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Repeated episodes of C5a-induced neutrophil influx do not result in pulmonary fibrosis

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Abstract

Multiple reactive oxygen species-induced epithelial injury by glucose, glucose oxidase, and lactoperoxidase instillation in the lung results in a progressive interstitial fibrosis. To test the hypothesis that multiple pulmonary inflammatory responses alone would not result in fibrosis, three sequential inflammatory reactions were produced at weekly intervals in hamster lungs via intratracheal instillation of human recombinant C5a. Numbers of neutrophils and total inflammatory cells in bronchoalveolar lavage (BALF) increased significantly at 24 h after each C5a treatment compared with saline controls. Neutrophils increased by 3-, 33-, and 34-fold compared with the corresponding controls at 24 h after the first, second, and third doses, respectively, but returned to control levels by six days postinstillation. LTB4 levels increased by 24% and 20% compared with the corresponding controls at 24 h after the first and second doses but were not different from controls at other times. Hydroxyproline levels in treated animals did not differ significantly from control levels throughout the study. Protein levels were significantly increased at 24 h after the second and third doses and six days after the third dose compared with the corresponding controls. Occasional foci of neutrophils in alveolar spaces were observed at 24 h after each dose, but they decreased in frequency after six days. No foci of neutrophils were observed six days after the final dose, although some epithelial degeneration was observed by transmission electron microscopy. Our results indicate that pulmonary inflammation resulting from repeated influx of neutrophils in response to multiple instillations of C5a in the lung does not cause sufficient injury to result in pulmonary fibrosis.

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References

  1. Karlinski, J.B., andC.H. Goldstein. 1980. Fibrotic lung diseases: a perspective.J. Lab. Clin. Med. 96:939–942.

    Google Scholar 

  2. Terzaghi, M., P. Nettesheim, andM.L. Williams. 1978. Repopulation of denuded tracheal grafts with normal, preneoplastic, and neoplastic epithelial cell populations.Cancer Res. 38:4546–4553.

    Google Scholar 

  3. Witschi, H.P. 1988. Interpretation of early lesions in the mouse lung: Fibrogenesis and tumorigenesis.In Inhalation Toxicology: The Design and Interpretation of Inhalation Studies and Their Use in Risk Assessment. ILSI Monographs. U. Mohr, D. Dungworth, G. Kimmerle, J. Lewkowski, R. McClellan, and W. Stöber, editors. Springer-Verlag, New York. 195–208.

    Google Scholar 

  4. Cochrane, C.G. 1968. Immunologic tissue injury mediated by neutrophilic leukocytes.Adv. Immunol. 9:97–161.

    Google Scholar 

  5. Till, G.O., K.J. Johnson, R. Kunkel, andP.A. Ward. 1982. Intravascular activation of complement and acute lung injury: Dependency on neutrophils and toxic oxygen metabolites.J. Clin. Invest. 69:1126–1135.

    Google Scholar 

  6. Cochrane, C.G., andA. Janoff. 1974. The Arthus reaction: A model of neutrophils and complement mediated injury.In The inflammatory Process, Vol. 3. B.W. Zweifach, L. Grant, and R.L.T. McCluskey. editors. Academic Press, New York. 103–107.

    Google Scholar 

  7. Johnson, K.J. andP.A. Ward. 1974. Acute pulmonary alveolitis.J. Clin. Invest. 54:349–357.

    Google Scholar 

  8. Weiss, S.J. 1989. Tissue destruction by neutrophils.N. Engl. J. Med. 320:365–376.

    Google Scholar 

  9. Klebanoff, S.J. 1988. Phagocytic cells: Products of oxygen metabolism.In Inflammation: Basic Principles and Clinical Correlates. J.I. Gallin, I.M. Goldstein, and R. Snyderman. editors. Raven Press, New York. 391–444.

    Google Scholar 

  10. Thrall, R.S., S.H. Phan, J.R. Mccormick, andP.A. Ward. 1981. The development of bleomycin-induced pulmonary fibrosis in neutrophil-depleted and complement-depleted rats.Am. J. Pathol. 105:76–81.

