- Email: [email protected]
Hypothesis: is lung disease after silicate inhalation caused by oxidant generation?
967
occurrence of and the related
mother’s condition. Intervention before the
placentomegaly,
fulminant
hydrops,
maternal illness is more likely to succeed.
Open fetal
surgery has been successful in treatment of
otherwise fatal anatomical abnormalities, and
we now add to selected cases of CCAM those congenital appropriately lesions that are amenable to fetal surgical therapy.
REFERENCES 1. Adzick NS, Harrison MR, Glick PL, et al. Fetal cystic adenomatoid malformation: prenatal diagnosis and natural history. J Pediatr Surg
1985; 20: 438-88. 2 Donn SM, Martin JN, White SJ. Antenatal ultrasound findings in cystic malformation. Pediatr Radiol 1981; 10: 180-82. 3. Adzick NS, Harrison MR, Hu LM, et al. Compensatory growth after pneumonectomy in fetal lambs: a morphologic study. Surg Forum
1986; 37: 309-11. 4. Harrison MR, Bressack MA, Churg AM, et al. Correction of congenital diaphragmatic hernia in utero II. Simulated correction permits fetal lung growth with survival at birth. Surgery 1980; 88: 260-68. 5. Harrison MR, Anderson J, Rosen MA, et al. Fetal surgery in the primate I. Anaesthetic, surgical, and tocolytic management to maximize fetal-neonatal survival., J Pediatr Surg 1982; 17: 115-22. 6. Nakayama DK, Harrison MR, Seron-Ferre M, et al. Fetal surgery in the primate II. Uterine electromyographic response to operative procedure and pharmacologic agents. J Pediatr Surg 1984; 19: 333-39.
Hypothesis:
is
7. Adzick NS, Harrison MR, Glick PL, et al. Fetal surgery in the primate III. Maternal outcome after fetal surgery. J Pediatr Surg 1986; 21: 477-80. 8. Harrison MR, Adzick NS, Longaker MT, et al. Successful repair in utero of a fetal diaphragmatic hernia after removal of herniated viscera from the left thorax. N Engl J Med 1990; 322: 1582-84. 9. Crombleholme TM, Harrison MR, Langer JC, et al. Early experience with open fetal surgery for congenital hydronephrosis. J Pediatr Surg 1988; 23: 1114-21. 10. Harrison MR, Langer JC, Adzick NS, et al. Correction of congenital diaphragmatic hernia in utero V. Initial clinical experience. J Pediatr
Surg 1990; 25: 47-57. 11. Adzick NS, Harrison MR, Flake AW, et al. Automatic uterine stapling devices in fetal operation: experience in a primate model. Surg Forum
1985; 36: 479-80. 12. Chin KY, Tang MY. Congenital adenomatoid malformation of one lobe of a lung with general anasarca. Arch Pathol 1949; 48: 221-29. 13. Clark SL, Vitale DJ, Minton SD, et al. Successful fetal therapy for cystic adenomatoid malformation associated with second trimester hydrops. Am J Obstet Gynecol 1987; 157: 294-97. 14. Longaker MT, Laberge JM, Dansereau J, et al. Primary fetal hydrothorax: natural history and management. J Pediatr Surg 1989; 24: 573-76. 15. Rodeck CH, Fisk NM, Fraser DI, et al. Long-term in-utero drainage of fetal hydrothorax. N Engl J Med 1988; 319: 1135-38. 16. Langer JC, Harrison MR, Schmidt KG, et al. Fetal hydrops and death from sacrococcygeal teratoma: Rationale for fetal surgery. Am J Obstet Gynecol 1989; 160: 1145-50. 17. Goodlin RC. Mirror syndromes. In: Goodlin RC, ed. Care of the fetus. New York: Masson, 1979: 48-50.
lung disease after silicate inhalation caused by oxidant generation?
