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Published ahead of print on January 9, 2003, doi:10.1164/rccm.200210-1207OC
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American Journal of Respiratory and Critical Care Medicine Vol 167. pp. 1516-1521, (2003)
© 2003 American Thoracic Society

Original Article

Methylprednisolone Causes Matrix Metalloproteinase–dependent Emphysema in Adult Rats

Kang-Hyeon Choe, Laimute Taraseviciene-Stewart, Robertas Scerbavicius, Lajos Gera, Rubin M. Tuder and Norbert F. Voelkel

Division of Pulmonary Sciences and Critical Care Medicine and Pulmonary Hypertension Center, Division of Biochemistry, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado; and Division of Cardiopulmonary Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland

Correspondence and requests for reprints should be addressed to Norbert F. Voelkel, M.D., Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Box C 272, 4200 E. Ninth Avenue, Denver, CO 80262. E-mail: Norbert.Voelkel{at}uchsc.edu


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Previous investigations have shown that corticosteroids affect the development and maturation of the developing lung in utero and in neonatal animals. Systemic corticosteroids are routinely used for the treatment of acute exacerbations of chronic obstructive pulmonary disease, and inhaled corticosteroids are more frequently being prescribed for the long-term treatment of patients with chronic obstructive pulmonary disease. Because corticosteroids can affect matrix metalloproteinases and because the concept of protease/antiprotease imbalance is an important concept regarding the pathogenesis of emphysema, we examined the effects of chronic steroid treatment on lung structure in adult rats. Rats treated with 2 mg/kg of methylprednisolone daily for 1, 2, or 4 weeks had an increased mean linear intercept and a decrease of the surface–volume ratio when compared with age-matched control animals, and the animals showed increased matrix metalloproteinase-9 activity in their lungs on zymography. Rats treated concomitantly with methylprednisolone and a broad-spectrum matrix metalloproteinase inhibitor (GM6001) did not develop emphysema. We conclude that systemic treatment of adult rats with the antiinflammatory steroid methylprednisolone increases the activity of matrix metalloproteinases in the lung and causes emphysema.

Key Words: corticosteroid • matrix metalloproteinase • emphysema

Chronic obstructive lung diseases are a group of chronic disorders with a varying degree of small airway inflammation and emphysematous lung parenchyma destruction (1). Although chronic inhalation of tobacco smoke is by far the most common cause of chronic obstructive lung disorders and chronic tobacco smoke exposure of mice (2) and guinea pigs (3) has been shown to cause emphysema, a number of genetic animal models have recently been developed that allow the examination of mechanisms of lung parenchyma destruction in the absence of chronic tobacco smoke exposure (4–7). For example, we demonstrated recently that chronic vascular endothelial growth factor receptor inhibition causes alveolar septal cell apoptosis, loss of lung capillaries, and emphysema both in neonatal (8) and adult rats (9). Because more frequently steroids are used for the treatment of the so-called exacerbations of chronic obstructive pulmonary disease (10–12) and because it has been reported that steroids can affect or modulate matrix metalloproteinases (13–15), we wished to examine the effects of chronic steroid treatment on alveolar septal structures in adult rats. Here we show that treatment of adult rats for 1, 2, and 4 weeks with methylprednisolone causes activation of matrix metalloproteinase-9 in the lung tissue of methylprednisolone-treated adult rats as well as emphysema. This new experimental model of emphysema demonstrates that lung parenchyma destruction can be caused by an anti-inflammatory agent.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animal Experiments
Our experimental protocol was approved by the Animal Care and Use Committee of the University of Colorado Health Sciences Center. Six-week-old male Sprague–Dawley rats were purchased from a commercial vendor. The animals were divided into three groups: (1) the control group (n = 6), (2) the methylprednisolone-treated group (n = 8), and (3) the methylprednisolone + matrix metalloproteinase inhibitor–treated group (n = 6). The methylprednisolone-treated groups were injected daily with 2 mg/kg of methylprednisolone for 1, 2, and 4 weeks intraperitoneally. Methylprednisolone + matrix metalloproteinase inhibitor–treated animals were, in addition, injected with 10 mg/kg of GM6001 (kindly provided by John Stewart, University of Colorado, Denver, CO) intraperitoneally in diluent (0.5% carboxymethylcellulose sodium, 0.9% sodium chloride, 0.4% polysorbate 80, 0.9% benzyl alcohol). The control animals were injected with deionized water.

Tissue Processing
After completion of the treatment period, rats were anesthetized with ketamine (60 mg/kg) and xylazine (8 mg/kg) intramuscularly. The chest was opened and lung and heart were quickly isolated and excised. The left lung was inflated with 0.5% low melting agarose at the constant pressure of 25 cm H2O and fixed in 10% formalin (16). Paraffin-embedded tissues were sectioned for histologic analysis.