    Google Scholar 

  11. Nakashima, J. 1989. Oxidant injury, inflammation, epithelial repair and interstitial fibrosis in the hamster lung following intratracheal exposure to glucose oxidase, glucose and lactoperoxidase: Biochemical, bronchoalveolar lavage and morphological correlates. Dissertation. University of California, Davis, California.

    Google Scholar 

  12. Giri, S.N., Z. Chen, W.R. Younker, andM.J. Schiedt. 1983. Effects of intratracheal administration of bleomycin on GSH-shuttle enzymes, catalase, lipid peroxidation and collagen content in the lungs of hamsters.Toxicol. Appl. Pharmacol. 71:132–141.

    Google Scholar 

  13. Giri, S.N., D.M. Hyde, andJ.M. Nakashima. 1986. Analysis of bronchoalveolar lavage fluid from bleomycin-induced pulmonary fibrosis in hamsters.Toxicol. Pathol. 14:149–157.

    Google Scholar 

  14. Willcox, M.L., A. Kervitsky, L.C. Watters, andT.E. King. 1988. Quantification of cells recovered by bronchoalveolar lavage: comparison of cytocentrifuge preparations with the filter method.Am. Rev. Respir. Dis. 138:74–80.

    Google Scholar 

  15. Lowry, O.H., N.J. Rosebrough, A.L. Farr, andR.J. Randall. 1951. Protein measurement with the Folin phenol reagent.J. Biol. Chem. 193:265–275.

    Google Scholar 

  16. Woessner, J.F. 1961. The determination of hydroxyproline in tissue and protein samples containing small proportions of this amino acid.Arch. Biochem. Biophys. 93:440–447.

    Google Scholar 

  17. Giri, S.N., andD.M. Hyde. 1987. Increases in severity of lung damage and mortality by treatment with cyclo and lipoxygenase inhibitors in bleomycin and hyperoxia model of lung injury in hamsters.Pathology 19:150–158.

    Google Scholar 

  18. SAS Institute Inc. 1985. SAS/STAT Guide for Personal Computers. Version 6 edition. SAS Institute Inc., Cary, North Carolina. 183–260.

    Google Scholar 

  19. Regal, J.F. 1988. Role of arachidonate metabolites in C5a-induced bronchoconstriction.J. Pharmacol. Exp. Ther. 246:542–547.

    Google Scholar 

  20. Regal, J.F., andR.L. Bell. 1987. Mediators of C5a-induced bronchoconstriction in the guinea pig.Int. Arch. Allergy Appl. Immunol. 84:414–423.

    Google Scholar 

  21. Lundberg, C., M. Gardinali, andT.E. Hugli. 1987. Complement activation and membrane lipids in lung vascular injury.Am. Rev. Respir. Dis. 136:459–462.

    Google Scholar 

  22. Larsen, G.L., B.C. Mitchell, andP.M. Henson. 1981. The pulmonary response of C5 sufficient and deficient m ce to immune complexes.Am. Rev. Respir. Dis. 123:434–439.

    Google Scholar 

  23. Warren, J.S., S.L. Kunkel, K.J. Johnson, andP.A. Ward. 1987. In vitro activation of rat neutrophils and alveolar macrophages with IgA and IgG immune complexes: Implications for immune complex-induced lung injury.Am. J. Pathol. 129:578–588.

    Google Scholar 

  24. Desai, U., D.L. Kreutzer, H. Showell, C.V. Arroyave, andP.A. Ward. 1979. Acute inflammatory pulmonary reactions induced by chemotactic factors.Am. J. Pathol. 96:71–83.

    Google Scholar 

  25. Worthen, G.S., C. Haslett, L.A. Smedly, A.J. Roes, R.S. Gumbay, J.E. Henson, andP.M. Henson. 1986. Lung vascular injury induced by chemotactic factors: enhancement by bacterial endotoxins.Fed Proc. 45:7–12.