Inhaled silicate dusts may cause lung disease through their surface coordination of iron with subsequent oxidant generation via the Fenton reaction. Pneumoconiosis, irritant bronchitis, focal emphysema, and carcinoma may be produced by oxidants either directly through lipid peroxidation and protein inactivation, or indirectly by oxidant-mediated release of cytokines such as platelet-derived growth factor. The increased incidence of tuberculosis observed among silicate workers could be explained by accumulation of iron complexed by dust particles in the lung and made available to dormant mycobacteria as a virulence factor.
is decreased and the haemolytic effect of silicate is reduced. In-vivo investigations show a correlation between the toxicity of a mineral dust and the distribution of oxygen atoms on the crystal surface.2 Common to all silicates is some concentration of surface silanol groups (SiOH), which have an acidic pKa and favour dissociation at a physiological pH.3 Dissociation of silanols contributes to a net negative charge on the silicate surface, which generates a capacity for adsorption of both organic and inorganic cations.4 Smaller metal cations can be coordinated by the silanol groups; their adsorption and bonding do not depend upon the ionic charges or surface acidity of the silicate, but upon the geometry of these coordination bonds. The resultant selectivity is the basis for silicate use in both water softeners and ion-exchange
negative charge
chromatography. 5.6 Introduction Inhalation of silica, asbestos, clay, talc, mica, zeolite, and other silicate dusts can result in a wide range of lung diseases, which include pneumoconiosis, irritant bronchitis, focal emphysema, bronchogenic carcinoma, mesothelioma, and an increased incidence of tuberculosis. The mechanism of toxicity is not known but is associated with characteristics of the silicate surface. In-vitro data indicate that cytotoxicity is associated with a negative surface charged if the crystal surface is coated with any inorganic or organic cation, this
ADDRESSES Division of Allergy, Critical Care, and Respiratory Medicine, Department of Medicine, Duke University Medical Center (A. J Ghio, MD, T. P. Kennedy, MD, R M Schapira, MD) and Department of Chemistry, Duke University (Prof A. L Crumbliss, PhD), Durham, North Carolina; and Division of Respiratory, Critical Care, and Occupational (Pulmonary) Medicine, Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA (Prof J R. Hoidal, MD) Correspondence to Dr A. J Ghio, Box 3177, Duke University Medical Center, Durham, North Carolina 27710, USA
968
Iron and silicates Ferric ions react with surface silanol groups of amorphous silica to make a silicato-iron coordination complex.’ Fe 31 + m(SiOH) ⇆ Fe (OSi)m3m+ + mH++ In amorphous silica, the free energy production of the reaction of the silanol groups with Fe3 is greater than with any other metal cation, so ferric ions will displace all other metal cations from this surface if no other restrictions or conditions other than a thermodynamic drive apply. Fe3+ is adsorbed even at a pH of 2-0, the isoelectric point of silica where silanol groups would not normally be ionised, which indicates that non-ionic attractive forces may be involved in formation of the silicato-iron complex. Crystalline silicates also show a dose-dependent adsorption of inorganic iron;8-10 coordination of the ferric ion requires involvement of three silanol groups on surfaces of silanol gel and crystal zeolite, while eight silanol groups contribute to complex formation on the surface of crystal montmorillonite. Once coordinated to the silicate surface, iron can mediate an electron exchange via the Fenton reaction when it is reduced from the ferric to the ferrous (Fe2+) state."
Fe3+
O2- ⇆Fe2+ + O2 H202 - Fe3+ + OH + OHThe hydroxyl radical (’OH) that may be produced by this reaction at the surface of the crystal is a potent oxidant, which can initiate lipid peroxidation of cell membranes and oxidatively inactivate essential cell proteins.12 Requirements of this reaction include chelated iron, hydrogen peroxide (H2O2), and a reductant. H202 can be produced by activated phagocytes or as a by-product of aerobic metabolism, and its production by alveolar macrophages is increased after asbestos exposure.13 The superoxide anion (O2-) is an important reductant in biological systems, formed by the respiratory burst of phagocytes and also by aerobic Fe2+
+
+
metabolism.14 Ascorbate is another substance that can actively reduce iron and is found in extracellular fluid of the
lung.15 The capacity of silicate dusts to generate oxidants has been established for silica, asbestos, clays, and talcs;this activity falls after treatment with iron chelators, which indicates that silicates act as Fenton catalysts.16 Lipid peroxidation has been confirmed after exposure to asbestos and silica in rat microsomes and whole lung, and also falls after iron chelation.17,18 We suggest that lung disease after silicate inhalation is caused by the surface coordination of iron by dust particles and subsequent production of oxidants via the Fenton reaction. Involvement of structural iron within the crystal in such a reaction is unlikely because lattice dimensions preclude entry of the necessary reductants and oxidants.19
