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(Chest. 2002;121:1231-1238.)
© 2002 American College of Chest Physicians

Evidence of Chronic Damage to the Pulmonary Microcirculation in Habitual Users of Alkaloidal ("Crack") Cocaine*

Gayle Cocita Baldwin, PhD; Ruth Choi, BS; Michael D. Roth, MD, FCCP; Angela H. Shay, BS; Eric C. Kleerup, MD, FCCP; Michael S. Simmons, BS and Donald P. Tashkin, MD

* From the Divisions of Hematology-Oncology (Dr. Baldwin, Ms. Choi, and Ms. Shay) and Pulmonary and Critical Care Medicine (Drs. Roth, Kleerup, and Tashkin, and Mr. Simmons), Department of Medicine, UCLA School of Medicine, Los Angeles, CA.

Correspondence to: Gayle Cocita Baldwin, PhD, Division of Hematology-Oncology, Department of Medicine, 11-934 Factor, UCLA School of Medicine, Los Angeles, CA 90095-1678; e-mail: gbaldwin{at}mednet.ucla.edu


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Study objective: To evaluate BAL cells obtained from habitual users of alkaloidal ("crack") cocaine alone or in combination with tobacco, for evidence of cocaine-associated alveolar injury.

Design: Prospective cohort study.

Patients: A total of 36 healthy men and women (mean age [SD], 37.5 [7.5] years), including 10 cocaine-only smokers (CS), 6 cocaine-plus-tobacco smokers (CTS), 10 tobacco smokers (TS), and 10 nonsmokers (NS), underwent fiberoptic bronchoscopy and BAL.

Methods: Cytospins were prepared from BAL cells and stained with Wright-Giemsa for cell differentials and Gomori’s stain for detection of hemosiderin. Endothelin (ET)-1 levels were determined from lavage fluid by enzyme-linked immunosorbent assay.

Results: None of the cocaine users reported episodes of hemoptysis or respiratory distress, and routine spirometry findings were within normal limits in all subjects. While there was little effect on total cell numbers or differential counts, the percentages of hemosiderin-positive alveolar macrophages (AMs) were markedly increased in CS (33.8 ± 8.7% [SEM]) compared to TS and NS (< 2%; p < 0.05). The percentages of hemosiderin-laden AMs were also numerically increased in CTS (11.8 ± 7.8%), but this value was not statistically significant from that of TS or NS. ET-1 levels were significantly increased in the fluid recovered from CS (6.2 ± 0.8 pg/mL) when compared to NS (1.2 ± 0.4 pg/mL) and TS (1.3 ± 0.2 pg/mL) [p < 0.05], while ET-1 levels were elevated to a lesser extent in CTS (2.5 ± 0.6 pg/mL). ET-1 levels correlated with the percentage of hemosiderin-positive AMs when CS were analyzed in conjunction with CTS (r = 0.64; p = 0.0004).

Conclusion: Clinically inapparent alveolar hemorrhage occurs frequently in otherwise healthy crack cocaine smokers and is associated with elevated levels of ET-1, indicative of cocaine-induced pulmonary microvascular injury.

Key Words: endothelin-1 • hemosiderin • macrophages • microvasculature • pulmonary

Unlike cocaine powder, which is water soluble (cocaine HCl), "crack" cocaine (alkaloidal cocaine) is lipid-soluble and resists thermal degradation, so that it can be smoked. When smoked, it produces a near-instantaneous euphoric effect due to its rapid absorption via the pulmonary circulation. Because of this property and growing concern over the risks of HIV transmission by the IV route, smoking of crack cocaine has largely replaced other modes of recreational cocaine use, including nasal insufflation and IV injection of cocaine HCl. Use of crack cocaine increased rapidly in the early to mid-1980s, reaching a 3.9% annual prevalence among young individuals by 1987.1 Subsequently, use prevalence declined for a few years, after which it has gradually risen again, reaching 2.7% by 1999.1 Consequently, crack cocaine continues to remain a major drug of abuse in the United States.

