Skip to main content
SpringerLink
Log in

Attenuation of acute inflammatory effects of silica in rat lung by 21-aminosteroid, U74389G

  • Original Articles
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Chemical alteration of the glucocorticoid, methylprednisolone, has led to the introduction of a new class of compounds called the 21-aminosteroids (21-ASs). The purpose of this study was to investigate the effect of the 21-AS, U74389G, on silica-induced acute lung injury. Male Fischer 344 rats were treated intraperitoneally with saline or U74389G in a total dose of 15 mg/kg divided into three injections of 5 mg/kg separated by 4 h. Following the first treatment, animals from the two groups were intratracheally instilled with silica (10 mg/100 g body wt in 0.5 ml of saline) or saline vehicle (0.5 ml). Twenty-four hours after the instillations, bronchoalveolar lavage (BAL) was performed. In the animals not receiving U74389G, marked increases in total protein, (β-glucuronidase, and lactate dehydrogenase (LDH) activities and number of neutrophils (PMNs) were demonstrated in the BAL fluid of the silica-treated animals compared to their controls. Silica also caused dramatic increases in the luminol-dependent chemiluminescence (CL) of lung tissue and BAL cells. The CL reaction was decreased by superoxide dismutase (SOD) andN-nitro-l-arginine methyl ester hydrochloride (L-NAME), a nitric oxide (NO) synthase inhibitor. In animals treated with U74389G, there was attenuation of the silica-induced increases in biochemical, cellular, and chemiluminescent indices of damage. This study demonstrates that U74389G significantly reduces acute lung injury caused by the intratracheal instillation of silica, and this drug may be of potential value for treatment of lung diseases in which damage caused by reactive oxygen species has been implicated.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kehrl, J. H., andA. S. Fauci. 1983. The clinical use of glucocorticoids.Ann. Allergy 50:2–8.

    PubMed  Google Scholar 

  2. DiRosa, M., A. Calignano, R. Carnuccio, A. Ialenti, andL. Sautebin. 1985. Multiple control of inflammation by glucocorticoids.Agents Actions 17:284–289.

    Google Scholar 

  3. Seale, J. P., andM. R. Compton. 1986. Side effects of corticosteroid agents.Med. J. Aust. 144:139–142.

    PubMed  Google Scholar 

  4. Jacobsen, E. J., J. M. McCall, D. E. Ayer, F. J. van Doornik, J. R. Palmer, K. L. Belonga, J. M. Braughler, E. D. Hall, D. J. Houser, M. A. Krook, andT. A. Runge. 1990. Novel 21-aminosteroids that inhibit iron-dependent lipid peroxidation and protect against central nervous system trauma.J. Med. Chem. 33:1145–1151.

    PubMed  Google Scholar 

  5. McCall, J. M., J. M. Braughler, andE. D. Hall. 1987. A new class of compounds for stroke and trauma: Effects of 21-aminosteroids on lipid peroxidation.Acta Anaesth. Belg. 38:417–420.

    PubMed  Google Scholar 

  6. Hall, E. D. 1987. Beneficial effects of the 21-aminosteroid U74006F in acute CNS trauma and hypovolemic shock.Acta Anaesth. Belg. 38:421–425.

    PubMed  Google Scholar 

  7. Hall, E. D. 1988. Effects of the 21-aminosteroid U74006F on post-traumatic spinal cord ischemia in cats.J. Neurosurg. 68:462–465.

    PubMed  Google Scholar 

  8. Aoki, N., andA. M. Lefer. 1990. Protective effect of a novel nonglucocorticoid 21-aminosteroid (U74006F) during traumatic shock in rats.J. Cardiovasc. Pharmacol. 15:205–210.

    PubMed  Google Scholar 

  9. Chumas, P. D., M. R. Del Bigio, J. M. Drake, andU. I. Tour. 1993. A comparison of the protective effect of dexamethasone to other potential prophylactic agents in a neonatal rat model of cerebral hypoxia-ischemia.J. Neurosurg. 79:414–420.

    PubMed  Google Scholar 

  10. Horton, J. W., andP. B. Walker. 1993. Oxygen radicals, lipid peroxidation, and permeability changes after intestinal ischemia and reperfusion.J. Appl. Physiol. 74:1515–1520.

    PubMed  Google Scholar 

  11. Stanley, J. J., J. R. Goldblum, T. S. Frank, G. B. Zelenock, andL. G. D'Alecy. 1993. Attenuation of renal reperfusion injury in rats by the 21-aminosteroid U74006F.J. Vasc. Surg. 17:685–689.

    PubMed  Google Scholar 

  12. Myers, S. I., R. Hernandez, D. J. White, andJ. W. Horton. 1993. Burn injury decreased splanchnic PG12 release is restored by treatment with lazaroid.Prostaglandins 45:535–546.

    PubMed  Google Scholar 

  13. Bowden, D. 1987. Macrophages, dust, and pulmonary diseases.Exp. Lung Res. 12:89–107.

    PubMed  Google Scholar 

  14. Lapp, N. L., andV. Castranova. 1993. How silicosis and coal worker's pneumoconiosis develop—a cellular assessment.In Occupational Medicine: State of the Art Reviews—The Mining Industry, Vol. 8, No. 1. D.E. Banks, editor. Hanley and Belfus, Philadelphia, 35–56.