Predicted features The
ferruginous body is a recognised index of exposure to many silicates. Iron-binding proteins are assumed to envelope the silicate and hence explain the close affiliation of the dust particle with both protein and iron .20 We suggest instead that ferruginous bodies result from bonding between the negatively charged silicate surface and the positively charged quaternary ammonium groups of proteins (including proteins that do not contain iron), and that most of the iron found in ferruginous bodies is coordinated onto the mineral dust from body sources. The capacity of a silicate in the lung to adsorb body sources of iron has been confirmed shortly after its introduction.21 Over longer periods, coordination of iron
from body sources onto the mineral dusts accounts for the low serum iron observed among workers exposed to silicates.22 Evidence that iron is complexed on the silicate dust can be found by use of specific stains for iron or by measurement of the iron content of lungs in which silicate content is increased;23 this iron can be mobilised from the silicate surface by a strong iron chelator.24 Parenchymal damage after silicate inhalation is classed as pneumoconiosis-a restrictive interstitial lung disease associated with increased collagen content. Macrophagederived peptide growth factors have been identified as possible mediators of collagen deposition.’s Bleomycin and paraquat are other fibrogenic agents that can generate oxidants through iron-dependent mechanisms;2S,26 both also induce alveolar macrophages to secrete growth factors for fibroblasts .2728 Measures which displace ferric ion from the silicate surface, such as treatment with high concentrations of aluminium salts, diminish the fibrotic response to these dusts in sheep.29 Furthermore, macrophage secretion of platelet-derived growth factor after exposure to asbestos dust falls after treatment of the dust with an iron chelator.30 These findings support the hypothesis that fibrogenesis by silicates is mediated by oxidant production through the regulation of cytokine secretion. In the airways, chronic inhalation of silicates causes irritant bronchitis and emphysema. Oxidants stimulate mucous glycoprotein secretion by tracheal goblet cells,31 and increased mucus secretion after dust inhalation might have an antioxidant function.32 Increased mucus production in silicate workers, as in cigarette smokers, may therefore be a defence mechanism of the airways against free radicals.33 Emphysema can also be caused by oxidant exposure;34 oxidant production by silicate dusts would be limited to bronchial surfaces, and one would expect tissue destruction to be observed only in their immediate proximity. In the absence of other risk factors, the emphysema observed in association with silicate exposure is focal in distribution and functional loss is unusual. An increased risk of cancer is found with exposure to asbestos and possibly other silicates, and may also be caused by oxidant production. Endocytosis by mucosal cells could move silicate crystals adjacent to DNA, with the risk of oxidant-induced chromosome aberrations and exchanges.35 Differences in rates of cancer induction among silicates may reflect capacity to clear the dust from the lung; fibrous silicates such as asbestos or erionite would be more difficult to eliminate from the body, which would increase the duration of DNA exposure to oxidant stress.36 Silicate workers have an unexplained high incidence of pulmonary tuberculosis. Mycobacteria are dependent on iron for growth and produce the iron chelators mycobactin and exochelin to mobilise the metal from body stores; indeed, iron is considered a virulence factor for mycobacteria. We suggest that silicate particles act as a reserve of iron which can be used by mycobacteria and so explain the increased incidence of tuberculosis among those who inhale such mineral dusts. The iron made available from silicato-iron complexes may activate dormant tuberculosis by a mechanism similar to the effect of iron
repletion. 37 A characteristic of the pneumoconioses is progression of disease after the worker is removed from the site of exposure. Our hypothesis allows for continued adsorption of body sources of iron by the dust particles while they remain in the lung. Clinical and pathological progression could be caused
969
by continued oxidant production, while radiographic progression could be explained by deposition of collagen and raised local iron concentrations. Moreover, iron content of the lung, rather than total dust burden 311 determines the
radiological support of
of pneumoconioses-further essential role for silicato-iron coordination
appearances an
complexes.
Implications hypothesis indicates that detoxification of requires elimination of silicato-iron coordination complexes from the lung. One approach is to prevent entry of these silicates into the lung by strict control of dust levels-a widely recognised, if not invariably If confirmed, silicate dusts
our
measure. The alternative would be treatment with iron chelators in an attempt to eliminate the source of oxidants, the coordinated iron, or supplementation of the antioxidant defences of the lung.