Smoking cocaine exposes the lung to the alkaloidal cocaine vapor itself, as well as to a variety of other inhaled substances, including toxic pyrolysis products (eg, methyl ethyl ecgonine), impurities, contaminants with which cocaine may be "cut" (eg, caffeine, phencyclidine, procaine, lidocaine2 ), and combustion products of the fuel used to ignite the cocaine. Heavy and repeated exposure of the lung to cocaine smoked in this manner has been associated with a broad spectrum of pulmonary complications,3 including acute severe exacerbations of asthma,4 5 6 noncardiogenic pulmonary edema,7 diffuse alveolar hemorrhage,8 recurrent pulmonary infiltrates with eosinophilia,9 10 nonspecific interstitial pneumonitis,11 bronchiolitis obliterans with organizing pneumonia,12 and acute pulmonary infiltrates associated with a spectrum of clinical and histologic findings, referred to as "crack lung."13 The mechanism by which cocaine smoking might cause these varied types of pulmonary injury is not well understood. Although reports of acute lung damage requiring urgent medical care are relatively rare, it is likely that the frequency of these severe pulmonary complications is underreported.

Pulmonary parenchymal and vascular pathology in cocaine addicts has been studied in two autopsy series of patients dying from cocaine intoxication or its complications.14 15 In both of these studies, hemosiderin-laden macrophages were noted in a relatively large percentage of the cases. After acute alveolar hemorrhage, alveolar macrophage (AMs) phagocytose and digest hemoglobin-producing hemosiderin. The percentage of AMs with stainable hemosiderin is therefore a semiquantitative marker of recent alveolar hemorrhage, with hemosiderin appearing within 50 h of alveolar bleeding and persisting for as long as 12 days after cessation of bleeding.16 The necropsy findings in cocaine addicts14 15 are therefore consistent with recent alveolar hemorrhage. Moreover, the high proportion of hemosiderin positivity in these autopsied patients and the absence of ascertainable antemortem evidence of hemoptysis suggest that occult alveolar hemorrhage in habitual cocaine smokers may be more common than clinically recognized. While the mechanism underlying alveolar hemorrhage in crack addicts is unclear, it could be the result of cocaine-induced microvascular injury. The latter has been invoked as a possible cause of the diffusion impairment that has been observed in some17 18 19 but not all20 21 22 regular cocaine smokers who underwent systematic testing of lung function.

The present study was conducted to evaluate chronic alveolar hemorrhage in a nonrandom volunteer sample of apparently healthy habitual crack users and non-cocaine-using control subjects participating in an ongoing longitudinal study of the pulmonary effects of regular cocaine smoking.17 This subset of subjects volunteered to undergo fiberoptic bronchoscopy with BAL, enabling us to examine possible effects of heavy habitual cocaine inhalation on airway pathology23 and AM function.24 We utilized hemosiderin-positive AMs as a marker of recent alveolar hemorrhage, and compared the percentages of positive AMs recovered by BAL from the lungs of cocaine-only smokers (CS) and cocaine-plus-tobacco smokers (CTS) with the percentage of these cells obtained from non-cocaine-using control subjects, including nonsmokers (NS) and tobacco smokers (TS). As another potential marker of alveolar injury, we assessed levels of endothelin (ET)-1, an endothelium-derived vasoconstrictor peptide and a potential indicator of cell damage, in the BAL specimens of the four subject groups. Others have reported that cocaine stimulates release of ET-1 in cultured endothelial cells,25 26 and can be found in the urine and plasma of cocaine-intoxicated subjects.26 Our results show a striking and significant increase in both hemosiderin-positive AMs and levels of ET-1 in the BAL fluid of cocaine smokers.


