Abstract
This paper describes the effects of the thiol compounds glutathione and N-acetylcysteine and the seleno-organic agent Ebselen on the development of Sephadex-induced lung edema and cell infiltration in the rat. Neither thiol had any effect upon the development of the edema when administered in large, repeated doses. In contrast, when Ebselen was co-administered with the thiols, there was a dose-dependent inhibition of the development of the edema, but lung weights could not be returned to normal values. However, when the thiols were omitted and Ebselen was administered alone, the development of the edema was totally blocked. In addition, in Ebselen-only treated animals there was a selective inhibition of the infiltration of lymphocytes, basophils and eosinophils into the lung lumen without affecting the populations of macrophages and neutrophils. Again, the Ebselen-induced effect was reduced by coadministration of either thiol. These findings are discussed in terms of the potential mechanism of action of Ebselenin vivo and of the possibility of Ebselen being of therapeutic potential in cases of diffuse pulmonary inflammation in humans.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- O2 7 :
-
Superoxide anion
- H2O2 :
-
Hydrogen peroxide
- OH:
-
Hydroxyl radical
- PMN:
-
Polymorphonuclear leucocytes
- ACU:
-
Alveolar-capillary unit
- GSH:
-
Glutathione
- NAC:
-
N-acetylcysteine
- Ebselen:
-
2-phenyl-1,2-benziososelenazol-3(2H)-one
- DMSO:
-
Dimethylsulfoxide
- PEG:
-
Polyethylene glycol
- GSH-px:
-
Glutathione peroxidase
- DMTU:
-
Dimethylthiourea
- LT:
-
Leukotriene
References
R. K. Albert,Sites of leakage in pulmonary edema in the pulmonary circulation and acute lung injury, pp. 189–208 (Ed. S. I. Seid) Futura Publishing Co. Inc., New York 1985.
P. M. Henson and R. B. Johnston,Tissue injury in inflammation. Oxidants, proteinases and cationic proteins, J. Clin. Invest.79, 669–674 (1987).
B. A. Freeman and J. O. Crapo,Biology of diseases. Free radicals and tissue injury, Lab. Invest.47, 412–426 (1982).
N. Suttorp and L. M. Simon,Lung cell oxidant injury: enhancement of polymorphonuclear leucocyte mediated cytotoxicity in lung cells exposed to sustained in vitro hyperoxia, J. Clin. Invest.70, 342–350 (1982).
S. J. Weiss, F. Young, A. Lobuglio, A. Slivka and N. F. Nimej,Role of hydrogen peroxide in neutrophil-mediated destruction of cultured endothelial cells, J. Clin. Invest.68, 714–721 (1981).
N. Suttorp, W. Toepfer and L. Roka,Antioxidant defence mechanisms of endothelial cells: glutathione redox cycle versus catalase, Am. J. Physiol.251, 671–680 (1986).
P. J. Kadowitz, D. B. McNamara and A. L. Hyman,Leukotrienes, the pulmonary circulation and vascular injury, Int. Ref.1, 123–134 (1985).
L. Källström, R. Brattsand, V. Lövgren, E. Svensjö and K. Roempke,A rat model for testing anti-inflammatory action in lung and the effect of glucocorticoids (GCS) in this model, Agents and Actions17, 355–357 (1985).
R. G. Crystal, P. B. Bittermann, S. I. Rennard, A. J. Hance and B. A. Keogh,Interstitial lung diseases of unknown causes. Disorders characterized by chronic inflammation of the lower respiratory tract, N. Engl. J. Med.310, 154–166 (1985).
R. G. Crystal, P. B. Bittermann, S. I. Rennard, A. J. Hance and B. A. Keogh,Interstitial lung diseases of unknown causes. Disorders characterized by chronic inflammation of the lower respiratory tract, N. Engl. J. Med.310, 235–244 (1985).
G. Semenzato, M. Chilosi, E. Ossi, L. Trentin, G. Pizzolo, A. Cipriani, C. Agostini, R. Zambello, G. Marcer and G. Gasparotto,Bronchiolalveolar lavage and lung histology. Comparative analysis of inflammatory and immunocompetent cells in patients with sarcoidosis and hypersensitivity pneumonitis, Am. Rev. Respir. Dis.132, 400–404 (1985).