practised,
REFERENCES 1. Nolan RP,
Langer AM, Harington JS, Oster G, Selikoff IJ. Quartz hemolysis as related to its surface functionalities. Environ Res 1981; 26:
503-20. 2. Weissner JH, Henderson JD Jr, Sohnle PG, Mandel NS, Mandel GS. The effect of crystal structure on mouse lung inflammation and fibrosis. Am Rev Respir Dis 1988; 138: 445-50. 3. Iler RK. The chemistry of silica. New York: Wiley, 1979: 622-727. 4. Grim RE. Clay mineralogy. New York: McGraw-Hill, 1968: 185-233, 353-411. 5. Torii K. Utilization of natural zeolites in Japan. In: Sand LB, Mumpton FA, eds. Natural zeolites. Occurrence, properties, use. New York: Pergamon, 1978: 441-50. 6. Unger KK. Porous silica: its properties and use as support in column liquid chromatography. New York: Elsevier, 1979. 7. Dugger DL, Stanton JH, Irby BN, McConnell BL, Cummings WW, Maatman RW. The exchange of twenty metal ions with the weakly acidic silanol group of silica gel. J Phys Chem 1964; 68: 757-60. 8. Fordham AW. Sorption and precipitation of iron on kaolinite. Factors involved in sorption equilibria. Aust J Soil Res 1969; 7: 185-97. 9. Rees LVC. Mossbauer spectroscopic studies of ferrous ion exchange in zeolite A. In: Jacobs PA, Jaeger NI, Jiru P, Schulz-EkloffG, eds. Metal microstructures in zeolites. Preparation, properties, applications. (Proceedings of a workshop, Bremen, September 22-24, 1982.) New York: Elsevier, 1982: 55-59. 10. Herrara R, Peech M. Reaction of montmorillonite with iron (III). Proc Soil Sci Soc Am 1970; 34: 740-45. 11. Cohen G. The Fenton reaction. In: Greenwald RA, ed. CRC handbook of methods for oxygen radical research. Boca Raton: CRC Press, 1985: 55-64.
12.Halliwell B, Gutteridge JMC. Oxygen toxicity, oxygen radicals, transition metals and disease. Biochem J 1984: 219: 1-14. 13. Rom WN, Bitterman PB, Rennard SI, Cantin A, Crystal RG. Characterization of the lower respiratory tract inflammation of nonsmoking individuals with interstitial lung disease associated with chronic inhalation of inorganic dusts. Am Rev Respir Dis 1987; 136: 1429-34. 14. Graf E, Mahoney JR, Bryant RG, Eaton JW. Iron-catalyzed hydroxyl radical formation. Stringent requirement for free iron coordination site. J Biol Chem 1984; 259: 3620-24. 15. Slade R, Stead AG, Graham JA, Hatch GE. Comparison of lung antioxidant levels in humans and laboratory animals. Am Rev Respir Dis 1985; 131: 742-44. 16. Kennedy TP, Dodson R, Rao NV, et al. Dusts causing pneumoconiosis generate OH and produce hemolysis by acting as Fenton catalysts. Arch Biochem Biophys 1989; 269: 359-64. 17. Gulumian M, Kilroe-Smith TA. Crocidolite-induced lipid peroxidation. Role of antioxidants. Environ Res 1987; 44: 254-59. 18. Zsoldos T, Tigy A, Montsko T, Puppi A. Lipid peroxidation in the membrane damaging effect of silica-containing dust on rat lungs. Exp Pathol 1983; 23: 73-77. 19. Addison CC, Addison WE, Neal GH, Sharp JH. Amphiboles. The oxidation of crocidolite. J Chem Soc 1962; 1: 1468-71. 20. Suzuki Y, Churg J. Formation of the asbestos body. A comparative study with three types of asbestos. Environ Res 1969; 3: 107-18. 21. Koerton HK, Brederoo P, Ginsel LA, Daems WT. The endocytosis of asbestos by mouse peritoneal macrophages and its long-term effect on
accumulation and labyrinth formation. Eur J Cell Biol 1986; 40: 25-36. 22. Niculescu T, Dumitru R, Burnea D. Changes of copper, iron, and zinc in the serum of patients with silicosis, silicotuberculosis, and active lung tuberculosis. Environ Res 1981; 25: 260-68. 23. Guest L. The endogenous iron content, by Mossbauer spectroscopy, of human lungs: lungs from various occupational groups. Ann Occup Hyg 1978; 21: 151-57. 24. Dobrilla G, Dusi U, Lechi A, Innecco A, Cavallini G, Dalla-Vestra P. Preliminary data on some aspects of iron metabolism in silicosis. Med Lav 1967; 58: 122-30. 25. Duncan CA. Lung metabolism of xenobiotic compounds. Clin Chest Med 1989; 10: 49-58. 26. Bus JJ, Gibson JE. Paraquat: model for oxidant-initiated toxicity. Environ Health Perspect 1984; 55: 37-46. 