   Materials and Methods
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Results
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Subjects
A total of 36 subjects were evaluated (10 NS, 10 CS, 6 CTS, and 10 TS). All subjects were participants in an ongoing study evaluating the effects of habitual use of cocaine on the lung.23 Subjects were 23 to 50 years of age, with no known medical illnesses, and were selected for inclusion because they were either lifelong NS or habitual CS, TS, or CTS. Current cocaine use was verified by positive urine levels of cocaine metabolite. While most of the crack users had used marijuana in the past, none were currently smoking marijuana. Exclusion criteria included a history of smoking (> 20 times per lifetime) any substance other than cocaine, tobacco, or marijuana; IV drug abuse (> 5 times per lifetime or within the previous year); a history of chronic lung disease (eg, asthma, interstitial lung disease); a history or clinical evidence of significant cardiovascular or other serious medical illness; positive HIV serologic findings; a recent (< 6 weeks) upper or lower respiratory illness; significant occupational exposure to hazardous dusts or fumes; or evidence of pregnancy.

Preliminary examination included a detailed respiratory and drug-use questionnaire, a medical history, physical examination, forced expiratory spirometry,27 urine drug screen, pregnancy tests (female subjects only), platelet count, coagulation studies, and HIV serology. Measurements of single-breath diffusing capacity of the lung for carbon monoxide (DLCO)28 had been performed in a minority of the subjects prior to bronchoscopy as part of another study. All volunteers provided written informed consent in accordance with the policies of the UCLA School of Medicine Human Subject Protection Committee.

Bronchoscopy and AM Recovery
With minor modifications, fiberoptic bronchoscopy with BAL was performed as previously described.29 Subjects were admitted to the Outpatient Medical Procedure Suite of the UCLA Medical Center, and prepared with a combination of topical anesthesia (4% lidocaine by nebulizer, 20% benzocaine spray to the posterior pharynx, and 2% lidocaine to the bronchus as needed) and conscious sedation (IV midazolam and meperidine according to the UCLA Medical Center conscious sedation guidelines). A Pentax videobronchoscope (model VB1830T2; Pentax Precision Instrument Corporation; Orangeburg, NY) was advanced into the airway and wedged sequentially into the lateral and then medial subsegments of the right middle lobe. Each subsegment was lavaged with a total of 150 mL of sterile saline solution by first instilling and retrieving a 20-mL aliquot (to obtain a bronchial wash), and then by serially instilling and retrieving 40-mL, 40-mL, and 50-mL aliquots (to obtain the BAL sample). The BAL samples were passed through 100-µm sterile nylon filters (Becton Dickinson; San Jose, CA) to remove mucus and particulate matter, pooled, and centrifuged at 200g for 8 min at 4°C. For ET-1 enzyme-linked immunosorbent assays (ELISAs) [R&D Systems; Minneapolis, MN], 3-mL aliquots of the pooled supernatants were acidified to remove interfering proteins prior to freezing (equal volume 1% trifluoroacetic acid). The remaining pooled supernatants were aliquoted and stored at - 70°C. Cell pellets containing AMs were also pooled, washed in RPMI-1640 (Bio-Whittaker; Walkersville, MD) and counted. AMs were kept on ice in polypropylene tubes to avoid cell loss from adherence. Total cell yield was determined by hemocytometer counts, with viability assessed by trypan blue exclusion. Cytocentrifuge preparations of AMs were prepared for both differential and hemosiderin analyses.

Analysis of Hemosiderin-Positive AMs
Cytocentrifuge preparations were prepared and stained either by Wright-Giemsa for differential analysis, or Gomori’s iron stain for hemosiderin analysis. For Gomori’s stain, cytocentrifuge slides were fixed in methanol and rinsed in distilled water. Slides were then placed in a vented staining dish in equal parts of 20% HCl and 10% potassium ferrocyanide, microwaved for 3 min, agitated, and left to stand for 30 s. Slides were washed thoroughly in distilled water and counterstained with nuclear fast red. Iron pigment stains bright dark blue to purple, whereas nuclei stain red and cytoplasm stains pink to rose. Total numbers of hemosiderin-positive cells were viewed by light microscopy and scored by one screener, who was not informed as to the smoking category of the sample. In all cases, 5,000 cells were counted manually and positive cells were expressed as a percentage of 5,000.

