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(Chest. 2001;119:422-427.)
© 2001 American College of Chest Physicians

Increased Lower Respiratory Tract Iron Concentrations in Alkaloidal ("Crack") Cocaine Users*

Tariq M. Janjua, MD; Amy E. Bohan, MD and Lewis J. Wesselius, MD, FCCP

* From the Pulmonary Section, Department of Medicine, Carl T. Hayden VA Medical Center, Phoenix, AZ.

Correspondence to: Lewis J. Wesselius, MD, Chief, Pulmonary Section, Carl T. Hayden VA Medical Center, 650 E. Indian School Rd, Phoenix, AZ 85012; e-mail: wesselius.lewis{at}phoenix.va.gov


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: We hypothesized that the use of inhaled alkaloidal ("crack") cocaine could increase lung content of iron, either by inducing alveolar hemorrhage or by other mechanisms. Intrapulmonary accumulation of iron could promote chronic lung diseases in crack users. The goal of this study was to determine whether iron and ferritin content of alveolar macrophages or fluid recovered by BAL was increased in subjects using crack, compared with nonsmokers.

Methods: BAL was performed in 31 volunteer subjects, including healthy nonsmokers (n = 7), subjects smoking crack alone (n = 7), as well as subjects smoking both crack and cigarettes (n = 7) or cigarettes alone (n = 10). Iron content of alveolar macrophages and BAL fluid was determined by a colorimetric method and ferritin content of alveolar macrophages, and BAL fluid was measured by a two-sided immunoradiometric method.

Results: Alveolar macrophages recovered from crack users contained more iron than did alveolar macrophages from nonsmokers (25.4 ± 2.9 nmol/106 vs 5.5 ± 0.6 nmol/106 [mean ± SE]; p < 0.01). There were similar increases in alveolar macrophage ferritin as well as BAL fluid iron and ferritin in crack users, compared with nonsmokers. BAL fluid ferritin concentrations in subjects smoking both crack and cigarettes were increased, compared with subjects smoking crack alone or cigarettes alone (p < 0.05).

Conclusions: Use of crack increases intrapulmonary concentrations of iron and ferritin. Effects of crack on extracellular ferritin concentrations may be additive with effects of cigarette smoking. Although the mechanism(s) causing pulmonary iron accumulation were not identified by this study, it may be a result of occult alveolar hemorrhage or increased vascular permeability. The increase in lung iron burden in habitual crack users could promote chronic lung diseases in these subjects.

Key Words: alveolar macrophage • cocaine • ferritin • iron


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The inhalation of alkaloidal ("crack") cocaine can induce a variety of acute pulmonary disorders, including alveolar hemorrhage, acute pulmonary edema, and interstitial pneumonitis.1 There is evidence that use of crack is also associated with the development of chronic lung injury, as indicated by decreased lung diffusing capacity.2 3 4 However, little is known about the mechanism of lung injury associated with crack use.

A prior study5 demonstrated occult alveolar hemorrhage at autopsy in 58% of crack users, even though death was due to unrelated causes. This observation suggests that occult alveolar hemorrhage occurs frequently in subjects using crack. Repeated alveolar hemorrhage associated with crack use could increase lung iron burden as a result of accumulation of hemoglobin-derived iron. Alveolar hemorrhage and iron accumulation could contribute to the development of altered lung function in crack users. Chronic alveolar hemorrhage associated with idiopathic pulmonary hemosiderosis, for example, is accompanied by damage to the alveolar-capillary membrane and decreased lung diffusing capacity.6 7 Although the mechanisms contributing to the lung injury are uncertain, iron-catalyzed oxidative injury to alveolar structures may be a contributing factor.

The clinical diagnosis of occult alveolar hemorrhage in patients has generally been based on the bronchoscopic recovery of alveolar macrophages that stain positively for hemosiderin-bound iron.8 However, prior studies9 10 11 indicate that this finding may be transient and is not specific for alveolar hemorrhage. The staining technique used in the assessment of occult alveolar hemorrhage is actually based on a semiquantitative assessment of alveolar macrophage iron content. A prior study11 compared this method of assessing cell iron content with direct measurement of alveolar macrophage iron and demonstrated a moderate correlation. However, alveolar macrophage iron content can be increased by factors other than alveolar hemorrhage, including cigarette smoking and mineral dust exposures, so that the finding of increased alveolar macrophage iron content is not specific for alveolar hemorrhage.11 12 13 14

