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. 1992;127(1):11–24. doi: 10.1007/BF01309571

Pathogenesis of cytomegalovirus-associated pneumonitis in ICR mice: possible involvement of superoxide radicals

T Ikeda 1,2, K Shimokata 1, T Daikoku 2, T Fukatsu 3, Y Tsutsui 4, Y Nishiyama 2
PMCID: PMC7102218  PMID: 1333750

Summary

We have studied the pathogenesis of murine cytomegalovirus (MCMV) pneumonitis in immunocompetent ICR mice and in mice treated with cyclophosphamide (CP). Intranasal infection of immunocompetent mice with MCMV resulted in transient and self-limited pulmonary lesions. When mice were given 200 mg/kg of CP one day before virus infection, transient splenic atrophy and subsequent splenic hypertrophy were induced, and the lesions in the lung were markedly augmented in their number and size although there was no significant enhancement of the virus growth. The augmentation coincided with the period of splenic hypertrophy. A marked increase in the number of pulmonary lesions was also induced in mice given 100 mg/kg of CP every 4 days following the initial dose of 200 mg/kg. In these mice, however, continuous splenic atrophy and augmented replication of MCMV in the lung were observed. When the activity of xanthine oxidase (XO) in lung tissue homogenates was measured, the activity was found to significantly increase after intranasal infection with MCMV irrespective of CP administration and there was a good correlation between the elevation of XO activity and the degree of pathological changes in the lung. In addition, we found that the administration of allopurinol, a specific inhibitor of XO and superoxide dismutase, a superoxide radical scavenger, reduced the number of the pulmonary lesions. These results suggest that superoxide radicals are involved in the pathogenesis of MCMV-associated pneumonitis in ICR mice.

Keywords: Superoxide, Cyclophosphamide, Superoxide Dismutase, Xanthine, Superoxide Radical