Quantitation of Human ET-1
ET-1 was quantitated in the BAL specimen using a commercially available ELISA. Prior to ELISA assay, frozen samples were thawed, diluted 1:2 in extraction solvent (acetone: 1 mol/L HCl: water, 40:1:5), and lyophilized in a centrifugal evaporator overnight. Standards, reagents, and test samples were then prepared and assayed according to the instructions of the manufacturer.

Data Analysis
One-way analysis of variance was used to compare the means of the percentage of hemosiderin-positive AMs, levels of ET-1, and alveolar cytology between all smoking groups. Tukey’s studentized range test was used for pair-wise multiple comparisons testing. Correlation analysis was used to examine the relationship between the percentage of hemosiderin-positive cells and levels of ET-1. Correlations of duration and amount of cocaine smoked vs hemosiderin positivity and levels of ET-1 were also determined. A significance level of 0.05 was used for all tests.


   Results
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 Materials and Methods
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Discussion
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Subjects
Thirty-six subjects were studied (22 men and 14 women; mean age, 37.5 ± 7.5 years), including 10 NS, 10 CS, 6 CTS, and 10 TS. Subject characteristics are described in Table 1 . Cocaine smokers (both CS and CTS) had a history of current or recent (within 6 months) smoking of alkaloidal cocaine on a regular basis for >= 8.1 years and an average of >= 1.0 g/wk during the past year. CS and CTS had last smoked cocaine between 1 h and 48 h before bronchoscopy, except for one CTS who had last smoked cocaine approximately 1 week before the procedure. There was otherwise no significant difference in the amount of cocaine use between these two groups. The presence of cocaine metabolites in the urine was confirmed in all 10 CS and all 6 CTS.


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  		Table 1.. Subject Characteristics*

 
Use of tobacco in TS varied from 20 to 50 cigarettes per day, except in one subject, who consumed only 7 cigarettes per day. The use of tobacco by CTS, varied from 2 to 25 cigarettes per day, with most subjects smoking from 10 to 20 cigarettes per day. While the daily use of tobacco was less in CTS as compared to TS (p = 0.05), both groups smoked their last cigarette between 0.25 h and 24 h prior to bronchoscopy, and had a minimum lifetime exposure in the ranges of 7 to 10 pack-years. All subjects had normal values for FVC and FEV1, as well as for the FEV1/FVC ratio.30 Values for DLCO were also within normal limits31 in all subjects in whom these measurements were obtained (two CS, 128% and 98% predicted; three CTS, 96%, 83%, and 98% predicted; one TS, 102% predicted; and one NS, 80% predicted).

Increased Percentage of Hemosiderin-Laden AMs in the BAL Fluid of Cocaine Smokers
We found a marked increase in percentages of AMs staining positive for hemosiderin by Gomori’s iron stain when BAL cytocentrifuge preparations from CS were compared to similar preparations from either NS and TS (CS, 33.6 ± 8.7% [SEM]; TS, 1.4 ± 0.7%; NS, 1.9 ± 0.7%; p < 0.05; Fig 1 , 2 ). While the average percentage of hemosiderin-positive cells from CTS (11.8 ± 7.8%) was not significantly increased above the levels observed in either NS or TS, values in two CTS subjects were, however, outside the normal range (Fig 2) . In the CTS group, there was no obvious correlation between the intensity, duration, or timing of recent exposure to cocaine and the levels of hemosiderin-positive AMs. No increase in the percentage of hemosiderin-positive AMs was noted in the absence of cocaine smoking. None of the subjects reported hemoptysis. More than one third of cocaine smokers reported black sputum production, and approximately 15% experienced chest pain immediately following cocaine smoking. Additionally, the BAL fluid from cocaine smokers (CS and CTS) was uniformly blackened by the presence of carbonaceous material. In contrast to the relationship between cocaine use and hemosiderin staining, CS had relatively normal cell differentials when compared to NS (Table 2 ). Increases in the total numbers of alveolar cells and AMs were restricted to TS, while CTS had increased numbers of eosinophils compared to NS (Table 2) . No other statistically significant differences in alveolar cytology were observed when smoking groups were compared to NS. There was, however, a trend toward increased total cell counts (p = 0.095) and AM numbers (p = 0.055) in CS, suggestive but not diagnostic of a low-grade alveolitis. Furthermore, while the total number of AMs was primarily increased in relation to tobacco smoking, only cocaine smoking was associated with an increase in hemosiderin-laden macrophages, suggesting that alveolar hemorrhage is not simply a hallmark of inflammation.



