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Oxidant injury of the extracellular matrix: Potential role in the pathogenesis of pulmonary emphysema

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Abstract

This paper reviews evidence supporting a role for oxidants in the pathogenesis of pulmonary emphysema. Recent studies have shown that connective tissue components are directly degraded by oxidantsin vitro. Exposure of animals to oxidant gases causes degradation of lung connective tissue and results in an emphysematous lesion in the lung several weeks after recovery. Oxidant injury is also associated with an influx of inflammatory cells which release proteolytic enzymes. It is proposed that the emphsematous lesion found after exposure to an oxidant gas is the result of two mechanisms causing degradation of lung connective tissue: direct cleavage by free radicals and enzymatic proteolysis. It is possible that oxidant injury to the extracellular matrix is involved in the pathogenesis of emphysema in humans since cigarette smoke contains an exceedingly high concentration of oxidants.

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References

  1. Andley UP, Chakrabarti B (1983) Role of singlet oxygen in the degradation of hyaluronic acid. Biochem Biophys Res Commun 115:894–901

    Article  PubMed  CAS  Google Scholar 

  2. Bartlett D Jr, Faulkner CS II, Cook K (1974) Effect of chronic ozone exposure on lung elasticity in young rats. J Appl Physiol 37:92–96

    PubMed  CAS  Google Scholar 

  3. Betts WH, Cleland LG (1982) Effect of metal chelators and anti-inflammatory drugs on the degradation of hyaluronic acid. Arthr Rheum 25:1469–1476

    Article  CAS  Google Scholar 

  4. Brooksby GA, Dennis RL, Staley RW (1966) Effects of prolonged exposure of rats to increased oxygen pressures. In: Brown IW Jr (ed) Third international conference on hyperbaric medicine. National Academy of Sciences, Washington, pp 208–215

    Google Scholar 

  5. Brooksby GA, Staley RW (1966) Static volume-pressure relations in lungs of rats exposed to 100 percent oxygen. Physiologist 9:144 (Abstract)

    Google Scholar 

  6. Carp H, Janoff A (1979) In vitro suppression of serum elastase-inhibitory capacity by reactive oxygen species generated by phagocytozing polymorphonuclear leukocytes. J Clin Invest 63:793–797

    PubMed  CAS  Google Scholar 

  7. Cohen AB (1979) Potential adverse effects of lung macrophages and neutrophils. Fed Proc 38:2644–2647

    PubMed  CAS  Google Scholar 

  8. Cohen AB, Chenoweth DE, Hulgi TE (1982) The release of elastase, myeloperoxidase, and lysozyme from human alveolar macrophage. Am Rev Respir Dis 126:241–247

    PubMed  CAS  Google Scholar 

  9. Carpo JD, Barry BE, Foscue HA, Shelburne J (1980) Structural and biochemical changes in rat lungs occurring during exposures to lethal and adaptive doses of oxygen. Am Rev Respir Dis (1980) 122:123–143

    Google Scholar 

  10. Crapo JD, Barry BE, Chang L-Y, Mercer RR (1984) Alterations in lung structure caused by inhalation of oxidants. J Toxicol Environ Health 13:301–321

    Article  PubMed  CAS  Google Scholar 

  11. Curran SF, Amoruso MA, Goldstein BD, Riley DJ, Edelman NH, Berg RA (1984) Degradation of soluble collagen. Possible mechanism of emphysema. Chest 85(Suppl):43S-44S

    Google Scholar 

  12. Deneke SM, Fanburg BL (1980) Normobaric oxygen toxicity of the lungs. New Engl J Med 303:76–86

    Article  PubMed  CAS  Google Scholar 

  13. DiGuiseppi J, Fridovich I (1984) The toxicology of molecular oxygen. CRC Crit Rev Toxicol 12:315–342

    CAS  Google Scholar 

  14. DróM, Kucharz E, Szyja J (1977) Effect of chronic exposure to nitrogen dioxide on collagen content in lung and skin of guinea pigs. Environ Res 13:369–377

    Article  Google Scholar 

  15. Dubick MA, Rucker RB, Last JA, Lollini LO, Cross CE (1981) Elastin turnover in murine lung after repeated ozone exposure. Toxicol Appl Pharmacol 58:203–210

    Article  PubMed  CAS  Google Scholar 

  16. Ehrlich R, Fenters JD (1973) Influence of nitrogen dioxide on experimental influenza in squirrel monkeys. In: Proceedings of the third international clean air congress. VDI-Verlag, Düsseldorf, pp A11-A13