Lung iron content is increased by various experimental lung injuries, including intrapulmonary instillation of silica and inhalation of ozone.15 16 These experimental lung injuries increase lung iron, at least in part, by increasing lung vascular permeability, resulting in an influx of serum-derived iron. Prior studies17 18 suggest that the use of crack also increases lung permeability, although this has not been demonstrated in all studies. Therefore, cocaine-induced alveolar hemorrhage, effects of cocaine on lung permeability, or possibly other effects of cocaine could lead to increased lung iron content. In order to assess whether crack use increases lung iron content, we specifically recruited a group of subjects using crack who denied use of tobacco or regular use of other illicit drugs. We also compared a group of subjects that smoked both cigarettes and crack with a group smoking comparable amounts of tobacco alone in order to assess whether these combined exposures might enhance lung iron accumulation. A control group of healthy nonsmokers was also included in the study. In this study, we report that crack users have a marked increase in lower respiratory tract content of iron and ferritin.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Subjects
Volunteer subjects were recruited by local advertisement and enrollment of subjects recently admitted to the substance abuse treatment unit. To be included in this study, subjects were required to have a history of recent smoking of crack (within 1 week) and prior regular use of inhaled cocaine for at least 6 months. Subjects were excluded from participation in this study if there was a reported history of regular IV drug use within the last year or if there was use of marijuana or other illicit drugs on a regular basis (more than once a week). Subjects using crack and not smoking cigarettes denied use of any tobacco products. Subjects smoking crack and tobacco or tobacco alone had smoked at least one pack of cigarettes daily for at least 7 years. Subjects recruited for the study were excluded if they admitted to regular use (more than once a week) of illicit drugs other than crack. The use of marijuana, if it occurred less than once a week, did not exclude volunteers. Some of the data on subjects smoking tobacco alone had been included in a prior study.19 The characteristics of all study subjects and quantification of crack and cigarette consumption are provided in Table 1 . All subjects gave informed consent to participate in this study, and the study protocol was approved by the institutional human subjects review committee.


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  		Table 1.. Characteristics of Study Subjects*

 
BAL
BAL was performed using methods that have been described previously.13 Briefly, the subjects received topical anesthesia to the oropharynx with tetracaine (2%) and were premedicated with midazolam. Bronchoscopy was performed transorally, and the bronchoscope was wedged initially into the right middle lobe. A total of 200 mL of saline solution was instilled in 50-mL aliquots, followed by immediate suctioning of each aliquot. The lavage procedure was subsequently repeated in the lingula, and the recovered fluid was pooled for analysis. Cells were recovered by centrifugation, and a total cell count was determined from an aliquot using a hemacytometer. A cell differential count was determined by counting 200 cells on a stained (Diff-Quick; American Scientific Products; McGaw Park, IL) cytotcentrifuge preparation.

Iron and Ferritin Measurements
The iron content of alveolar macrophages and BAL fluid was determined by a method based on the use of ferrozine, as described by Fish.20 This method involves the use of an iron-releasing reagent (0.6 N HCl and 2.25% weight/volume KMnO4), which releases iron complexed in biological samples. The sensitivity of this method is 1 µg/dL. The ferritin content of alveolar macrophages and BAL fluid was measured using a solid-phase, two-sided immunoradiometric assay using antibodies to L-type ferritin (Hybritech; San Diego CA), as described by the manufacturer. This assay has a sensitivity of 0.7 ng/mL.

Statistical Analysis
Data are expressed as mean ± SE. Differences between groups were analyzed by analysis of variance, and a correction for multiple comparisons was utilized (Student-Newman-Keuls method). In all tests, statistical significance was identified at the p < 0.05 level.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
BAL Cell Recovery
The number of cells recovered by BAL in study subjects is provided in Table 2 . Total cell recovery by BAL in subjects smoking crack was increased compared with nonsmokers. There was a significantly greater increase in total cell recovery in subjects smoking both cigarettes and crack, compared with subjects using only crack, although values were not significantly different from subjects smoking cigarettes alone (Table 2) . In all smoking groups, the increase in total cell recovery was attributable predominantly to an increase in recovery of alveolar macrophages. There were no subjects with evidence of acute alveolar hemorrhage, as indicated by the finding of grossly bloody fluid or significant numbers of erythrocytes in recovered cell populations.


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  		Table 2.. Cell Recovery by BAL*

 
Alveolar Macrophage Iron and Ferritin
The iron content of alveolar macrophages recovered from subjects using crack was significantly increased compared with control subjects (Fig 1 ). The mean iron content of alveolar macrophages in crack users was approximately fivefold greater than the iron content of alveolar macrophages recovered from nonsmokers. The alveolar macrophage iron content was higher in subjects using both crack and tobacco when compared to those smoking only crack or only cigarettes; however, the differences were not significant (Fig 1) . Similarly, the ferritin content of alveolar macrophages recovered from crack users was also increased compared with alveolar macrophages from control subjects (Fig 2 ). There was approximately a fivefold increase in ferritin content of alveolar macrophages in crack users compared with control subjects. Again, the ferritin content of alveolar macrophages recovered from subjects using both crack and tobacco was higher when compared to subjects smoking crack alone or tobacco alone, although differences were not significant.