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  		Figure 1.. Prominent hemosiderin-laden AMs in the BAL fluid of a CS (left, A), which are absent in the BAL fluid of a TS (middle, B) or a NS (right, C). Cytocentrifuge preparations were prepared and stained with Gomori’s iron stain for hemosiderin analysis (original x 200). Iron pigment stains bright dark blue to purple, whereas nuclei stain red and cytoplasm stains pink to rose.

 


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  		Figure 2.. Increased percentage of hemosiderin-positive AMs in the BAL specimen of cocaine smokers. Total numbers of hemosiderin-positive cells were viewed by light microscopy and scored (number of positive cells per field of 5,000 total cells, expressed as a percentage) by one screener, who was not informed as to the smoking category of the sample.

 

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  		Table 2.. Bronchoalveolar Cell Profile*

 
Levels of ET-1 Increased in the BAL of Cocaine Smokers
As shown in Figure 3 , the levels of ET-1 were significantly (p < 0.05) elevated in the BAL specimens of CS (6.2 ± 0.8 pg/mL [SEM], n = 10) when compared to NS (1.2 ± 0.4 pg/mL, n = 10) and TS (1.3 ± 0.2 pg/mL, n = 10). ET-1 levels in the BAL fluid were increased approximately sixfold in CS and approximately twofold in CTS (2.5 ± 0.6 pg/mL, n = 6) when compared to either NS or TS (Fig 3) . Mean ET-1 values of CS but not CTS were significantly different from those of NS and TS.



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  		Figure 3.. Levels of ET-1 increased in the BAL fluid of cocaine smokers. ET-1 was quantitated in the BAL fluid using a commercially available ELISA. Prior to ELISA assay, frozen samples were thawed, diluted 1:2 in the extraction solvent (acetone: 1 mol/L HCl: water, 40:1:5), and lyophilized in a centrifugal evaporator overnight. Standards, reagents, and test samples were then prepared and assayed according to the instructions of the manufacturer.

 
Increased ET-1 Levels Correlate With Increased Numbers of Hemosiderin-Positive Cells
As shown in Figure 4 , a linear regression analysis between ET-1 levels and the percentage of AMs staining for hemosiderin revealed a significant correlation when CS were analyzed in conjunction with CTS (r = 0.64, p = 0.004). When CS were analyzed alone, the regression coefficient was 0.52, but this r value does not reach statistical significance because of the small sample size. No correlation was observed between ET-1 levels and hemosiderin-positive cells in the NS and TS groups.



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  		Figure 4.. Increased ET-1 levels correlate with increased numbers of hemosiderin-positive cells in cocaine smokers. Correlation analysis was used to examine the relationship between the percentage of hemosiderin-positive cells and levels of ET-1 for the CS and CTS. Levels of ET-1 correlated significantly with hemosiderin positivity (r = 0.64; p < 0.05). • = CS; {blacktriangleup} = CTS.

 

   Discussion
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 Materials and Methods
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References
 
Diffuse alveolar hemorrhage associated with dyspnea and hemoptysis is believed to be a relatively common manifestation of cocaine abuse,3 although its occurrence has been underemphasized in the literature. Since the inception of the crack cocaine epidemic in the mid-1980s, several cases of acute pulmonary hemorrhage have been reported in temporal association with cocaine smoking.8 13 32 33 In some cases, diffuse alveolar hemorrhage has been associated with the acute crack lung syndrome,13 which is characterized by dyspnea, cough, fever, diffuse pulmonary infiltrates, and hypoxemia. Lung biopsy in these patients has yielded a spectrum of other histopathologic findings, including pulmonary edema, interstitial lung disease, pulmonary eosinophilia, and diffuse alveolar damage. In two separate studies, signs of alveolar hemorrhage were noted at autopsy in a high proportion of cocaine users dying of acute severe complications of cocaine intoxication.14 15 Hemosiderin-laden macrophages, indicative of chronic alveolar hemorrhage, were observed in 7 of 20 cases (35%) in one series14 and in 21 of 52 cases (40%) in the other.15

