A murine model of smoke inhalation

E. Matthew1, G. Warden2, and J. Dedman1,2

1 Department of Molecular and Cellular Physiology, University of Cincinnati Medical Center, Cinncinnati 45267-0576; and 2 Shriner Burns Hospital for Children, Cincinnati, Ohio 45229


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The United States has one of the world's largest per capita fire death rates. House fires alone kill >9,000 Americans annually, and smoke inhalation is the leading cause of mortality from structural fires. Animal models are needed to develop therapies to combat this problem. We have developed a murine model of smoke inhalation through the design, construction, and use of a controlled-environment smoke chamber. There is a direct relationship between the quantity of wood combusted and mortality in mice. As with human victims, the primary cause of death from smoke inhalation is an elevated blood carboxyhemoglobin level. Lethal (78%) and sublethal (50%) carboxyhemoglobin levels were obtained in mice subjected to varying amounts of smoke. Mice exposed to wood smoke demonstrated more dramatic pathology than mice exposed to cotton or polyurethane smoke. A CD-1 model of wood smoke exposure was developed, demonstrating type II cell hypertrophy, cytoplasmic blebbing, cytoplasmic vacuolization, sloughing, hemorrhage, edema, macrophage infiltration, and lymphocyte infiltration. The bronchoalveolar lavage fluid of smoke-exposed mice demonstrated a significant increase in total cell counts compared with those in control mice. These findings are comparable to the lung tissue response observed in human victims of smoke inhalation.

carboxyhemoglobin; smoke inhalation; bronchoalveolar lavage; cell count


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

SMOKE INHALATION is the leading cause of death in victims of structural fires (8). Although major advances have been made in the treatment of burns, advances in the treatment of smoke inhalation injury have been limited (10). Smoke inhalation injury can be characterized according to the time period postinjury. The first 36 h involves treatment of the initial hypoxic insult, carbon monoxide and cyanide toxicity, early airway edema, bronchorrhea, and bronchoconstriction. Mucosal sloughing, tracheobronchitis, increased lung water, and impaired gas exchange characterize days 1-5 postexposure. The final stage is the inflammation-infection stage, in which the risk of nosocomial pneumonia increases markedly, coinciding with further impairment of lung function (8).

As observed in human victims, animal models of smoke inhalation injury characterized by other investigators demonstrate not only mortality (23) but also lung tissue damage (18, 25, 26, 28), elevation of inflammatory mediators (1, 9), and the deleterious effects of the inhalation of noxious gases (8, 29, 33). Sheep (25, 30), dogs (5), and rabbits (21) are among the best characterized of these animal models. Despite the valuable information generated through these studies, the current understanding of the mechanisms behind the observed pathophysiology of smoke inhalation damage is limited. To dissect the pathways involved in smoke inhalation damage, a molecular understanding is necessary. Because of the availability of inbred strains and the ability to target specific genes and genetically target specific cell types (12, 31), the mouse may prove to be an excellent experimental model in which to evaluate and develop treatment strategies for lung injury. Therefore, a mouse model for smoke inhalation has been established through the use of a novel murine smoke chamber and subsequent determination of the dose-death relationship, percent carboxyhemoglobin (COHb), lung pathology, bronchoalveolar lavage (BAL) fluid cell count, and tumor necrosis factor (TNF)-alpha levels. This model reflects the carbon monoxide-induced mortality and tissue damage observed in human patients.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Smoke chamber. The smoke chamber (Fig. 1A) consists of a power supply, an incinerator (Fig. 1B), a circulation fan, and an inhalation chamber. The power supply, with an adjustable voltage source, controls the DC current through a series circuit to the resistive element within the incinerator. Not only is the amount of heat generated regulated by the adjustable power supply, but the incinerator also has a tempered glass door for visual monitoring of the rate of combustion. The resistive element consists of removable nichrome wire that is coiled tightly (Fig. 1B) to allow more heat per area than an uncoiled wire. A circulation fan (Minispiral AC, EG & G Rotron, Saugerties, NY) with adjustable speed is connected to the inlet of the incinerator and circulates the smoke through the inhalation chamber (3.48 liters) in this closed system (4.08 liters). The inhalation chamber containing the mice consists of a Plexiglas cylinder with wire mesh near the bottom and an inlet from the incinerator below the wire mesh.