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  		Figure 1.. Iron content of alveolar macrophages (AM) recovered from control (nonsmoking) subjects, subjects smoking only crack cocaine, subjects smoking crack cocaine and tobacco, and subjects smoking only tobacco. * = p < 0.01 compared with control subjects.

 


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  		Figure 2.. Ferritin content of alveolar macrophages recovered from control (nonsmoking) subjects, subjects smoking only crack cocaine, subjects smoking crack cocaine and tobacco, and subjects smoking only tobacco. * = p < 0.01 compared with control subjects. See Figure 1 for abbreviation.

 
BAL Fluid Iron and Ferritin
The iron content of BAL fluid recovered from nonsmokers was < 10 ng/mL in all subjects, as noted in a prior study.19 The iron content of BAL fluid recovered from crack users was significantly increased compared with that present in control subjects (Fig 3 ). The iron concentrations in BAL fluid recovered from subjects using both crack and tobacco were higher than concentrations in subjects using crack alone or tobacco alone; however, differences were not statistically significant



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  		Figure 3.. Iron content of BAL fluid recovered from control (nonsmoking) subjects, subjects smoking only crack cocaine, subjects smoking crack cocaine and tobacco, and subjects smoking only tobacco. * = p < 0.01 compared with control subjects.

 
There were increases in BAL fluid concentrations of ferritin in subjects smoking crack compared with control subjects (Fig 4 ). The increases in extracellular ferritin in subjects smoking crack cocaine was approximately 17-fold compared with control subjects. There were even greater increases in ferritin concentrations in BAL fluid recovered from subjects using both crack and tobacco, which were significantly greater than concentrations in subjects smoking crack alone or tobacco alone (Fig 4) . The mean concentration of ferritin in BAL fluid recovered from subjects using both crack and tobacco was > 30-fold greater than concentrations in control subjects.



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  		Figure 4.. Ferritin content of BAL fluid recovered from control (nonsmoking) subjects, subjects smoking only crack cocaine, subjects smoking crack cocaine and tobacco, and subjects smoking only tobacco. * = p < 0.001 compared with control subjects; + = p < 0.05 compared with subjects smoking only crack cocaine or tobacco alone.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The principal finding of this study is that crack users have an increased lower respiratory tract content of iron and ferritin, both within alveolar macrophages and in alveolar epithelial lining fluid. These findings extend prior reports11 12 13 14 that lung iron content is increased by cigarette smoking, mineral dust exposures, and in alveolar hemorrhage syndromes. The similar increase in lung content of both iron and ferritin suggests that most of the increased iron was ferritin bound. Although binding of iron to ferritin within cells provides partial protection against iron-catalyzed injury, there is experimental evidence20 that extracellular ferritin-bound iron can promote lung injury. Therefore, our findings suggest a mechanism whereby crack use could promote chronic lung injury.

The increase in pulmonary iron concentrations in crack users that we noted could be caused by occult alveolar hemorrhage in these subjects. A prior study5 suggests that occult alveolar hemorrhage occurs commonly in crack users. We did not find evidence of acute alveolar hemorrhage, as indicated by the recovery of bloody BAL fluid in any of our subjects, although this does not rule out recent alveolar hemorrhage.10 The accumulation of iron within alveolar macrophages is consistent with alveolar hemorrhage but is not specific for this diagnosis. Another mechanisms that could increase alveolar macrophage content of iron would be increased lung epithelial permeability, which has been demonstrated in some studies17 18 of crack cocaine users. Alternatively, particulates accumulating in alveolar macrophages of crack cocaine users, which has also been previously noted,21 22 23 could increase cell iron content.

Alveolar macrophages recovered from crack users demonstrate altered function, including decreased bacterial killing and impaired capacity to prevent tumor cell growth.24 Accumulation of iron in alveolar macrophages of crack users may contribute to these reported alterations in alveolar macrophage function. Iron accumulation has been shown to alter alveolar macrophage function, including cytokine expression, and can lead to cell injury.25 26 However, it is uncertain whether iron accumulation is the only cause of altered function in alveolar macrophages recovered from crack users.

