S. Pittalis, and S. Barni. Enhanced secretion of tumour necrosis factor in patients with myocardial infarction. Eur. J. Med. 1: 277-280, 1992[Medline].

6.   Mayberg, H. S., S. K. Brannan, R. K. Mahurin, P. A. Jerabek, J. S. Brickman, J. L. Tekell, J. A. Silva, S. McGinnis, T. G. Glass, C. C. Martin, and P. T. Fox. Cingulate function in depression: a potential predictor of treatment response. Neuroreport 8: 1057-1061, 1997[Medline].

7.   Ter Horst, G. J., R. W. M. Hautvast, M. J. L. De Jongste, and J. Korf. Neuroanatomy of cardiac activity-regulating circuitry: a transneuronal retrograde viral labelling study in the rat. Eur. J. Neurosci. 8: 2029-2041, 1996[Medline].

8.   Ter Horst, G. J., J. G. Nagel, M. J. L. De Jongste, and Y. D. Van der Werf. Selective blood brain barrier dysfunction after intravenous injections of rTNF in the rat. In: Neurochemistry: Cellular, Molecular and Clinical Aspects, edited by A. Teelken, and J. Korf. New York: Plenum, 1997, p. 141-146.

9.   Ter Horst, G. J., and F. Postema. Forebrain parasympathetic control of heart activity: retrograde transneuronal viral labeling in rats. Am. J. Physiol. 273 (Heart Circ. Physiol. 42): H2926-H2930, 1997[Abstract/Free Full Text].

10.   Van der Werf, Y. D., M. J. L. De Jongste, and G. J. Ter Horst. The immune system mediates blood brain barrier damage: possible implications for pathophysiology of neuropsychiatric illnesses. Acta Neuropsychiatr. 7: 114-121, 1995.

11.   Worrall, N. K., K. Chang, W. S. LeJeune, T. P. Misko, P. M. Sullivan, T. B. Ferguson, Jr., and J. R. Williamson. TNF- causes reversible in vivo systemic vascular barrier dysfunction via NO-dependent and -independent mechanisms. Am. J. Physiol. 273 (Heart Circ. Physiol. 42): H2565-H2574, 1997[Abstract/Free Full Text].

Gert J. Ter Horst, Department of Biological Psychiatry University of Groningen 9700 RB Groningen, The Netherlands