27. Kovacs EJ, Kelley J. Intra-alveolar release of a competence-type growth factor after lung injury. Am Rev Respir Dis 1986; 133: 68-72. 28. Schoenberger CI, Rennard SI, Bitterman PB, Fokoda ZY, Ferrans J, Crystal RG. Paraquat-induced pulmonary fibrosis. Am Rev Respir Dis 1984; 129: 168-73. 29. DuBois F, Begin R, Cantin A, et al. Aluminium inhalation reduces silicosis in a sheep model. Am Rev Respir Dis 1988; 137: 1172-79. 30. Schapira RM, Osornio AR, Ghio AJ, Kennedy TP, Brody AR. Deferoxamine attenuates secretion of platelet-derived growth factor by alveolar macrophages exposed to asbestos in vitro. Am Rev Respir Dis 1990; 141: S414. 31. Adler KB, Holdern-Stauffer WJ, Repine JE. Oxygen metabolites stimulate release of high-molecular-weight glycoconjugates by cell and organ cultures of rodent respiratory epithelium via an arachidonic acid-dependent mechanism. J Clin Invest 1990; 85: 75-85. 32. Hale WB, Turner B, LaMont JT. Oxygen radicals stimulate guinea pig gallbladder glycoprotein secretion in vitro. Am J Physiol 1987; 253: G627-30. 33. Cross CE, Halliwell B, Allen A. Antioxidant protection: a function of tracheobronchial and gastrointestinal mucus. Lancet 1984; i: 1328-30. 34. Riley DJ, Kerr JS. Oxidant injury of the extracellular matrix: potential role in the pathogenesis of pulmonary emphysema. Lung 1985; 163: 1-13. 35. Libbus BL, Illeny SA, Craighead JE. Induction of DNA strand breaks in cultured rat embryo cells by crocidolite asbestos as assessed by nick translation. Cancer Res 1989; 49: 5713-18. 36. Smith WE, Hubert DD, Sobel HJ, Marquet E. Biologic tests of tremolite in hamsters. In: Lemen R, Dement JM, eds. Dusts and disease. Park Forest South, Illinois: Pathotox, 1979: 335-39. 37. Murray MJ, Murray AB, Murray MB, Murray CJ. The adverse effect of iron repletion on the course of certain infections. Br Med J 1978; ii: 1113-15. 38. Bergman I. The relation of endogenous non-haem iron in formalin-fixed lungs to radiological grade of pneumoconiosis. Ann Occup Hyg 1970; 13: 163-69. iron
From The Lancet The
green-bearded oyster
There is an unfounded prejudice against the green-bearded oyster which ought to be removed. The common notion is that the greening of the gills of the oyster is either a sign of disease or that copper has especially invaded the mollusc. Neither view is correct. At a time when economical food problems present themselves in all directions it is deplorable that there should be at our disposal a bountiful supply of these nutrient delicacies, greenbeard oysters, in the salt estuaries of the Essex coast and that they should not meet with public favour because they have assimilated a green colouring material in their gills. The colouring is neither a sign of unhealthy condition nor of copper accumulation. It merely means that with the approach of winter there occurs in these salt marsh creeks a growth of a green sea moss, a purely vegetable product which is appreciated as food by the oysters lying in the adjacent beds. The greenness of the turtle might be objected to on the same lines and with similar unreasonableness. It is curious that while this prejudice exists in this country a quality of greenness, far from being objected to, is actually cultivated in the country where delicate food and attractive ways of placing it before the consumer have been specially cultivated. In France the greening of oysters is a matter of study, a kind of finishing process, and the most esteemed oyster in that country is the greenbeard, the "huitres verts."
(Oct 23,1915)
occurrence of and the related
mother’s condition. Intervention before the
placentomegaly,
fulminant
hydrops,
maternal illness is more likely to succeed.
Open fetal
surgery has been successful in treatment of
otherwise fatal anatomical abnormalities, and
we now add to selected cases of CCAM those congenital appropriately lesions that are amenable to fetal surgical therapy.