Lung Tissue Homogenates
The right main bronchus was resected, and the right lung was homogenized immediately after harvest in a buffer containing 50 mM N-2-hydroxyethylpiperazine-N'-ethane sulfonic acid, 1 mM dithiothreitol, 0.1% Triton X-100, and 10% glycerol. The homogenates were centrifuged at 10,000 x g for 15 minutes, and supernatants were stored at -80°C until they were used.

Morphometry
Lung sections of 5 µm thickness were stained with hematoxylin and eosin. The mean linear intercept, as a measure of interalveolar septal wall distance, was measured by light microscopy at a magnification of x100. The mean linear intercept was obtained by dividing the length of a line drawn across the lung section by the total number of intercepts encountered in 36 lines per rat lung, as described previously (17). The alveolar surface–volume ratio was measured by examining 10 random fields per lung, using Weibel's multipurpose test grid and the formula described by Chalkley and coworkers (18).

Zymography
Zymography was performed using 10% Tris–glycine gels containing 0.1% gelatin (Invitrogen Life Technologies Inc., Carlsbad, CA). Twenty micrograms of lung extract protein were loaded per well, and gels were electrophoresed. Gels were washed with 2.5% Triton X-100 for 30 minutes and subsequently incubated in 50 mM Tris–hydrogen chloride, containing 6.7 mM calcium chloride, 200 mM sodium chloride, and 0.02% Brij 35 at 37°C for 12 to 24 hours. The gels were stained with Coomassie brilliant blue and destained.

Immunohistochemistry
Anti–proliferating cell nuclear antigen antibodies and anti–matrix metalloproteinase-9 antibodies (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) were used. Immunolocalization was performed on paraffin-embedded rat lung tissue sections. After deparaffinization, the sections were rehydrated and submitted to microwave treatment (800 W/15 minutes) in 10 mM citric monohydrate solution. After quenching of endogenous peroxidase with 3% hydrogen peroxide, the sections were exposed to anti–proliferating cell nuclear antigen antibodies (1:50) or anti–matrix metalloproteinase-9 antibodies (1:200). Then immunodetection was performed using a biotinylated secondary antibody (Vector Laboratories, Burlingame, CA). Peroxidase-conjugated streptavidin with diaminobenzidine completed the stain. Negative controls for nonspecific binding included normal rat serum.

Immunofluorescence Staining for Localization of the Matrix Metalloproteinase-9
After deparaffinization, the rat lung tissue sections were rehydrated and steamed in BORG decloaker for 45 minutes. The sections were exposed to anti–matrix metalloproteinase-9 antibodies (1:200) and anti–Factor VIII antibodies (1:800; DAKO Corporation, Carpinteria, CA) overnight at room temperature. Then the sections were blocked with normal horse serum and exposed to anti-goat and anti-rabbit fluorescent antibodies (1:200; Molecular Probes, Inc., Eugene, OR). 4',6-diamidino-2-phenylindole dihydrochloride-containing mounting media was used.

Statistical Analysis
All the data are expressed as mean ± SEM. Statistical analysis was performed with SPSS for Windows software package (SPSS Inc., Chicago, IL). The differences between groups were compared using one-way analysis of variance with Student–Newman–Keuls post hoc test. Statistical difference was accepted at p values less than 0.05.


   RESULTS
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DISCUSSION
 REFERENCES
 
Morphometry
Compared with adult control rat lungs, methylprednisolone-treated rat lungs had enlarged airspaces. The mean linear intercept, interalveolar wall distance, in the methylprednisolone-treated group was greater than that in the control group (80.2 ± 1.2 µm vs. 65.9 ± 0.8 µm, p < 0.01), and the surface–volume ratio was decreased in the methylprednisolone-treated animals when compared with control animals after 4 weeks of treatment (0.108 ± 0.014 vs. 0.192 ± 0.005 µm-1, p < 0.01) (Figure 1) . The larger mean linear intercept of the methylprednisolone-treated lungs could already be noted after 1 week of treatment (Figure 2) .



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  		Figure 1. Histology of rat lungs. (A) Section of a lung from a control rat, showing normal alveolar structures. (B) Section of a lung from a rat treated with methylprednisolone for 4 weeks, showing enlarged airspaces. (C) Lung section from a rat treated with the combination of methylprednisolone and GM6001 (a nonspecific metalloproteinase inhibitor), showing near normal alveolar structures. (D) Mean linear intercept (MLI) in control animals and in animals treated with methylprednisolone. The MLI values in methylprednisolone-treated rat lungs were significantly greater when compared with lungs from control rats. Treatment with GM6001 prevented the methylprednisolone-induced increase in the MLI of the lungs. (E) Surface–volume ratio. The surface–volume ratio values in methylprednisolone-treated rat lungs were significantly lower than those in control rat lungs. Treatment with GM6001 prevented the methylprednisolone-induced decrease in the surface–volume ratio of the lungs. CTL = control; MP = methylprednisolone. *p Values less than 0.05 compared with control and MP + GM6001 groups. All histologic sections are shown at x100.