P. Andersson, M. Chignard, C. Brange, T. Nilsson, M. Juhlin and Le-Couedic,Effect of glucocorticosteroid treatment on antigen-induced mediator release from sensitized guinea pig lungs. In:Glucocorticosteroids, inflammation and bronchial hypersensitivity, pp. 132–135 (Eds. J. C. Hogg, R. Ellul-Mecallef and R. Brattsand) Excerpta Medica, Amsterdam 1985.
I. A. Cotgreave, A. Eklund, K. Larsson and P. Moldéus,No penetration of orally administered N-acetylcysteine into broncheoalveolar lavage fluid, Eur. J. Respir. Dis.70, 73–77 (1987).
I. A. Cotgreave, R. C. Grafström and P. Moldéus,Modulation of pneumotoxicity by cellular glutathione and precursors, Bull. Eur. Physiopathol. Respir.22, 263s-266s (1986).
C. E. Petterson, J. A. Butler, F. D. Bryne and M. L. Rhodes,Oxidant lung injury: Intervention with sulfhydryl reagents, Lung163, 23–32 (1985).
Eur. Pat. Appl. 44, 1971; Ger. 3,027,073; Jpn. K-8256,427; US 4,352,799. A. Nattermann and Cie GmbH, Köln, West Germany.
A. Müller, R. Cadenas, P. Graf and H. Sies,A novel biologically active seleno-organic compound I. Glutathione peroxidase activity in vitro and anti-oxidant capacity of PZ51 (Ebselen), Biochem. Pharmac.33, 3235–3240 (1984).
M. Hayashi and T. F. Slater,Inhibitory effects of Ebselen on lipid peroxidation in rat liver microsomes, Free Rad. Res. Comm.2, 179–185 (1986).
I. A. Cotgreave, M. S. Sandy, M. Berggren, P. Moldéus and M. T. Smith,N-acetylcysteine and glutathione dependent protective effect of PZ51 (Ebselen) against diquat-induced cytotoxicity in isolated hepatocytes, Biochem. Pharmacol.36, 2899–2904 (1987).
H. Safayhi, G. Tiegs and A. Wendel,A novel biologically active seleno-organic compound V. Inhibition by Ebselen (PZ51) of rat peritoneal neutrophil lipoxygenase, Biochem. Pharmac.34, 2691–2694 (1985).
P. Kuhl, H. O. Borbe, H. Fischer, A. Römer and H. Safahi,Ebselen reduces the formation of LTB 4 in human and porcine leucocytes by isomerisation to its 5S-12R-6-trans isomer, Prostaglandins31, 1029 (1986).
M. J. Parnham, S. Leyck, P. Kuhl, J. Schalkwijk and W. B. Van den Berg,Ebselen: A new approach to the inhibition of peroxide-dependent inflammation, Int. J. Tiss Reac9, 45–50 (1987).
A. Wendel and G. Tiegs,A novel biologically active selenoorganic compound VI. Protection by Ebselen (PZ51) against galactosamine/endotoxin-induced hepatitis in mice, Biochem. Pharmac.35, 2115–2118 (1986).
R. Brattsand, L. Källström, U. Johansson and M. Dahlbäck,Routes of administration and rapid inactivation as determinants of the lung specific actions of glucocorticosteroids. Glucocorticoids, inflammation and bronchial hypersensitivity, pp. 145–153, Excerpta Medica, Amsterdam 1985.
I. A. Cotgreave, U. Johansson, P. Moldéus and R. Brattsand,The effect of acute cigarette smoke inhalation on pulmonary and systemic cysteine and glutathione redox states in the rat, Toxicology45, 203–212 (1987).
R. L. Byyny,Withdrawl from glucocorticoid therapy, N. Engl. Med.295, 30–32 (1976).
Author information
Authors and Affiliations
Additional information
To whom correspondence should be addressed.
Rights and permissions
About this article
Cite this article
Cotgreave, I.A., Johansson, U., Westergren, G. et al. The anti-inflammatory activity of Ebselen but not thiols in experimental alveolitis and bronchiolitis. Agents and Actions 24, 313–319 (1988). https://doi.org/10.1007/BF02028288
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02028288