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Fig. 1.   Smoke chamber. The smoke chamber (A) consisted of a power supply, incinerator, circulating fan, and inhalation chamber. The power supply controlled current to the resistive element (nichrome wire) of the incinerator (B), which combusted the material of interest. A fan circulated the smoke throughout the closed system.

Murine smoke exposure. Adult female Swiss albino outbred mice (CD-1, Charles River) were given a mix of ketamine (100 µg/g body wt), xylazine (5 µg/g body wt), and acepromazine (2.5 µg/g body wt) and placed in pairs into the smoke chamber (Fig. 1A) for defined periods of wood smoke exposure. Untreated pine lumber (12 × 1 × 4 inches) was cut into small uniform rectangular pieces (20 × 3 × 3 mm) weighing a total of 0.1-0.5 g and placed between the heating coils in the incinerator (Fig. 1B). The wood was burned slowly so that it would not produce a flame. As the incinerator filled with smoke, the fan was turned on to circulate the smoke into the chamber with the anesthetized mice. After a defined period, the mice were removed, and the survivors were allowed to awaken from the anesthesia (Fig. 2). Control mice were also anesthetized and placed in the smoke chamber with intermittent exposure to air circulated by the fan but no smoke. In order to determine which material produced the greatest lung damage 48 or 72 h after a 12- to 15-min exposure, initial studies involved the pyrolysis of 10 mg/kg body wt of cotton, polyurethane, and wood (hardwood) to which female Swiss albino inbred mice (FVB/n, Jackson Laboratories) anesthetized with chloral hydrate (0.1 ml/g body wt) were exposed.


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Fig. 2.   Smoke exposure. After initial pathology studies, wood was chosen from among cotton, polyurethane, and wood as the pyrolysis material of interest. Mortality studies demonstrated that 10 mg wood/g body wt (300 mg/30-g mouse) for 20 min was the dose that produced a percent mortality (~40%) closest to LD50 and was therefore chosen as the dose for pathological measurements and for carboxyhemoglobin (COHb), tumor necrosis factor (TNF)-alpha , and bronchoalveolar lavage (BAL) fluid studies.

Dose-mortality studies. Mice were placed in the inhalation chamber for 20 min and exposed to smoke from the smoldering of increasing quantities of pine wood (3-17 mg/g body wt). Mice were observed for at least 7 days and then killed. No other parameters were measured in these mice.

COHb measurements. Immediately after removal from the smoke chamber, blood was collected in a heparinized tube from the tail vein of each mouse. COHb levels were measured spectrophotometrically with a CIBA Corning Co-ox 270 meter. Samples (~50 µl) were collected every hour postexposure until COHb levels returned to normal.

Lung pathology. Lungs were infused via the airway with 1.4 ml of 10% formalin at 25-cm fluid height (the distance between the lungs and the meniscus of the formalin in the reservoir), embedded in paraffin, sectioned (4 µm), and stained with hematoxylin and eosin to examine the pathology.

BAL fluid cell count. BAL was performed as described in Lung pathology 48 h after smoke exposure. Total cell counts were performed with a hemocytometer and Gentian violet stain.

TNF-alpha measurements. Mice were anesthetized and exsanguinated. The diaphragm was cut, the chest was opened, and a blunt-end catheter was inserted into the trachea. Three 1-ml aliquots of Hanks' balanced salt solution (GIBCO BRL, Life Techologies, Grand Island, NY) were instilled into the lungs and removed three times, each with a 1-ml syringe. The supernatant from the first milliliter of BAL fluid was frozen at -70°C. The cells from all three aliquots were pooled, resuspended in RPMI 1640 medium (GIBCO BRL) with 10% FBS and 1% penicillin-streptomycin, and used for 22-h cell culture at 37°C in 5% CO2 with 1 µg/ml of lipopolysaccharide (LPS). The supernatant of the cultured cells was removed and frozen at -70°C. TNF-alpha levels were determined for both the initial lavage supernatant and postculture supernatant with an ELISA kit (BioSource, Camarillo, CA).