    Google Scholar 

  15. Richards, I. M., R. L. Griffin, S. F. Fidler, andE. J. Jacobsen. 1993. Effect of the 21-aminosteroid, U74389F, on hyperoxic lung injury in rats.Agents Actions 39:C136-C138.

    PubMed  Google Scholar 

  16. Henderson, R. F. 1984. Use of bronchoalveolar lavage to detect lung damage.Environ. Health Perspect. 56:112–129.

    Google Scholar 

  17. Khan, M. F., andG. S. D. Gupta. 1991. Cellular and biochemical indices of bronchoalveolar lavage for detection of lung injury following insult by airborne toxicants.Toxicol. Lett. 58:239–255.

    PubMed  Google Scholar 

  18. Hartree, E. 1972. Determination of protein: A modification of the Lowry method that gives a linear photometric response.Anal. Biochem. 48:422–427.

    PubMed  Google Scholar 

  19. Lockard, V., andR. Kennedy. 1976. Alterations in rabbit alveolar macrophages as a result of traumatic shock.Lab. Invest. 35:501–506.

    PubMed  Google Scholar 

  20. Wroblewski, F., andJ. S. LaDue. 1955. Lactic acid dehydrogenase activity in blood.Proc. Soc. Exp. Biol. Med. 90:210–213.

    PubMed  Google Scholar 

  21. Goodman, G. B., P. D. Kaplan, I. Stachura, V. Castranova, W. H. Pailes, andN. L. Lapp. 1992. Acute silicosis responding to corticosteroid therapy.Chest 101:366–370.

    PubMed  Google Scholar 

  22. Henderson, R. F., J. R. Harkema, J. A. Hotchkiss, andD. S. Boehme. 1991. Effect of blood leukocyte depletion on the inflammatory response of the lung to quartz.Toxicol. Appl. Pharmacol. 109:127–136.

    PubMed  Google Scholar 

  23. Weiss, S. I., andA. F. LoBuglio. 1982. Biology of disease: phagocyte-generated oxygen metabolites and cellular injury.Lab. Invest. 47:5–18.

    PubMed  Google Scholar 

  24. Wang, J. F., P. Komarov, H. Sies, andH. DeGroot. 1991. Combination of nitric oxide synthase to luminol dependent chemiluminescence by phorbol ester activated Kupffer cells.Biochem. J. 279:311–314.

    PubMed  Google Scholar 

  25. Radi, R., T. P. Cosgrove, J. S. Beckman, andB. A. Freeman. 1993. Peroxynitrite-induced luminol chemiluminescence.Biochem. J. 290:51–57.

    PubMed  Google Scholar 

  26. Radi, R., J. S. Beckman, K. Bush, andB. A. Freeman. 1991. Peroxynitrite oxidation of sulphydryls.J. Biol. Chem. 266:4244–4250.

    PubMed  Google Scholar 

  27. Moreno, J. J., andW. A. Pryor. 1992. Inactivation of alpha-1-proteinase inhibitor by peroxynitrite.Chem. Res. Toxicol. 5:425–431.

    PubMed  Google Scholar 

  28. McCall, T., R. M. J. Palmer, andS. Moncada. 1991. Induction of nitric oxide synthase in rat peritoneal neutrophils and its inhibition by dexamethasone.Eur. J. Immunol. 21:2523–2527.

    PubMed  Google Scholar 

  29. Braughler, J. M., J. F. Pregenzer, R. L. Chase, L. A. Duncan, E. J. Jacobsen, andJ. M. McCall. 1987. Novel 21-aminosteroids as potent inhibitors of iron-dependent lipid peroxidation.J. Biol. Chem. 262:10438–10440.

    PubMed  Google Scholar 

  30. Braughler, J. M., R. L. Chase, G. L. Neff, P. A. Yonkers, J. S. Day, E. D. Hall, V. H. Sethy, andR. A. Lahti. 1988. A new 21-aminosteroid antioxidant lacking glucorticoid activity stimulates adrenocorticotropin secretion and blocks arachidonic acid release from mouse pituitary tumor (AtT-20) cells.J. Pharmacol. Exp. Ther. 244:423–427.

    PubMed  Google Scholar 

  31. Barnes, P. J., andI. Adcock. 1993. Anti-inflammatory actions of steroids: Molecular mechanisms.TiPS 14:436–441.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Robert C. Byrd Health Sciences Center of West Virginia University, P.O. Box 9223, 26506-9223, Morgantown, West Virginia

    James M. Antonini, Knox Van Dyke, Michael DiMatteo & Mark J. Reasor

Authors
  1. James M. Antonini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Knox Van Dyke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael DiMatteo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mark J. Reasor
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Antonini, J.M., Van Dyke, K., DiMatteo, M. et al. Attenuation of acute inflammatory effects of silica in rat lung by 21-aminosteroid, U74389G. Inflammation 19, 9–21 (1995). https://doi.org/10.1007/BF01534376

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01534376

Keywords

Search

Navigation