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(Chest. 2005;127:1076-1077.)
© 2005 American College of Chest Physicians

Vascular Permeability in Active Pulmonary Tuberculosis

Ken-ichiro Inoue, MD, PhD; Hirohisa Takano, MD, PhD; Rie Yanagisawa, PhD and Toshikazu Yoshikawa, MD, PhD

National Institute for Environmental Studies, Tsukuba, Japan Kyoto Prefectural University of Medicine, Kyoto, Japan

Correspondence to: Ken-ichiro Inoue, MD, Inhalation Toxicology Research Team, and Pathophysiology Research Team, National Institute for Environmental Studies, 16–2 Onogawa, Tsukuba, 305-8506, Japan; e-mail: inoue.kenichirou{at}nies.go.jp

To the Editor:

We read with great interest the recent prospective clinical study by Alatas et al1 (June 2004). We would like to add few comments to their work. First of all, we are interested in the wide variance of the serum vascular endothelial growth factor (VEGF) levels in patients with active pulmonary tuberculosis as compared with those in patients with inactive pulmonary tuberculosis or in healthy subjects. In particular, we want to be informed of the detailed profiles of patients with > 1,000 pg/mL of VEGF levels. Were there any correlative factors such as clinical symptoms or laboratory data with the high levels of VEGF? As Alatas and colleagues described in the discussion, larger clinical studies are needed to find the factors in close association with VEGF titers.

We also want to introduce another candidate for an indicator of active pulmonary tuberculosis. Metallothionein is a highly conserved, low-molecular-weight, cysteine-rich protein. Metallothionein has been proposed to play an important role in homeostasis and detoxication of heavy metals. Metallothionein can serve as a sacrificial scavenger for hydroxyl radicals in vitro2 and protects against free radical-induced DNA damage.345 Since proinflammatory cytokines, including tumor necrosis factor-{alpha}, interleukin (IL)-1, IL-6, and interferon-{gamma}, induce hepatic metallothionein gene expression, the role of metallothionein in inflammatory diseases has been focused. Recently, we have demonstrated that metallothionein-null (-/-) mice were more susceptible than corresponding wild-type mice to lung inflammation, especially to lung edema, which were induced by intratracheal challenge with bacterial endotoxin.6 We confirmed that metallothionein proteins in the lungs were detected in endothelial cells and alveolar epithelial cells of wild-type mice, whereas they were not detected in those of metallothionein (-/-) mice by immunohistochemistry. After endotoxin challenge, metallothionein deficiency enhanced vacuolar degeneration of pulmonary endothelial cells and type I alveolar epithelial cells, and caused focal loss of the basement membrane without any significant differences in the enhanced local (lung) expression of proinflammatory cytokines and chemokines or in the activation of nuclear factor-{kappa}B pathway in the lung between the two genotypes. We concluded that endogenous metallothionein is defensive against acute lung injury related to bacterial endotoxin, possibly via the protection of pulmonary vascular integrity.6 Additional researches targeting metallothionein in pulmonary tuberculosis might throw new therapeutic strategies to this persistent infectious disease.

References

  1. Alatas, F, Alatas, O, Metintas, M, et al (2004) Vascular endothelial growth factor levels in active pulmonary tuberculosis. Chest 125,2156-2159[Abstract/Free Full Text]
  2. Thornalley, PJ, Vasak, M Possible role for metallothionein in protection against radiation-induced oxidative stress: kinetics and mechanism of its reaction with superoxide and hydroxyl radicals. Biochim Biophys Acta 1985;827,36-44[CrossRef][Medline]
  3. Abel, J, de Ruiter, N Inhibition of hydroxyl-radical-generated DNA degradation by metallothionein. Toxicol Lett 1989;47,191-196[CrossRef][ISI][Medline]
  4. Chubatsu, LS, Meneghini, R Metallothionein protects DNA from oxidative damage. Biochem J 1993;291,193-198
  5. Schwarz, MA, Lazo, JS, Yalowich, JC, et al Metallothionein protects against the cytotoxic and DNA-damaging effects of nitric oxide. Proc Natl Acad Sci U S A 1995;92,4452-4456[Abstract/Free Full Text]
  6. Takano, H, Inoue, K, Yanagisawa, R, et al Protective role of metallothionein in acute lung injury induced by bacterial endotoxin. Thorax 2004;59,1059-1062

Fusun Alatas, MD; Ozkan Alatas, MD; Muzaffer Metintas, MD; Aysen Ozarslan, MD; Sinan Erginel, MD and Hüseyin Yildirim, MD

Osmangazi Universitesi Tip Fakültesi, Eskisehir, Turkey

Correspondence to: Fusun Alatas, MD, Osmangazi Universitesi Tip Fakültesi, Gogüs Hastaliklari ABD, 26470-Eskisehir, Turkey; e-mail: fusunalatas{at}yahoo.com

To the Editor:

We thank Dr. Inoue and colleagues for their comments on our recently published article.1 Indeed, the active tuberculosis patients have a wide range of vascular endothelial growth factor (VEGF) levels in our study. The lowest and highest levels that we observed were 202 pg/mL and 1,538 pg/mL, respectively. We have five patients with VEGF levels > 1,000 pg/mL. All of these patients have bilateral infiltration in their chest radiographs. A significant correlation (p < 0.05) was observed between VEGF levels and fever in active pulmonary tuberculosis patients. However, there was not any other correlation between VEGF levels and clinical or laboratory data.

Metallothionein may be an interesting marker since the imbalance between oxidants and the antioxidant defense system is an important issue in both tuberculosis and other inflammatory diseases.2 The investigations to determine a marker for the active form of tuberculosis will continue in the future.

References

  1. Alatas, F, Alatas, O, Metintas, M, et al Vascular endothelial growth factor levels in active pulmonary tuberculosis. Chest 2004;125,2156-2159
  2. Wild, I, Seaman, T, Hoal, EG, et al Total antioxidant levels are low during active TB and rise with anti-tuberculosis therapy. IUBMB Life 2004;56,101-106[ISI][Medline]




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