    Google Scholar 

  17. Evans MJ (1984) Oxidant gases. Environ Health Perspect 55:85–95

    Article  PubMed  CAS  Google Scholar 

  18. Fantone JC, Ward PA (1983) Mechanisms of neutrophil-dependent lung injury. In: Ward PA (ed) Immunology of inflammation. Elsevier Science Publishing Co, New York, pp 89–120

    Google Scholar 

  19. Fels AOS, Pawlowski NA, Cramer EB, King TKC, Cohn ZA, Scott WA (1982) Human alveolar macrophages produce leukotriene B4 Proc Natl Acad Sci USA 79:7866–7870

    Article  PubMed  CAS  Google Scholar 

  20. Fligiel SEG, Lee EC, McCoy P, Johnson KJ, Varani J (1984) Protein degradation following treatment with hydrogen peroxide. Am J Pathol 115:418–425

    PubMed  CAS  Google Scholar 

  21. Forman JH, Fisher AB (1981) Anti-oxidant defense. In: Gilbert DL (ed) Oxygen and living processes: an interdisciplinary approach. Springer-Verlag, New York, pp 235–249

    Google Scholar 

  22. Fox, RB, Hoidal JR, Brown DM, Repine JE (1981) Pulmonary inflammation due to oxygen toxicity: involvement of chemotactic factors and polymorphonuclear leukocytes. Am Rev Respir Dis 123:521–523

    PubMed  CAS  Google Scholar 

  23. Frank L, Massaro D (1980) Oxygen toxicity. Am J Med 69:117–126

    Article  PubMed  CAS  Google Scholar 

  24. Freeman BA, Crapo JD (1982) Free radicals and tissue injury. Lab Invest 47:412–426

    PubMed  CAS  Google Scholar 

  25. Freeman G, Haydon GB (1964) Emphysema after low-level exposure to NO2. Arch Environ Health 8:125–128

    PubMed  CAS  Google Scholar 

  26. Freeman G, Crane SC, Stephens RJ, Furiosi NJ (1968) Pathogenesis of the nitrogen dioxide-induced lesion in the rat lung: a review and presentation of new observations. Am Rev Respir Dis 98:429–443

    PubMed  CAS  Google Scholar 

  27. Freeman G, Crane SC, Stephens RJ, Furiosi NJ (1969) The subacute nitrogen dioxide-induced lesion of the rat lung. Arch Environ Health 18:609–612

    PubMed  CAS  Google Scholar 

  28. Fridovich I (1978) The biology of oxygen radicals. Science 201:875–879

    Article  PubMed  CAS  Google Scholar 

  29. Glass M, Kaplan JE, Macarak E, Aukberg SJ, Fisher AB (1984) Serum fibronectin is elevated during normobaric and hyperbaric oxygen exposure in rats. Am Rev Respir Dis 130:237–241

    PubMed  CAS  Google Scholar 

  30. Greenwald RA, Moy WW (1979) Inhibition of collagen gelation by action of the superoxide radical. Arthr Rheum 22:251–259

    Article  CAS  Google Scholar 

  31. Greenwald RA, Moy WW (1980) Effect of oxygen-derived free radicals on hyaluronic acid. Arth Rheum 23:455–463

    Article  CAS  Google Scholar 

  32. Gross P, deTreville RTP, Babyak MA, Kaschak M, Tolker EB (1968) Experimental emphysema. Effect of chronic nitrogen dioxide exposure and papain on normal and pneumoconiotic lungs. Arch Environ Health 16:51–58

    PubMed  CAS  Google Scholar 

  33. Halliwell B (1978) Superoxide-dependent formation of hydroxyl radical in the presence of iron salts. Its role in degradation of hyaluronic acid by a superoxide-generating system. FEBS Lett 96:238–242

    Article  PubMed  CAS  Google Scholar 

  34. Harada RN, Vatter AE, Repine JE (1984) Macrophage effector function in pulmonary oxygen toxicity: hyperoxia damages and stimulates alveolar macrophages to make and release chemotaxins for polymorphonuclear leukocytes. J Leukocyte Biol 35:373–383

    PubMed  CAS  Google Scholar 

  35. Harrison GA (1971) Ultrastructural changes in rat lung during long-term exposure to oxygen. Exp Med Surg 29:96–107

    PubMed  CAS  Google Scholar 

  36. Hatton DV, Leach CS, Nicogossian AE, DiFerrante N (1977) Collagen breakdown and nitrogen dioxide inhalation. Arch Environ Health 32:33–36

    PubMed  CAS  Google Scholar 

  37. Haydon GB, Davidson JT, Lillington GA, Wasserman K (1963) Nitrogen dioxide-induced emphysema in rabbits. Am Rev Respir Dis 95:797–805