REFERENCES 1. Adzick NS, Harrison MR, Glick PL, et al. Fetal cystic adenomatoid malformation: prenatal diagnosis and natural history. J Pediatr Surg
1985; 20: 438-88. 2 Donn SM, Martin JN, White SJ. Antenatal ultrasound findings in cystic malformation. Pediatr Radiol 1981; 10: 180-82. 3. Adzick NS, Harrison MR, Hu LM, et al. Compensatory growth after pneumonectomy in fetal lambs: a morphologic study. Surg Forum
1986; 37: 309-11. 4. Harrison MR, Bressack MA, Churg AM, et al. Correction of congenital diaphragmatic hernia in utero II. Simulated correction permits fetal lung growth with survival at birth. Surgery 1980; 88: 260-68. 5. Harrison MR, Anderson J, Rosen MA, et al. Fetal surgery in the primate I. Anaesthetic, surgical, and tocolytic management to maximize fetal-neonatal survival., J Pediatr Surg 1982; 17: 115-22. 6. Nakayama DK, Harrison MR, Seron-Ferre M, et al. Fetal surgery in the primate II. Uterine electromyographic response to operative procedure and pharmacologic agents. J Pediatr Surg 1984; 19: 333-39.
Hypothesis:
is
7. Adzick NS, Harrison MR, Glick PL, et al. Fetal surgery in the primate III. Maternal outcome after fetal surgery. J Pediatr Surg 1986; 21: 477-80. 8. Harrison MR, Adzick NS, Longaker MT, et al. Successful repair in utero of a fetal diaphragmatic hernia after removal of herniated viscera from the left thorax. N Engl J Med 1990; 322: 1582-84. 9. Crombleholme TM, Harrison MR, Langer JC, et al. Early experience with open fetal surgery for congenital hydronephrosis. J Pediatr Surg 1988; 23: 1114-21. 10. Harrison MR, Langer JC, Adzick NS, et al. Correction of congenital diaphragmatic hernia in utero V. Initial clinical experience. J Pediatr
Surg 1990; 25: 47-57. 11. Adzick NS, Harrison MR, Flake AW, et al. Automatic uterine stapling devices in fetal operation: experience in a primate model. Surg Forum
1985; 36: 479-80. 12. Chin KY, Tang MY. Congenital adenomatoid malformation of one lobe of a lung with general anasarca. Arch Pathol 1949; 48: 221-29. 13. Clark SL, Vitale DJ, Minton SD, et al. Successful fetal therapy for cystic adenomatoid malformation associated with second trimester hydrops. Am J Obstet Gynecol 1987; 157: 294-97. 14. Longaker MT, Laberge JM, Dansereau J, et al. Primary fetal hydrothorax: natural history and management. J Pediatr Surg 1989; 24: 573-76. 15. Rodeck CH, Fisk NM, Fraser DI, et al. Long-term in-utero drainage of fetal hydrothorax. N Engl J Med 1988; 319: 1135-38. 16. Langer JC, Harrison MR, Schmidt KG, et al. Fetal hydrops and death from sacrococcygeal teratoma: Rationale for fetal surgery. Am J Obstet Gynecol 1989; 160: 1145-50. 17. Goodlin RC. Mirror syndromes. In: Goodlin RC, ed. Care of the fetus. New York: Masson, 1979: 48-50.
lung disease after silicate inhalation caused by oxidant generation?
Inhaled silicate dusts may cause lung disease through their surface coordination of iron with subsequent oxidant generation via the Fenton reaction. Pneumoconiosis, irritant bronchitis, focal emphysema, and carcinoma may be produced by oxidants either directly through lipid peroxidation and protein inactivation, or indirectly by oxidant-mediated release of cytokines such as platelet-derived growth factor. The increased incidence of tuberculosis observed among silicate workers could be explained by accumulation of iron complexed by dust particles in the lung and made available to dormant mycobacteria as a virulence factor.