BAL fluid recovered from crack users contained significant amounts of extracellular ferritin, indicating increased iron and ferritin concentrations present in alveolar epithelial lining fluid. The finding of increased extracellular ferritin is significant, since a prior study27 suggests that extracellular ferritin promotes lung injury in experimental animals. The effects of crack on extracellular ferritin accumulation within the lungs appeared to be additive to the effects of cigarette smoking, since subjects that smoked cigarettes and crack had significantly higher ferritin concentrations, compared with subjects smoking crack alone or a group of subjects smoking comparable amounts of tobacco alone. Since cigarette smoke mobilizes iron from extracellular ferritin, which can then potentially promote iron-catalyzed lung injury, there may be synergistic detrimental effects of exposure to both crack and cigarettes.28

Several possible factors may limit the conclusions of the current study, including the effect of the use other illicit drugs by study subjects, and the potential of inaccurate smoking information provided by study subjects. We screened all subjects and excluded subjects who reported regular use of other illicit drugs, although we did not exclude crack users with infrequent use of marijuana (less than once a week). In both groups of crack users, there were subjects who reported occasional use of marijuana. Therefore, it is possible that some iron accumulation in the lungs of subjects smoking crack was attributable to the concurrent use of marijuana. It is also possible that some subjects may have used other illicit inhaled or IV agents that were not reported and which could influence our results. A prior study29 suggests that IV drugs may also lead to an increase in iron content of lung macrophages. It is also possible that smoking histories obtained from study subjects were not accurate, making it difficult to make conclusions about the relative effects of crack and cigarette smoking on lung iron accumulation.

Prior studies30 have implicated increased pulmonary concentrations of iron in the development of lung neoplasms, presumably by enhancing generation of hydroxyl radicals that can promote DNA injury. Systemic iron overload associated with thalassemia has also been shown to promote development of a restrictive lung disease and hypoxemia consistent with pulmonary fibrosis.31 Although these prior studies support the concept that iron accumulation within the lungs can promote lung disease, the exact role of intrapulmonary iron in the pathogenesis of lung disease in crack users is uncertain.

In summary, the current study demonstrates that lung iron content is markedly increased in habitual crack users. Although the mechanism(s) contributing to the accumulation of iron are not clear from these studies, subclinical alveolar hemorrhage or increased lung permeability could be contributing factors. The increase in pulmonary iron burden in crack users may contribute to impaired alveolar macrophage function in these subjects and could potentially promote the development of chronic pulmonary diseases.


   Footnotes
 
Supported by the VA Research Service.