    Google Scholar 

  38. Haydon GB, Freeman G, Furiosi NJ (1965) Covert pathogenesis of NO2 induced emphysema in the rat. Arch Environ Health 11:776–783

    PubMed  CAS  Google Scholar 

  39. Hëllstrom B, Nergårdh A (1965) The effect of high oxygen concentrations and hypothermia on the lung of the newborn mouse. Acta Paediatr Scand 54:457–466

    Google Scholar 

  40. Hoidal JR, Niewoehner DE (1982) Lung phagocyte recruitment and metabolic alterations induced by cigarette smoke in humans and hamsters. Am Rev Respir Dis 126:548–552

    PubMed  CAS  Google Scholar 

  41. Hunninghake GW, Davidson JM, Rennard S. Szapiel S, Gadek JE, Crystal RG (1981) Elastin fragments attract macrophage precursors to diseased sites in pulmonary emphysema. Science 212:925–926

    Article  PubMed  CAS  Google Scholar 

  42. Johnson A, Blumenstock FA, Malik AB (1984) Role of oxygen radicals in pulmonary vascular injury. In: Bors W, Saran M, Tait D (eds) Oxygen radicals in chemistry and biology. Walter de Gruyter, Berlin, pp 931–938

    Google Scholar 

  43. Johnson D, Travis J (1979) The oxidative inactivation of human α1-proteinase inhibitor. Further evidence for methionine at the reactive site. J Biol Chem 254:4022–4026

    PubMed  CAS  Google Scholar 

  44. Kapanci Y (1983) Oxygen-induced alveolar lesions in humans and experimental animals. Electron microscopic and morphometric studies. Bull Eur Physiopathol Respir 14:128P-129P

    Google Scholar 

  45. Kaplan HP, Thomas AA, Back KC, Robinson FR (1968) Evaluation of animals continuously exposed to a 5 psia pure oxygen space cabin atmosphere for eight months. Aerosp Med 39:117–120

    Google Scholar 

  46. Katzenstein A-LA, Bloor CM, Liebow AA (1976) Diffuse alveolar damage—the role of oxygen, shock, and related factors. Am J Pathol 85:210–228

    Google Scholar 

  47. Kleinerman J, Wright GW (1962) Experimental production of lesion resembling human microbullous emphysema. Fed Proc 21:439–442

    Google Scholar 

  48. Kleinerman J, Cowdrey CR (1968) The effects of continuous high level nitrogen dioxide on hamsters. Yale J Biol Med 40:579–585

    PubMed  CAS  Google Scholar 

  49. Kleinerman J, Ip MPC (1979) Effects of nitrogen dioxide on elastin and collagen contents of lungs. Arch Environ Health 34:228–232

    PubMed  CAS  Google Scholar 

  50. Kuhn C, Senior RM, Pierce JA (1982) The pathogenesis of emphysema. In: Witschi H, Nettesheim P (eds) Mechanisms in respiratory toxicoloty. vol 2. CRC Press, Boca Raton, pp 155–211

    Google Scholar 

  51. Larsen GL, Henson PM (1983) Mediators of inflammation. Ann Rev Immunol 1:335–359

    Article  CAS  Google Scholar 

  52. Larsen GL, Parrish DA, Henson PM (1983) Lung defense. The paradox of inflammation. Chest 83(Suppl):1S-5S

    PubMed  CAS  Google Scholar 

  53. Lewis TR, Moorman WJ, Ludmann WF, Campbell KI (1973) Toxicity of long-term exposure to oxides of sulfur. Arch Environ Health 26:16–21

    PubMed  CAS  Google Scholar 

  54. Martin WJ II, James EG, Hunninghake GW, Crystal RG (1981) Oxidant injury of lung parenchymal cells. J Clin Invest 68:1277–1287

    PubMed  CAS  Google Scholar 

  55. Mason RP, Chignell CP (1982) Free radicals in pharmacology and toxicology—selected topics. Pharmacol Rev 33:189–211

    Google Scholar 

  56. McCord JM (1974) Free radicals and inflammation: protection of synovial fluid by superoxide dismutase. Science 185:529–531

    Article  PubMed  CAS  Google Scholar 

  57. Merritt TA (1982) Oxygen exposure in the newborn guinea pig lung lavage cell populations, chemotactic and elastase response: a possible relationship to neonatal bronchopulmonary dysplasia. Pediatr Res 10:798–805

    Google Scholar 

  58. Monboisse JC, Braquet P, Raudoux A, Borel JP (1983) Non-enzymatic degradation of acidsoluble calf skin collagen by superoxide ion: protective effect of flavonoids. Biochem Pharmacol 32:53–58