We now report a striking and significant increase in hemosiderin-positive AMs in the BAL fluid of healthy, generally asymptomatic smokers of crack cocaine. These findings suggest that a high proportion of seemingly healthy crack users have chronic alveolar hemorrhage that is clinically inapparent. In a larger sample of 202 healthy crack smokers from whom this volunteer sample was drawn, we previously noted a 6% prevalence of self-reported hemoptysis.17 However, in all of the latter cases, bloody sputum was experienced only infrequently. Although one brief report cites that 26% of habitual freebase cocaine users reported episodes of blood-streaked sputum,20 the frequency and severity of such episodes varied widely among the cocaine smokers. Observations made here are remarkable, since they suggest that alveolar hemorrhage is a common occurrence and not restricted to severely ill patients presenting with crack lung syndrome or patients dying of severe complications of cocaine intoxication.

We previously reported that short-term in vivo exposure to cocaine functionally activates circulating polymorphonuclear neutrophils (PMNs), suggesting that the pathologic changes associated with the acute crack lung syndrome, including alveolar hemorrhage, may be mediated by activated PMNs.34 Other components inhaled during crack smoking, such as pyrolysis products or carbonaceous byproducts from the fuel source, may also exert direct toxic effects on alveolar tissue. Either of these mechanisms could produce chronic, subtle damage to the lung microvasculature, resulting in repeated bouts of subclinical alveolar hemorrhage. Pulmonary microvascular injury has been invoked as a possible cause of the diffusion impairment observed in some16 17 18 but not all19 20 21 regular cocaine smokers who underwent systematic testing of lung function. The variability in reported measurement of diffusing capacity in these studies might be due to artificial elevations in the DLCO caused by intrapulmonary hemorrhage.35 Reports that cocaine stimulates release of ET-1 in cultured endothelial cells25 26 prompted us to investigate BAL fluid for the presence of ET-1. As we report here, significantly increased levels of ET-1 occur in the BAL fluid from CS. Moreover, levels of ET-1 correlated significantly with AM hemosiderin staining, suggesting a relationship between the release of this potent vasoconstrictor peptide and alveolar injury. It is possible that cocaine-mediated damage to the pulmonary microvasculature, reflected by increased levels of ET-1 (Fig 3) , leads to leakage of fluid and erythrocytes from injured pulmonary capillaries into the alveoli.

Interestingly, in contrast to the significant increases in ET-1 and hemosiderin-positive AMs that were found in CS, we failed to observe a consistent increase in these measures in the BAL samples collected from CTS. Elevations in levels of ET-1 or hemosiderin-positive AMs were observed in only three of the six CTS subjects. This finding was unexpected. Tobacco smoke has the capacity to cause alveolar damage due to oxidative stress and the action of neutrophil-derived proteases.36 The expectation was that evidence of alveolar injury would be magnified in combined CTS—the opposite of our finding. We considered the possibility that differences between the CS and CTS cohorts might be due to differences in the amount of cocaine smoked. However, neither the actual amounts of cocaine smoked per week nor the overall duration of regular crack use were significantly different between CS and CTS. While it is possible to speculate that tobacco smoking exerted a protective effect against cocaine-induced alveolar damage, there was no obvious correlation between tobacco use (pack-years or cigarettes per day) and study outcome measures. Moreover, the well-known detrimental effects of tobacco on the lung would argue against a protective influence of tobacco on crack-induced lung injury.37 38 Notably, no protective effect has been observed in the CTS cohort with respect to other measurements of alveolar injury, such as alveolar epithelial permeability39 40 or diffusion impairment.18 Alternatively, it is possible that tobacco smoking increases the clearance or degradation of hemosiderin-laden AMs and ET-1, or results in an inflammatory process, which dilutes these parameters. Total cell yield and the number of AMs were elevated in TS and CTS. It is also possible that the small number of subjects and marked response variability in the CTS group did not provide a representative assessment of alveolar injury in this cohort. This could contribute to our failure to observe a statistically significant effect of cocaine in combined smokers of cocaine and tobacco. These hypotheses are all speculative and we cannot exclude the possibility of other explanations. The underlying nature of the interaction between cocaine and tobacco with respect alveolar injury, if there is one, warrants further investigation.