Static lung compliance measurements. Treated and control mice were injected with a lethal dose of pentobarbital sodium (Abbott Laboratories, North Chicago, IL) and placed in a container containing 100% oxygen to ensure complete collapse of the alveoli by oxygen absorption before death. The tracheae were cannulated and connected to a syringe and pressure transducer (X-ducer, Motorola, Phoenix, AZ) via a three-way connector. After the diaphragm was opened, lungs were inflated in 100-µl increments every 5 s to a maximum inflation pressure of 30 cmH2O and then sequentially deflated. Pressure and volume on inflation and deflation were recorded. Pressure-volume curves were generated for each animal. Lung compliance was determined by calculating the slope of the linear portion of the deflation curve between +10 and -10 cmH2O.

Statistical analysis. All statistical comparisons were made by one-way ANOVA. P values < 0.05 were considered significant. These analyses were followed up by Student-Newman-Keuls tests in which P values < 0.05 were considered significant.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Dose-mortality studies. Mice were exposed to 20 min of smoke from the combustion of varying amounts of pine (mg wood/g body wt). Values are means ± SD. All the mice that received smoke from the combustion of smaller amounts (<= 5 mg/g of wood) survived the exposure, but with increasing dose, the percentage of mortality increased (0-24 h postexposure) to a 100% lethal dose (>= 13 mg/g of wood; Fig. 3).


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Fig. 3.   Dose-mortality studies. Mice were exposed to 20 min of smoke from the combustion of 0-17 mg wood/g body wt. n, No. of mice.

COHb measurements. The mean percent COHb of control mice was 0.2 ± 0.05%. The mean percent COHb of mice (n = 13) exposed to wood smoke (10.0 mg wood/g body wt) for 20 min was 50.1 ± 2.0%. The blood level of COHb of mice that died from smoke exposure was 77.6 ± 6.0%. Percent COHb levels were measured every hour in the mice from the sublethal smoke group until values were comparable to control values. The time needed for half the carbon monoxide bound to hemoglobin to be released was ~60 min (Fig. 4).


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Fig. 4.   Smoke-induced COHb levels of nonexposed mice, mice exposed to lethal quantities of wood smoke, and mice that recovered from sublethal (10 mg/g body wt for 20 min) smoke exposure. Values are means ± SE; n, no. of mice.

Lung pathology. The lungs of mice exposed to wood, cotton, and polyurethane smoke were fixed in 10% formalin 48 h after exposure. The distal lungs of mice exposed to wood smoke demonstrated cell death as evidenced by cytoplasmic vacuolization, cytoplasmic blebbing, and severe sloughing of the bronchiolar epithelium (Fig. 5, Table 1). Furthermore, peracute hemorrhage, capillary congestion, and peribronchiolar lymphocytic cuffing were present. In the proximal airways of these mice, cytoplasmic vacuolization of the tracheal epithelium (score = 2.5) was observed, along with cytoplasmic blebbing (score = 1) and cytoplasmic vacuolization (score = 4.5) of the epithelium of the mainstem bronchi (Fig. 5, Table 1). The distal lung pathology observed after cotton smoke inhalation included cytoplasmic blebbing, cytoplasmic vacuolization of the bronchiolar epithelium, very mild type II cell hypertrophy, and very mild neutrophil influx as well as cytoplasmic vacuolization (score = 2.5) and sloughing (score = 1.5) in the proximal lung (Table 1). Polyurethane smoke also produced cytoplasmic vacuolization, cytoplasmic blebbing, and hyperplasia in the distal lung as well as tracheal vacuolization (score = 2.5).


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Fig. 5.   Pathology in distal lung. Lungs were fixed with 10% formalin, sectioned (4 µm), and stained with hematoxylin and eosin. Pathology of control lung and representative lungs 48 (or 72) h after 12-15 min of cotton (alveolar histiocytosis), wood (congestion, hemorrhage, peribronchiolar lymphoid cuffing, vacuolization, edema), or polyurethane (sloughing) smoke (10 mg/kg body wt) exposure in FVB/n mice is shown. A, alveolus; V, vessel.