Received for publication May 15, 2000. Accepted for publication September 14, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Haim, DY, Lippmann, ML, Goldberg, SK, et al (1995) The pulmonary complications of crack cocaine: a comprehensive review. Chest 107,233-240[Free Full Text]
  2. Weiss, RD, Goldenheim, PD, Mirin, SM, et al (1981) Pulmonary dysfunction in cocaine smokers. Am J Psychiatry 138,1110-1112[Abstract/Free Full Text]
  3. Ithonen, J, Scholl, S, Glassroth, J (1984) Pulmonary dysfunction in free-base cocaine users. Arch Intern Med 144,2195-2197[Abstract]
  4. Tashkin, DP, Khalsa, ME, Gorelick, D, et al (1992) Pulmonary status of habitual cocaine smokers. Am Rev Respir Dis 145,92-100[ISI][Medline]
  5. Bailey, ME, Fraire, AE, Greenberg, SD, et al (1994) Pulmonary histopathology in cocaine abusers. Hum Pathol 25,203-207[CrossRef][ISI][Medline]
  6. Roberts, LN, Montessori, G, Patterson, JG (1972) Idiopathic pulmonary hemosiderosis: case report with pulmonary function tests and lveolar macrophage function and cytokine production. Am Rev Respir Dis 106,904-908[ISI][Medline]
  7. Corrin, B, Jagusch, M, Dewar, A, et al (1987) Fine structural changes in idiopathic pulmonary hemosiderosis. J Pathol 153,249-256[CrossRef][ISI][Medline]
  8. De Lassence, A, Fleury-Feith, J, Escudier, E, et al (1995) Alveolar hemorrhage: diagnostic criteria and results in 194 immunocompromised hosts. Am J Respir Crit Care Med 151,157-163[Abstract]
  9. Grebski, E, Hess, T, Hold, G, et al (1992) Diagnostic value of hemosiderin-containing macrophages in bronchoalveolar lavage. Chest 102,1794-1799[Abstract/Free Full Text]
  10. Sherman, JM, Winnie, G, Thomassen, MJ, et al (1984) Time course of hemosiderin production and clearance by human pulmonary macrophages. Chest 86,409-411[Abstract/Free Full Text]
  11. Corhay, JL, Wever, G, Bury, T, et al (1992) Iron content in human alveolar macrophages. Eur Respir J 5,804-809[Abstract]
  12. Mateos, F, Brock, JH, Perez-Arellano, JL (1998) Iron metabolism in the lower respiratory tract. Thorax 53,594-600[Free Full Text]
  13. Wesselius, LJ, Flowers, CH, Skikne, BS (1992) Alveolar macrophage content of isoferritins and transferrin: comparison of nonsmokers and smokers with and without chronic airflow obstruction. Am Rev Respir Dis 145,311-316[ISI][Medline]
  14. Guest, L (1978) The endogenous iron content, by Mossbauer spectroscopy, of human lungs: II. Lungs from various occupational groups. Ann Occup Hyg 21,151-157[Abstract/Free Full Text]
  15. Mills, PC, Roberts, CA, Smith, NC (1996) Effects of ozone and airway inflammation on glutathione status and iron homeostasis in the lungs of horses. Am J Veterinary Res 57,1359-1363[ISI][Medline]
  16. Ghio, AJ, Jaskot, RH, Hatch, GE (1994) Lung injury after silica instillation is associated with an accumulation of iron in rats. Am J Physiol 267(6 pt 1),L686-L692:[Abstract/Free Full Text]
  17. Susskind, H, Weber, DA, Volkow, ND, et al (1991) Increased lung permeability following long-term use of free-base cocaine (crack). Chest 100,903-909[Abstract/Free Full Text]
  18. Tashkin, DP, Kleerup, EC, Hoh, CK, et al (1997) Effects of "crack" cocaine on pulmonary alveolar permeability. Chest 112,327-335[Abstract/Free Full Text]
  19. Nelson, ME, O’Brien-Ladner, AR, Wesselius, LJ (1995) Regional variation in iron and iron-binding proteins within the lungs of smokers. Am J Respir Crit Care Med 153,1353-1358[Abstract]
  20. Fish, WW (1988) Rapid colorimetric micromethod for the quantitation of complexed iron in biologic samples. Methods Enzymol 158,357-364[ISI][Medline]
  21. Greenbaum, E, Copeland, A, Grewal, R (1993) Blackened bronchoalveolar lavage fluid in crack smokers. Am J Clin Pathol 100,481-487[ISI][Medline]
  22. Wesselius, LJ, Smirnov, IM, Nelson, ME, et al (1996) Alveolar macrophages accumulate iron and ferritin after in vivo exposure to iron or tungsten dusts. J Lab Clin Med 127,401-409[CrossRef][ISI][Medline]
  23. Giovagnoli, MR, Alderisio, M, Cenci, M, et al (1999) Carbon and hemosiderin-laden macrophages in sputum of traffic policeman exposed to air pollution. Arch Environ Health 54,284-290[ISI][Medline]
  24. Baldwin, GC, Tashkin, DP, Buckley, DM, et al (1997) Marijuana and cocaine impair alveolar macrophage function and cytokine production. Am J Respir Crit Care Med 156,1606-1613[Abstract/Free Full Text]
  25. O’Brien-Ladner, AR, Blumer, BM, Wesselius, LJ (1998) Differential regulation of human alveolar macrophage-derived interleukin-1{beta} and tumor necrosis factor-{alpha} by iron. J Lab Clin Med 132,497-506[CrossRef][ISI][Medline]
  26. Fuhrman, B, Oiknine, J, Aviram, M (1994) Iron induces lipid peroxidation in cultured macrophages, increases their ability to oxidatively modify LDL, and affects their secretory properties. Atherosclerosis 111,65-78[CrossRef][ISI][Medline]
  27. Folkesson, HG, Leanderson, P, Westrom, BR, et al (1993) Increased lung to blood passage of polyethylene glycols after intratracheal instillation of ferritin and asbestos fibers in the rat. Eur Respir J 6,96-101[Abstract]
  28. Lapenna, D, De Gioia, S, Mezzetti, A, et al (1995) Cigarette smoke, ferritin and lipid peroxidation. Am J Respir Crit Care Med 151,431-435[Abstract]
  29. Lockemann, U, Pueschel, K (1993) Siderophages in the lung of drug addicts. Forensic Sci Int 59,169-175[CrossRef][ISI][Medline]
  30. Weinberg, ED (1993) Association of iron with respiratory tract neoplasia. J Trace Elem Exp Med 6,117-123
  31. Cooper, DM, Mansell, AL, Weiner, MA, et al (1980) Low lung capacity and hypoxemia in children with thalassemia major. Am Rev Respir Dis 121,639-646[ISI][Medline]




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