is decreased and the haemolytic effect of silicate is reduced. In-vivo investigations show a correlation between the toxicity of a mineral dust and the distribution of oxygen atoms on the crystal surface.2 Common to all silicates is some concentration of surface silanol groups (SiOH), which have an acidic pKa and favour dissociation at a physiological pH.3 Dissociation of silanols contributes to a net negative charge on the silicate surface, which generates a capacity for adsorption of both organic and inorganic cations.4 Smaller metal cations can be coordinated by the silanol groups; their adsorption and bonding do not depend upon the ionic charges or surface acidity of the silicate, but upon the geometry of these coordination bonds. The resultant selectivity is the basis for silicate use in both water softeners and ion-exchange
negative charge
chromatography. 5.6 Introduction Inhalation of silica, asbestos, clay, talc, mica, zeolite, and other silicate dusts can result in a wide range of lung diseases, which include pneumoconiosis, irritant bronchitis, focal emphysema, bronchogenic carcinoma, mesothelioma, and an increased incidence of tuberculosis. The mechanism of toxicity is not known but is associated with characteristics of the silicate surface. In-vitro data indicate that cytotoxicity is associated with a negative surface charged if the crystal surface is coated with any inorganic or organic cation, this
ADDRESSES Division of Allergy, Critical Care, and Respiratory Medicine, Department of Medicine, Duke University Medical Center (A. J Ghio, MD, T. P. Kennedy, MD, R M Schapira, MD) and Department of Chemistry, Duke University (Prof A. L Crumbliss, PhD), Durham, North Carolina; and Division of Respiratory, Critical Care, and Occupational (Pulmonary) Medicine, Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA (Prof J R. Hoidal, MD) Correspondence to Dr A. J Ghio, Box 3177, Duke University Medical Center, Durham, North Carolina 27710, USA
968
Iron and silicates Ferric ions react with surface silanol groups of amorphous silica to make a silicato-iron coordination complex.’ Fe 31 + m(SiOH) ⇆ Fe (OSi)m3m+ + mH++ In amorphous silica, the free energy production of the reaction of the silanol groups with Fe3 is greater than with any other metal cation, so ferric ions will displace all other metal cations from this surface if no other restrictions or conditions other than a thermodynamic drive apply. Fe3+ is adsorbed even at a pH of 2-0, the isoelectric point of silica where silanol groups would not normally be ionised, which indicates that non-ionic attractive forces may be involved in formation of the silicato-iron complex. Crystalline silicates also show a dose-dependent adsorption of inorganic iron;8-10 coordination of the ferric ion requires involvement of three silanol groups on surfaces of silanol gel and crystal zeolite, while eight silanol groups contribute to complex formation on the surface of crystal montmorillonite. Once coordinated to the silicate surface, iron can mediate an electron exchange via the Fenton reaction when it is reduced from the ferric to the ferrous (Fe2+) state."
Fe3+
O2- ⇆Fe2+ + O2 H202 - Fe3+ + OH + OHThe hydroxyl radical (’OH) that may be produced by this reaction at the surface of the crystal is a potent oxidant, which can initiate lipid peroxidation of cell membranes and oxidatively inactivate essential cell proteins.12 Requirements of this reaction include chelated iron, hydrogen peroxide (H2O2), and a reductant. H202 can be produced by activated phagocytes or as a by-product of aerobic metabolism, and its production by alveolar macrophages is increased after asbestos exposure.13 The superoxide anion (O2-) is an important reductant in biological systems, formed by the respiratory burst of phagocytes and also by aerobic Fe2+
+
+
metabolism.14 Ascorbate is another substance that can actively reduce iron and is found in extracellular fluid of the
lung.15 The capacity of silicate dusts to generate oxidants has been established for silica, asbestos, clays, and talcs;this activity falls after treatment with iron chelators, which indicates that silicates act as Fenton catalysts.16 Lipid peroxidation has been confirmed after exposure to asbestos and silica in rat microsomes and whole lung, and also falls after iron chelation.17,18 We suggest that lung disease after silicate inhalation is caused by the surface coordination of iron by dust particles and subsequent production of oxidants via the Fenton reaction. Involvement of structural iron within the crystal in such a reaction is unlikely because lattice dimensions preclude entry of the necessary reductants and oxidants.19
Predicted features The
ferruginous body is a recognised index of exposure to many silicates. Iron-binding proteins are assumed to envelope the silicate and hence explain the close affiliation of the dust particle with both protein and iron .20 We suggest instead that ferruginous bodies result from bonding between the negatively charged silicate surface and the positively charged quaternary ammonium groups of proteins (including proteins that do not contain iron), and that most of the iron found in ferruginous bodies is coordinated onto the mineral dust from body sources. The capacity of a silicate in the lung to adsorb body sources of iron has been confirmed shortly after its introduction.21 Over longer periods, coordination of iron