Cardiovascular events are among the most common medical complications of cocaine abuse, including acute myocardial ischemia and/or infarction, arrhythmias and sudden death, myocarditis and cardiomyopathy, and systemic arterial hypertension.41 However, our subjects reported no symptoms of cardiovascular disease and underwent a complete medical history, physical examination, and 12-lead ECG, the findings of which were uniformly unremarkable. Cocaine use has also been associated with clotting abnormalities secondary to enhanced platelet aggregation.42 This could predispose to pulmonary thromboembolism with infarction, especially in the setting of cocaine-induced pulmonary vasoconstriction. Chest pain and dyspnea are not uncommonly associated with crack use,3 17 so that the occurrence of hemoptysis in conjunction with the latter symptoms would raise the clinical suspicion of a pulmonary embolic event as the cause of the hemoptysis. However, while one case of pulmonary infarction has been reported in association with crack cocaine,43 no evidence of pulmonary emboli or infarction has been noted in the reported autopsy studies in cocaine-related deaths.14 15

Pulmonary hypertension can also be associated with alveolar hemorrhage. In a postmortem study of four female habitual heavy crack users who presented with dyspnea and intermittent hemoptysis, Russell et al44 found large numbers of hemosiderin-laden macrophages in their BAL samples. These patients all had echocardiographic evidence of borderline to markedly elevated pulmonary artery pressures and morphologic changes in their pulmonary arteries on open-lung biopsy. This would suggest that crack-related pulmonary hypertension may have played an important role in the etiology of their alveolar hemorrhages. Pulmonary artery medial hypertrophy consistent with pulmonary hypertension has also been reported in 4 of 20 fatal cases of cocaine intoxication, of which 2 cases also exhibited evidence of chronic alveolar hemorrhage.14 Although cocaine-related pulmonary hypertension may be responsible for the alveolar hemorrhage noted in our subjects, they were asymptomatic. Additionally, in a separate study, when we examined 10 similar cocaine abusers for evidence of pulmonary hypertension by Doppler echocardiography, only 1 subject had a mild increase in mean pulmonary artery pressure (> 18 mm Hg).45 It therefore seems unlikely that cocaine-related pulmonary hypertension explains the alveolar hemorrhage observed in the large proportion of our asymptomatic crack users.

In summary, we found evidence of recent alveolar hemorrhage in a high proportion of generally asymptomatic habitual crack smokers compared to the near absence of hemosiderin-laden AMs in the BAL fluid of control subjects. AM hemosiderin positivity correlated well with levels of ET-1, suggesting that cocaine-stimulated release of this potent vasoconstrictor peptide from capillary endothelial cells in the lung may cause or reflect lung microcirculatory damage. Additional studies are needed for further examination of the impact of cocaine smoking on alveolar inflammation and microvascular injury and the mechanisms underlying these changes.


   Acknowledgements
 
The authors thank Wendy Aft for manuscript preparation.


   Footnotes
 
Abbreviations: AMs = alveolar macrophages; CS = cocaine-only smokers; CTS = cocaine-plus-tobacco smokers; DLCO = diffusing capacity of the lung for carbon monoxide; ELISA = enzyme-linked immunosorbent assay; ET = endothelin; NS = nonsmokers; PMNs = polymorphonuclear neutrophils; TS = tobacco smokers

Supported by National Institute on Drug Abuse grant No. RO1 DA 08254.

Received for publication May 1, 2001. Accepted for publication October 10, 2001.


   References
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 Materials and Methods
 Results
 Discussion
 References
 

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