                              
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Table 1.   Pathology of lower airways

Because the most severe pathology was observed after wood smoke exposure, wood smoke was used in the subsequent development of a CD-1 mouse model of smoke inhalation. As in the FVB/n mice, these mice demonstrated cytoplasmic blebbing, cytoplasmic vacuolization, and sloughing of the bronchiolar epithelium as well as perivascular edema, peracute hemorrhage, alveolar histiocytosis, lymphocytic influx into the alveoli, type II cell hypertrophy (Fig. 6, Table 1) and type I cell hyperplasia (Table 1) at 48 (or 24) h postexposure to 7-9 mg/g of wood smoke in the distal lung as well as cytoplasmic blebbing (score = 2.5), vacuolization, and sloughing in the proximal lung (Fig. 7). It is important to note that any score above 0 (normal lung) is significant after such an acute smoke exposure. A score of 5 would only be expected in a severely diseased lung and would usually require a longer-term exposure to such injurious agents.


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Fig. 6.   Pathology in distal lung. Lungs were fixed with 10% formalin, sectioned (4 µm), and stained with hematoxylin and eosin. Representative pathology (arrows) from CD-1 mice 48 (or 24) h after 20 min of exposure to smoke from 7 mg/g body wt (alveolar type II cell hypertrophy, cytoplasmic blebbing, sloughing, hemorrhage, edema, and alveolar histiocytosis) or 9 mg/g body wt wood smoke (cytoplasmic vacuolization, lymphocytic infiltration) is shown.



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Fig. 7.   Pathology in proximal lung. Lungs were fixed with 10% formalin, sectioned (4 µm), and stained with hematoxylin and eosin. Representative pathology (arrows) 48 h after 15 min of wood smoke exposure in FVB/n mice (top) and 24 h after 20 min of wood smoke exposure in CD-1 mice (bottom) is shown.

BAL fluid cell counts. The lungs of mice (Fig. 8) exposed to smoke demonstrated a 2.8-fold increase over control values in the mean total cell count.


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Fig. 8.   BAL fluid total cell count. Mice exposed to smoke revealed a significant increase in the mean total cell count (7.55 × 104 ± 4,716.99; n = 4 mice) compared with that in nonexposed mice (2.66 × 104 ± 9,208.59; n = 4 mice).

TNF-alpha levels. The mean TNF-alpha levels in the BAL fluid supernatant of mice 48 h after smoke exposure (10 mg/g body wt) were not significantly elevated. Elevation of the supernatant TNF-alpha level of BAL fluid cells cultured for 22 h in 1 µg/ml of LPS indicates that these cells were competent to release TNF-alpha (Fig. 9). LPS is found on gram-negative bacteria and has been demonstrated to stimulate TNF-alpha release from alveolar macrophages (24).


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Fig. 9.   Tumor necrosis factor (TNF)-alpha levels. Mean TNF-alpha levels in BAL supernatant from nonexposed mice (n = 3) and mice with sublethal smoke exposure (n = 3) were 17.4 ± 3.2 and 15 ± 3.1 pg/ml, respectively. The mean TNF-alpha level of supernatant from the cells of nonexposed (n = 3) mice cultured for 22 h with 1 µg/ml of lipopolysaccharide (LPS) was 4,577.0 ± 317.5 pg/ml.

Static lung compliance measurements. Static lung compliance values were determined from the linear portion of the deflation curve between -10 and +10 cmH2O. The mean static lung compliance in mice exposed to varying concentrations of wood smoke 24, 48, and 72 h postexposure were not significantly different from control values (Fig. 10).