from body sources onto the mineral dusts accounts for the low serum iron observed among workers exposed to silicates.22 Evidence that iron is complexed on the silicate dust can be found by use of specific stains for iron or by measurement of the iron content of lungs in which silicate content is increased;23 this iron can be mobilised from the silicate surface by a strong iron chelator.24 Parenchymal damage after silicate inhalation is classed as pneumoconiosis-a restrictive interstitial lung disease associated with increased collagen content. Macrophagederived peptide growth factors have been identified as possible mediators of collagen deposition.’s Bleomycin and paraquat are other fibrogenic agents that can generate oxidants through iron-dependent mechanisms;2S,26 both also induce alveolar macrophages to secrete growth factors for fibroblasts .2728 Measures which displace ferric ion from the silicate surface, such as treatment with high concentrations of aluminium salts, diminish the fibrotic response to these dusts in sheep.29 Furthermore, macrophage secretion of platelet-derived growth factor after exposure to asbestos dust falls after treatment of the dust with an iron chelator.30 These findings support the hypothesis that fibrogenesis by silicates is mediated by oxidant production through the regulation of cytokine secretion. In the airways, chronic inhalation of silicates causes irritant bronchitis and emphysema. Oxidants stimulate mucous glycoprotein secretion by tracheal goblet cells,31 and increased mucus secretion after dust inhalation might have an antioxidant function.32 Increased mucus production in silicate workers, as in cigarette smokers, may therefore be a defence mechanism of the airways against free radicals.33 Emphysema can also be caused by oxidant exposure;34 oxidant production by silicate dusts would be limited to bronchial surfaces, and one would expect tissue destruction to be observed only in their immediate proximity. In the absence of other risk factors, the emphysema observed in association with silicate exposure is focal in distribution and functional loss is unusual. An increased risk of cancer is found with exposure to asbestos and possibly other silicates, and may also be caused by oxidant production. Endocytosis by mucosal cells could move silicate crystals adjacent to DNA, with the risk of oxidant-induced chromosome aberrations and exchanges.35 Differences in rates of cancer induction among silicates may reflect capacity to clear the dust from the lung; fibrous silicates such as asbestos or erionite would be more difficult to eliminate from the body, which would increase the duration of DNA exposure to oxidant stress.36 Silicate workers have an unexplained high incidence of pulmonary tuberculosis. Mycobacteria are dependent on iron for growth and produce the iron chelators mycobactin and exochelin to mobilise the metal from body stores; indeed, iron is considered a virulence factor for mycobacteria. We suggest that silicate particles act as a reserve of iron which can be used by mycobacteria and so explain the increased incidence of tuberculosis among those who inhale such mineral dusts. The iron made available from silicato-iron complexes may activate dormant tuberculosis by a mechanism similar to the effect of iron
repletion. 37 A characteristic of the pneumoconioses is progression of disease after the worker is removed from the site of exposure. Our hypothesis allows for continued adsorption of body sources of iron by the dust particles while they remain in the lung. Clinical and pathological progression could be caused
969
by continued oxidant production, while radiographic progression could be explained by deposition of collagen and raised local iron concentrations. Moreover, iron content of the lung, rather than total dust burden 311 determines the
radiological support of
of pneumoconioses-further essential role for silicato-iron coordination
appearances an
complexes.
Implications hypothesis indicates that detoxification of requires elimination of silicato-iron coordination complexes from the lung. One approach is to prevent entry of these silicates into the lung by strict control of dust levels-a widely recognised, if not invariably If confirmed, silicate dusts
our
measure. The alternative would be treatment with iron chelators in an attempt to eliminate the source of oxidants, the coordinated iron, or supplementation of the antioxidant defences of the lung.
practised,
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From The Lancet The
green-bearded oyster
There is an unfounded prejudice against the green-bearded oyster which ought to be removed. The common notion is that the greening of the gills of the oyster is either a sign of disease or that copper has especially invaded the mollusc. Neither view is correct. At a time when economical food problems present themselves in all directions it is deplorable that there should be at our disposal a bountiful supply of these nutrient delicacies, greenbeard oysters, in the salt estuaries of the Essex coast and that they should not meet with public favour because they have assimilated a green colouring material in their gills. The colouring is neither a sign of unhealthy condition nor of copper accumulation. It merely means that with the approach of winter there occurs in these salt marsh creeks a growth of a green sea moss, a purely vegetable product which is appreciated as food by the oysters lying in the adjacent beds. The greenness of the turtle might be objected to on the same lines and with similar unreasonableness. It is curious that while this prejudice exists in this country a quality of greenness, far from being objected to, is actually cultivated in the country where delicate food and attractive ways of placing it before the consumer have been specially cultivated. In France the greening of oysters is a matter of study, a kind of finishing process, and the most esteemed oyster in that country is the greenbeard, the "huitres verts."
(Oct 23,1915)