    Article  PubMed  CAS  Google Scholar 

  59. Mundy GR, DeMartino S, Rowe DW (1981) Collagen and collagen-derived fragments are chemotactic for tumor cells. J Clin Invest 68:1102–1105

    PubMed  CAS  Google Scholar 

  60. Mustafa MG, Tierney DF (1978) Biochemical and metabolic changes in lung with oxygen, ozone, and nitrogen dioxide toxicity. Am Rev Respir Dis 118: 1061–1090

    PubMed  CAS  Google Scholar 

  61. Newman JH, Loyd JE, English OK, Ogletree ML, Fulkerson WJ, Brigham KL (1983) Effects of 100% oxygen on lung vascular function in awake sheep. J Appl Physiol: Respirat Environ Exercise Physiol 54:1379–1386

    CAS  Google Scholar 

  62. Niewoehner DE, Kleinerman J (1973) Effects of experimental emphysema and bronchiolitis on lung mechanics and morphometry. J Appl Physiol 35:25–31

    PubMed  CAS  Google Scholar 

  63. Norman V, Keith CH (1965) Nitrogen oxides in tobacco smoke. Nature 205:915–916

    Article  CAS  Google Scholar 

  64. Northway WH Jr, Rosan RC, Shahinian L Jr, Castellino RA, Gyepes MT Durbridge T (1969) Radiologic and histologic investigation of pulmonary oxygen toxicity in newborn guinea pigs. Invest Radiology 4:148–155

    Article  Google Scholar 

  65. Paegle RD, Spain D, Davis S (1974) Pulmonary morphology of chronic phase of oxygen toxicity in adult rats. Chest 66(Suppl):7S-8S

    Article  PubMed  Google Scholar 

  66. Pfister A, Nogues C (1974) Déterminisme des lésions pulmonaires provoqúees par l’oxygène ou l’ozone chez le rat. Pathol Biol 22:89–98

    PubMed  CAS  Google Scholar 

  67. Phan SH, Armstrong G, Sulavik MC, Schrier D, Johnson KJ, Ward PA (1982) A comparative study of pulmonary fibrosis induced by bleomycin and an O2 metabolite producing enzyme system. Chest 84(Suppl):44S-46S

    Google Scholar 

  68. Postlethwaite AE, Kang AH (1976) Collagen and collagen peptide-induced chemotaxis of human blood monocytes. J Exp Med 143:1299–1307

    Article  PubMed  CAS  Google Scholar 

  69. Postlethwaite AE, Seyer JM, Kang AH (1978) Chemotactic attraction of human fibroblasts to type I, II, and III collagens and collagen-derived peptides. Proc Natl Acad Sci USA 75:871–875

    Article  PubMed  CAS  Google Scholar 

  70. Pryor WA, Hales BJ, Premovic PI, Church DF (1983) The radicals in cigarette tar: their nature and suggested physiological implications. Science 220:425–427

    Article  PubMed  CAS  Google Scholar 

  71. Puig-Parellada P, Planas JM (1978) Synovial fluid degradation induced by free radicals.In vitro action of several free radical scavengers and anti-inflammatory drugs. Biochem Pharmacol 27:535–537

    Article  PubMed  CAS  Google Scholar 

  72. Richmond V, D’Aoust BG (1976) Effects of intermittent hyperbaric oxygen on guinea pug lung elastin and collagen. J Appl Physiol 41:295–301

    PubMed  CAS  Google Scholar 

  73. Riley DJ, Berg RA, Edelman NH, Prockop DJ (1980) Prevention of collagen deposition following pulmonary oxygen toxicity in the rat bycis-4-hydroxy-L-proline. J Clin Invest 65:643–651

    PubMed  CAS  Google Scholar 

  74. Riley DJ, Chae CU, Guss NH. Kerr JS (1983) Degradation of lung collagen produced by pulmonary oxygen toxicity in the rat. Assessment by hydroxyproline levels in lavage fluid. Am Rev Respir Dis 127:284 (Abstract)

    Google Scholar 

  75. Riley DJ, Kerr JS, Yu SY, Berg RA (1983) Acute oxygen exposure in rats depletes lung collagen but not lung elastin. Fed Proc 42:780 (Abstract)

    Google Scholar 

  76. Riley DJ, Kerr JS, Laskin DS, Guss HN, Curran SF, Berg RA (1984) Induction of a neutrophil inflammatory response in rats following intratracheal instillation of collagen peptides. Clin Res 32:563A (Abstract)