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Fig. 10.   Static lung compliance. Lung compliance values were determined from the linear portion of the deflation curve between -10 and +10 cmH2O. Values are means ± SE for control mice (90.67 ± 2.98 ml/cmH2O) and mice 24 (101.63 ± 6.71 ml/cmH2O) and 48 (97.64 ± 2.98 ml/cmH2O) h after exposure to the combustion of 4 mg wood/kg body weight (BW), 48 h after the combustion of 7 mg wood/kg BW (97.18 ± 3.79 ml/cmH2O), and 48 (99.54 ± 8.94 ml/cmH2O) and 72 h (92.09 ± 6.80 ml/cmH2O) after the combustion of 10 mg wood/kg BW; n, no. of mice. None of the groups differed statistically.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Through the implementation of a murine smoke chamber designed and constructed in this laboratory, a murine model of smoke injury has been developed. This model system was used to determine the relationship between dose and mortality as well as to evaluate lung tissue damage and carbon monoxide poisoning. This murine model reflects the injury and mortality seen in humans in that carbon monoxide-stimulated mortality was observed in addition to lung tissue damage. Furthermore, the nature of the lung tissue damage and the COHb levels immediately after exposure were similar to those observed in humans (27).

Fires and the smoke they produce are the most common source of carbon monoxide poisoning (16). Wood smoke in particular contains large quantities of carbon monoxide (7, 33). Tissue hypoxia is the most important effect of carbon monoxide (2, 16). The most reliable index of the amount of carbon monoxide in the body is the percentage of COHb (11). Nonsmokers have COHb levels of <3% (17). Mild cases of human carbon monoxide poisoning (<30% COHb) are usually accompanied by headaches, nausea, vomiting, and dizziness but no cardiovascular or neurological symptoms. Patients who do not show cardiovascular or neurological symptoms but have COHb levels between 30 and 40% are considered moderate cases that need to be monitored should symptoms arise (16). As carbon monoxide poisoning becomes severe (>40%), patients show tachychardia, tachypnea, neurological symptoms, and even coma. When blood COHb levels reach 40-50%, headache, confusion, and collapse may occur (32). A COHb level of 60-70% causes unconsciousness, intermittent convulsions, respiratory failure, and death if exposure continues (32). All patients are given 100% oxygen but the more severe cases involving coma may require hyperbaric oxygen. The percent COHb levels observed in our mice immediately after smoke exposure were comparable to the levels in humans for nonexposed and sublethal and lethal exposures.

The association between mortality and carbon monoxide poisoning was made as a result of both the time of death and blood levels of COHb. Mortality from an inflammatory response and lung tissue damage will not take place over such a short time span. Among the survivors of a dose producing 40% mortality, dangerously high levels of COHb were observed. Furthermore, the mean percent COHb of mice that died from exposure was significantly higher.

As with human subjects, our mice demonstrated tissue damage from smoke. This pathological response is likely a result of the particles in the smoke and noxious chemicals, many of which adhered to the smoke particles, as well as the inflammatory response to these agents. Large quantities of wood, cotton, and polyurethane are commonly found in homes. The initial studies in FVB/n mice showed more lung damage after wood smoke than either cotton or polyurethane smoke. To focus the study, we developed a murine model of wood smoke inhalation in CD-1 mice. In both CD-1 and FVB/n mice, wood smoke caused cell death (cytoplasmic vacuolization, cytoplasmic blebbing, sloughing), infiltration of immune cells (primarily lymphocytes and macrophages), and some peracute hemorrhage and capillary congestion as well as some alveolar hyperplasia and type II cell hypertrophy. The upper airways also demonstrated cell death. Any differences observed between 7 and 9 mg/g exposures are thought to be a result of variability in the murine response and not a result of dose.

Cytoplasmic vacuolization and cytoplasmic blebbing demonstrated cell death. Vacuolization was often accompanied by pychnotic nuclei, showing the progression of cell death. The bronchiolar sloughing was yet another indication of cell death and the severity of the lung damage. Sloughed cells, together with mucus, may form respiratory casts that produce airway obstruction and respiratory distress. Cell death may be a result of several factors including tissue hypoxia (2, 20) or damage by chemicals that have adhered to the smoke particles, reactive oxygen species (3) or proteases, cytokines, and other inflammatory mediators. Wood smoke contains large amounts of hydrogen cyanide and aldehydes (19, 29) such as acrolein. Aldehydes are irritants of mucous membranes, inducing denaturation of proteins, causing cellular death, pulmonary edema, and death (33).