    Google Scholar 

  26. Williams, T.J., andP.J. Jose. 1981. Mediation of increased vascular permeability after complement activation, histamine-independent action of rabbit C5a.J. Exp. Med. 153:136–153.

    Google Scholar 

  27. Snider, G.L., J.A. Hayes, andA.L. Korthy. 1978. Chronic interstitial pulmonary fibrosis produced in hamsters by endotracheal bleomycin.Am. Rev. Respir. Dis. 117:1099–1108.

    Google Scholar 

  28. Henson, P.M., K.M. McCarthy, andG.L. Larsen. 1979. Complement fragments, pulmonary macrophages, and alveolitis.Am. J. Pathol. 97:93–105.

    Google Scholar 

  29. Barr, B.C., D.M. Hydh, C.G. Plopper, andD.L. Dungworth. 1990. A comparison of terminal airway remodeling in chronic daily versus episodic ozone exposure.Toxicol. Appl. Pharmacol. 106:384–407.

    Google Scholar 

  30. Henson, P.M., G.L. Larsen, R.O. Webster, B.C. Mitchell, A.J. Goins, andJ.E. Henson. 1982. Pulmonary Microvascular alterations and injury induced by complement fragments: Synergistic effect of complement activation, neutrophil sequestration, and prostaglandins.In Mechanisms of Lung Microvascular Injury. A.B. Malik, N.C. Staub, editors. New York Academy of Sciences, New York. 287–300.

    Google Scholar 

  31. Irvin, C.G., N. Berend, andP.M. Henson, 1986. Airways hyperreactivity and inflammation produced by aerosolization of human C5a des Arg.Am. Rev. Respir. Dis. 134:777–783.

    Google Scholar 

  32. Smith, M.J.H. 1981. Leukotriene B4.Gen. Pharm. 12:211–216.

    Google Scholar 

  33. Czarnetzki, B.M., andJ. Grabbe. 1984. Biological and chemical characterization of eosinophil chemotactic factors from human leukocytes.Agents Actions (Suppl.) 12:204–216.

    Google Scholar 

  34. Mensing, H., B.M. Czarnetzki. 1984. Leukotriene B4 induces in vitro fibroblast chemotaxis.J. Invest. Dermatol. 82:9–12.

    Google Scholar 

  35. Palmer, R.M.J., andD.A. Yeats. 1981. Leukotriene B: A potent chemotactic agent and stimulus for lysosomal enzyme secretion for human neutrophils (PMN).Br. J. Pharmacol. 73:260–261.

    Google Scholar 

  36. Martin, T.R., B.P. Pistorese, E. Chi, R.B. Goodman, andM.A. Matthay, 1989. Effects of leukotriene B4 in the human lung: recruitment of neutrophils into the alveolar spaces without a change in protein permeability.J. Clin. Invest. 84:1609–1619.

    Google Scholar 

  37. Tonnesen, M.G. 1989. Neutrophil-endothelial cell interactions: Mechanisms of neutrophil adherence to vascular endothelium.J. Invest. Dermatol. 93:53S-58S.

    Google Scholar 

  38. Livingston, D.H., S.H. Appel, G. Sonnenfield, andM.A. Malangoni. 1989. The effect of tumor necrosis factor-α and interferon-γ on neutrophil function.J. Surg. Res. 46:322–326.

    Google Scholar 

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Authors and Affiliations

  1. Departments of Anatomy and Veterinary Pharmacology and Toxicology School of Veterinary Medicine, University of California, Davis, California

    Jane A. Harris, Dallas M. Hyde, Qingjian Wang, Mary Y. Stovall & Shiri N. Giri

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  1. Jane A. Harris
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  2. Dallas M. Hyde
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  3. Qingjian Wang
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  4. Mary Y. Stovall
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Harris, J.A., Hyde, D.M., Wang, Q. et al. Repeated episodes of C5a-induced neutrophil influx do not result in pulmonary fibrosis. Inflammation 15, 233–250 (1991). https://doi.org/10.1007/BF00918649

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