    Google Scholar 

  77. Roberts RJ (1984) Pulmonary oxygen toxicity in the premature and full-term infant. Its relationship to the development and pathogenesis of RDS. In: Stern L (ed) Hyaline membrane disease. Pathogenesis and pathophysiology. Grune and Stratton, New York, pp 211–232

    Google Scholar 

  78. Sandblom R, Johnson K, Killen P, Hudson L, Striker G (1982) Lung injury due to oxygen metabolites alters the composition of extracellular matrix. Fed Proc 41:941 (Abstract)

    Google Scholar 

  79. Senior RM, Griffin GL, Mecham RP (1982) Chemotactic responses of fibroblasts to tropoelastin and elastin-derived peptides. J Clin Invest 70:614–618

    PubMed  CAS  Google Scholar 

  80. Shak S, Perez HD, Goldstein IM (1983) A novel dioxygenation product of arachidonic acid possesses potent chemotactic activity for human polymorphonuclear leukocytes. J Biol Chem. 258:14948–14953

    PubMed  CAS  Google Scholar 

  81. Snider GL (1981) The pathogenesis of emphysema—twenty years of progress. Am Rev Respir Dis 124:321–324

    PubMed  CAS  Google Scholar 

  82. Sonbonya RE, Logvinoff MM, Taussig LM, Theriault A (1982) Morphometric analysis of the lung in prolonged bronchopulmonary dysplasia. Pediatr Res 16:969–972

    Google Scholar 

  83. Steadman BL, Jones RA, Rector DE, Siegel J (1966) Effects on experimental animals of long-term continuous inhalation of nitrogen dioxide. Toxicol Appl Pharmacol 9:160–170

    Article  PubMed  CAS  Google Scholar 

  84. Stokinger HE, Wagner WD, Dobrogorski OJ (1957) Ozone toxicity studies. III. Chronic injury to lungs of animals following exposure at a low level. AMA Arch Ind Health 16:514–522

    PubMed  CAS  Google Scholar 

  85. Suttorp N, Simon LM (1982) Lung cell oxidant injury. Enhancement of polymorphonuclear leukocyte-mediated cytotoxicity in lung cells exposed to sustained in vitro hyperoxia. J Clin Invest 70:342–350

    PubMed  CAS  Google Scholar 

  86. Taghizadeh A, Reynolds EOR (1976) Pathogenesis of bronchopulmonary dysplasia following hyaline membrane disease. Am J Pathol 82:241–246

    PubMed  CAS  Google Scholar 

  87. Tierney DF, Ayers L, Kasuyama RS (1977) Altered sensitivity to oxygen toxicity. Am Rev Respir Dis 115(Suppl):59–65

    PubMed  CAS  Google Scholar 

  88. Välimäki M, Niinikoski J (1973) Development and reversibility of pulmonary oxygen poisoning in the rat. Aerosp Med 44:533–538

    PubMed  Google Scholar 

  89. Vaughan TR Jr, Jennelle LF, Lewis TR (1969) Long-term exposure to low levels of air pollutants. Effects on pulmonary function in the beagle. Arch Environ Health 19:45–50

    PubMed  CAS  Google Scholar 

  90. Venkatasubramanian K, Joseph KT (1977) Action of singlet oxygen on collagen. Indian J Biochem Biophys 14:217–220

    PubMed  CAS  Google Scholar 

  91. Wedig K, Bruce M, Martin RJ, Fanaroff A, Boat T (1983) Elastin degradation products as an index of neonatal lung injury. Pediatr Res 17:393A (Abstract)

    Google Scholar 

  92. Weiss SJ, Regiani S (1984) Neutrophils degrade subendothelial matrices in the presence of alpha-1-proteinase inhibitor. Cooperative use of lysosomal proteinases and oxygen metabolites. J Clin Invest 73:1297–1303

    Article  PubMed  CAS  Google Scholar 

  93. Weir FW, Bath DW, Yevich P, Oberst FW (1965) Study of effects of continuous inhalation of high concentrations of oxygen at ambient pressure and temperature. Aerosp Med 36:117–120

    Google Scholar 

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  1. Department of Medicine, UMDNJ-Rutgers Medical School, Academic Health Science Center, CN 19, 08903, New Brunswick, New Jersey, USA

    David J. Riley & Janet S. Kerr

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  1. David J. Riley
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Supported by U.S. Public Health Service Grant HL 24264

Dr. Riley is the recipient of a Pulmonary Academic Award (HL 00443) from the National Heart, Lung, and Blood Institute, National Institutes of Health.

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Riley, D.J., Kerr, J.S. Oxidant injury of the extracellular matrix: Potential role in the pathogenesis of pulmonary emphysema. Lung 163, 1–13 (1985). https://doi.org/10.1007/BF02713801

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