The prominent increase in the BAL fluid cell counts after smoke exposure is consistent with that observed in humans as well as in other animal smoke models (6, 15). Furthermore, because smoke inhalation damage is mediated in part through a significant immune response, an increase in immune cells is not only expected but is consistent with the pathology findings.

TNF-alpha is a potent proinflammatory cytokine associated with lung injury. TNF-alpha levels have been demonstrated to be elevated in the BAL fluid of acute respiratory distress syndrome patients (4), and acute respiratory distress syndrome is a major cause of mortality in fire victims. Furthermore, direct administration of TNF induces lung endothelial injury, perivascular edema, and extravasation (13). Therefore, the role of TNF-alpha in the pathways that lead to smoke damage in this murine model was evaluated. Because TNF-alpha levels in the lavage fluid of mice exposed to smoke were not elevated compared with those of the nonexposed mice, it was concluded that TNF-alpha release was not stimulated by smoke. These values were compared with a positive control in which cells were stimulated with LPS, yielding a high TNF-alpha level; lavage fluid macrophages are therefore competent to release TNF-alpha and increased TNF-alpha can be detected by the ELISA assay used. However, because smoke exposure did not stimulate increases in TNF-alpha levels, TNF-alpha does not appear to mediate the damage in this murine model of smoke inhalation injury. These findings are consistent with a study (14) in sheep exposed to smoke, which demonstrated no detectable increase in TNF-alpha levels after smoke exposure, although endotoxin alone stimulated an increase in TNF-alpha levels. Alternatively, TNF-alpha levels may be detectable much earlier in the postexposure period than was measured in this model.

To evaluate the effects of smoke inhalation injury on lung function in mice, static lung compliance was measured. Smoke has been demonstrated to reduce lung compliance in several studies in sheep and dogs (10, 25, 26, 28). In contrast, this murine model of smoke inhalation injury demonstrated no significant changes in static lung compliance. The edema observed did not progress into the intra-alveolar regions to form hyaline membranes as observed in hyperoxic lung injury (22). During hyperoxic lung injury, the serum proteins in the intra-alveolar edema fluid inactivate pulmonary surfactant, resulting in the observed reductions in lung compliance (22). Any direct effects of smoke particles on pulmonary surfactant are also not sufficient to cause significant reductions in lung compliance.

To summarize, this murine model of lung injury reflects the injury and mortality observed in human patients and is therefore useful both for elucidating the mechanisms of smoke inhalation lung injury and for the development of treatment strategies. Due to the availability of inbred strains, the ability to target specific genes and genetically target specific cell types (12, 31), the mouse may prove to be an excellent experimental model in which to evaluate and develop treatment strategies for lung injury. In contrast to the methods of smoke exposure used in numerous other animal models (5, 21, 25), this murine smoke chamber allows for control of the environment around the animal to simulate conditions in structural fires. As with hyperoxic lung damage, much of the lung damage from smoke inhalation is the result of a vigorous inflammatory response. Therefore, future studies will include an extensive examination of the protective effects of the immunosuppressive agent cyclosporin A administered after smoke exposure. Cyclosporin A may inhibit or reduce the pathology observed in smoke-treated lungs similar to its action in hyperoxia-treated lungs (22).


    ACKNOWLEDGEMENTS

We gratefully acknowledge Fahrhad Bahremand for the construction of the murine smoke chamber. Technical assistance in measuring carboxyhemoglobin was kindly provided by Kathleen Good and associates in Laboratory Medicine at Shriners Hospital for Children (Cincinnati, OH). We thank Dr. Cora Ogle and associates (Shriner Burns Hospital, Cincinnati, OH) for assistance in measuring bronchoalveolar lavage levels of tumor necrosis factor-alpha and preparation of cytospin slides.


    FOOTNOTES

This work was supported by Shriners Hospital for Children Grant 01-HDQ-005.

Address for reprint requests and other correspondence: J. Dedman, Dept. of Molecular and Cellular Physiology, 231 Bethesda Ave., Univ. of Cincinnati Medical Center, PO Box 670576, Cincinnati, OH 45267-0576, (E-mail: john.dedman{at}uc.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 13 October 1999; accepted in final form 20 October 2000.


    REFERENCES
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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