References

  • 1.Akaike T, Ando M, Oda T, Doi T, Ijiri S, Araki S, Maeda H. Dependence on O2− generation by xanthine oxidase of pathogenesis of influenza virus infection in mice. J Clin Invest. 1990;85:739–745. doi: 10.1172/JCI114499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Appelbaum FR, Meyers JD, Fefer A, Flournoy N, Cheever MA, Greenberg PD, Hackman R, Thomas ED. Nonbacterial nonfungal pneumonia following marrow transplantation in 100 identical twins. Transplantation. 1982;33:265–268. doi: 10.1097/00007890-198203000-00011. [DOI] [PubMed] [Google Scholar]
  • 3.Avis PG, Bergel F, Bray RC (1955) Cellular constituents. The chemistry of xanthine oxidase. Part I. The preparation of a crystalline xanthine oxidase from cow's milk. J Chem Soc 1100–1105
  • 4.Babior BM, Kipnes RS, Curnutte JT. Biologic defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J Clin Invest. 1973;52:741–744. doi: 10.1172/JCI107236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Barry BE, Crapo JD. Patterns of accumulation of platelets and neutrophils in rat lungs during exposure to 100% and 85% oxygen. Am Rev Respir Dis. 1985;132:548–555. doi: 10.1164/arrd.1985.132.3.548. [DOI] [PubMed] [Google Scholar]
  • 6.Brody AR, Craighead JE. Pathogenesis of pulmonary cytomegalovirus infection in immunosuppressed mice. J Infect Dis. 1974;129:677–689. doi: 10.1093/infdis/129.6.677. [DOI] [PubMed] [Google Scholar]
  • 7.Cantin AM, North SL, Fells GA, Hubbard RC, Crystal RG. Oxidant-mediated epithelial cell injury in idiopathic pulmonary fibrosis. J Clin Invest. 1987;79:1665–1673. doi: 10.1172/JCI113005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Carp H, Janoff A. Possible mechanisms of emphysema in smokers. In vitro suppression of serum elastase-inhibitory capacity by fresh cigarette smoke and its prevention by antioxidants. Am Rev Respir Dis. 1978;118:617–621. doi: 10.1164/arrd.1978.118.3.617. [DOI] [PubMed] [Google Scholar]
  • 9.Cochrane CG, Spragg R, Revak SD. Pathogenesis of the adult respiratory distress syndrome. Evidence of oxidant activity in bronchoalveolar lavage fluid. J Clin Invest. 1983;71:754–761. doi: 10.1172/JCI110823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Emanuel D, Cunningham I, Jules-Elysee K, Brochstein JA, Kernan NA, Laver J, Stover D, White DA, Fels A, Polsky B, Castro-Malaspina H, Peppard JR, Bartus P, Hammerling U, O'Reilly RJ. Cytomegalovirus pneumonia after bone marrow transplantation successfully treated with the combination of ganciclovir and high-dose intravenous immune globulin. Ann Intern Med. 1988;109:777–782. doi: 10.7326/0003-4819-109-10-777. [DOI] [PubMed] [Google Scholar]
  • 11.Gill HK, Liew FY. Regulation of delayed-type hypersensitivity III. Effect of cyclophosphamide on the suppressor cells for delayed-type hypersensitivity to sheep erythrocytes in mice. Eur J Immunol. 1978;8:172–176. doi: 10.1002/eji.1830080306. [DOI] [PubMed] [Google Scholar]
  • 12.Grum CM, Ragsdale RA, Ketai LH, Simon RH. Plasma xanthine oxidase activity in patients with adult respiratory distress syndrome. J Crit Care. 1987;2:22–26. [Google Scholar]
  • 13.Grundy JE, Shanley JD, Griffiths PD. Is cytomegalovirus interstitial pneumonitis in transplant recipients an immunopathological condition? Lancet. 1987;ii:996–999. doi: 10.1016/s0140-6736(87)92560-8. [DOI] [PubMed] [Google Scholar]
  • 14.Hurd J, Heath RB. Effect of cyclophosphamide on infections in mice caused by virulent and avirulent strains of influenza virus. Infect Immun. 1975;11:886–889. doi: 10.1128/iai.11.5.886-889.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Jarasch E-D, Bruder G, Heid HW. Significance of xanthine oxidase in capillary endothelial cells. Acta Physiol Scand. 1986;548(Suppl):39–46. [PubMed] [Google Scholar]
  • 16.Jordan MC. Interstitial pneumonia and subclinical infection after intranasal inoculation of murine cytomegalovirus. Infect Immun. 1978;21:275–280. doi: 10.1128/iai.21.1.275-280.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Massey V, Brumby PE, Komai H, Palmer G. Studies on milk xanthine oxidase. Some spectral and kinetic properties. J Biol Chem. 1969;244:1682–1691. [PubMed] [Google Scholar]
  • 18.McCord JM, Wong K, Stokes SH, Petrone WF, English D. Superoxide and inflammation: a mechanism for the anti-inflammatory activity of superoxide dismutase. Acta Physiol Scand. 1980;492(Suppl):25–29. [PubMed] [Google Scholar]
  • 19.Oda T, Akaike T, Hamamoto T, Suzuki F, Hirano T, Maeda H. Oxygen radicals in influenza-induced pathogenesis and treatment with pyran polymer-conjugated SOD. Science. 1989;244:974–976. doi: 10.1126/science.2543070. [DOI] [PubMed] [Google Scholar]
  • 20.Quinnan GV, Manischewitz JE. The role of natural killer cells and antibody-dependent cell-mediated cytotoxicity during murine cytomegalovirus infection. J Exp Med. 1979;150:1549–1554. doi: 10.1084/jem.150.6.1549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Quinnan GV, Manischewitz JE, Ennis FA. Role of cytotoxic T lymphocytes in murine cytomegalovirus infection. J Gen Virol. 1980;47:503–508. doi: 10.1099/0022-1317-47-2-503. [DOI] [PubMed] [Google Scholar]
  • 22.Quinnan GV, Manischewitz JE, Kirmani N. Involvement of natural killer cells in the pathogenesis of murine cytomegalovirus interstitial pneumonitis and the immune response to infection. J Gen Virol. 1982;58:173–180. doi: 10.1099/0022-1317-58-1-173. [DOI] [PubMed] [Google Scholar]
  • 23.Reed EC, Bowden RA, Dandliker PS, Lilleby KE, Meyers JD. Treatment of cytomegalovirus pneumonia with ganciclovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplants. Ann Intern Med. 1988;109:783–788. doi: 10.7326/0003-4819-109-10-783. [DOI] [PubMed] [Google Scholar]
  • 24.Riccardi C, Barlozzari T, Santoni A, Herberman RB, Cesarini C. Transfer to cyclophosphamide-treated mice of natural killer (NK) cells and in vivo natural reactivity against tumors. J Immunol. 1981;126:1284–1289. [PubMed] [Google Scholar]
  • 25.Rose RM, Crumpacker C, Waner JL, Brain JD. Murine cytomegalovirus pneumonia. Description of a model and investigation of pathogenesis. Am Rev Respir Dis. 1982;125:568–573. doi: 10.1164/arrd.1982.125.5.568. [DOI] [PubMed] [Google Scholar]
  • 26.Selgrade MK, Daniels MJ, Hu PC, Miller FJ, Graham JA. Effects of immunosuppression with cyclophosphamide on acute murine cytomegalovirus infection and virus-augmented natural killer cell activity. Infect Immun. 1982;38:1046–1055. doi: 10.1128/iai.38.3.1046-1055.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Shanley JD, Pesanti EL, Nugent KM. The pathogenesis of pneumonitis due to murine cytomegalovirus. J Infect Dis. 1982;146:388–396. doi: 10.1093/infdis/146.3.388. [DOI] [PubMed] [Google Scholar]
  • 28.Southorn PA, Powis G. Free radicals in medicine. II. Involvement in human disease. Mayo Clin Proc. 1988;63:390–408. doi: 10.1016/s0025-6196(12)64862-9. [DOI] [PubMed] [Google Scholar]
  • 29.Stockman GD, Heim LR, South MA, Trentin JJ. Differential effects of cyclophosphamide on the B and T cell compartments of adult mice. J Immunol. 1973;110:277–282. [PubMed] [Google Scholar]
  • 30.Strausz J, Müller-Quernheim J, Steppling H, Ferlinz R. Oxygen radical production by alveolar inflammatory cells in idiopathic pulmonary fibrosis. Am Rev Respir Dis. 1990;141:124–128. doi: 10.1164/ajrccm/141.1.124. [DOI] [PubMed] [Google Scholar]
  • 31.Tate RM, Repine JE. Neutrophils and the adult respiratory distress syndrome. Am Rev Respir Dis. 1983;128:552–559. doi: 10.1164/arrd.1983.128.3.552. [DOI] [PubMed] [Google Scholar]
  • 32.Tsutsui Y, Naruse I. Murine cytomegalovirus infection of cultured mouse embryos. Am J Pathol. 1987;127:262–270. [PMC free article] [PubMed] [Google Scholar]
  • 33.Tubaro E, Lotti B, Santiangeli C, Cavallo G. Xanthine oxidase increase in polymorphonuclear leucocytes and macrophages in mice in three pathological situations. Biochem Pharmacol. 1979;29:1945–1948. doi: 10.1016/0006-2952(80)90108-2. [DOI] [PubMed] [Google Scholar]
  • 34.Turk JL, Poulter LW. Selective depletion of lymphoid tissue by cyclophosphamide. Clin Exp Immunol. 1972;10:285–296. [PMC free article] [PubMed] [Google Scholar]

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