 


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  		Figure 2. MLI of control (CTL) and methylprednisolone (MP)-treated rat lungs. Already after 1 week of treatment, a significant increase in the MLI was noted. *p Values less than 0.05.

 
Treatment with the nonspecific matrix metalloproteinase inhibitor (GM6001) prevented the increase in the mean linear intercept and the decrease in the surface–volume ratio in methylprednisolone-treated rats (Figure 1).

Immunohistochemistry for Proliferating Cell Nuclear Antigen
The immunohistochemistry for proliferating cell nuclear antigen showed no difference in the number of proliferating cell nuclear antigen–positive cells among control lungs, lungs from methylprednisolone-treated animals, and lungs from methylprednisolone + GM6001–treated animals (Figure 3) , indicating that methylprednisolone did not inhibit lung cell growth.



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  		Figure 3. Immunohistochemistry for proliferating cell nuclear antigen (PCNA) counterstained with hematoxylin, showing positive staining (arrows) for proliferating cells in the alveolar septa. (A) Control (CTL) rat lungs. (B) Methylprednisolone (MP)-treated rat lungs. (C) Lungs from a rat treated with methylprednisolone and GM6001. (D) The percentage of PCNA-positive alveolar septal cells. There was no significant difference among the three groups. All sections are shown at x400.

 
Zymography
In the gelatin zymogram, methylprednisolone-treated rat lung extracts demonstrated a significant increase in matrix metalloproteinase-9 activities when compared with control lungs. Treatment with GM6001 reduced the lung tissue activity of the matrix metalloproteinase-9 (Figure 4) . Figure 5 shows that an increase in the matrix metalloproteinase-9 activity already occurred after 2 weeks of steroid treatment. Matrix metalloproteinase-2 activity was also detected in the lung tissue extract, but there was no difference of matrix metalloproteinase-2 activity in the lungs from the three animal groups.



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  		Figure 4. Zymogram. (A) Gelatin gel zymogram obtained with total rat lung tissue extracts at 4 weeks of treatment. (B) Relative density of the zymogram showing gelatinolytic activity. Methylprednisolone-treated rat lungs have increased matrix metalloprotenase-9 activity compared with the control rat lungs. Lungs from rats treated with methylprednisolone and GM6001 showed a decreased MMP-9 activity. CTL = control; MMP-2 = matrix metalloproteinase-2; MMP-9 = matrix metalloproteinase-9; MP = methylprednisolone. *p Values less than 0.05 compared with control and MP + GM6001 groups for MMP-9.

 


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  		Figure 5. (A) Zymogram of MMP-9 (matrix metalloproteinase-9) activity of lung extracts after varying duration of methylprednisolone (MP) treatment. (B) The MMP-9 activity progressively increased with the duration of treatment. CTL = control; MMP-2 = matrix metalloproteinase-2. *p Values less than 0.05 compared with the control group.

 
Immunohistochemistry and Immunofluorescence for Matrix Metalloproteinase-9
The immunohistochemistry for matrix metalloproteinase-9 showed endothelial cell location of matrix metalloproteinase-9 in control animals and in methylprednisolone-treated rat lungs expansion of the staining pattern to alveolar septal cells. The expression of matrix metalloproteinase-9 in the lungs from GM6001-treated animals resembled that observed in the animals not treated with methylprednisolone (Figures 6 and 7) .



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  		Figure 6. Immunohistochemistry for MMP-9 counterstained with hematoxylin. (A) Lung section from a control rat, showing rare positive staining. (B) The methylprednisolone-treated rat lung shows a number of positive staining alveolar septal cells and small vessel cells (arrows). (C) Lung from a rat treated with methylprednisolone and GM6001, showing an appearance more comparable with the control lungs. All sections are shown at x400.

 


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  		Figure 7. Immunofluorescence stain for colocalization of MMP-9. (A) A section from a control rat lung. (B) A section from a methylprednisolone-treated rat lung. (C) A section from a rat treated with methylprednisolone and GM6001. In control rat lungs, MMP-9 was confined to endothelial cells of the small vessels, whereas in the lungs from methylprednisolone-treated rats MMP-9 was expressed not only in the endothelial cells in the vessels but also in the alveolar septal cells (arrows). Treatment of GM6001 decreased the expression of MMP-9 in alveolar septal cells to the levels comparable with the control rat lungs.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The data presented here demonstrate that treatment of adult rats for 1, 2, and 4 weeks with methylprednisolone causes pulmonary emphysema. Because the immunohistochemistry for proliferating cell nuclear antigen showed no difference in the number of proliferating cell nuclear antigen–positive cells between untreated and methylprednisolone-treated rats, it is unlikely that the steroid treatment did inhibit lung cell growth. The gelatin zymogram of lung tissues from methylprednisolone-treated rats showed an increase in the activity of matrix metalloproteinase-9 after 2 and 4 weeks of methylprednisolone treatment. The immunohistochemistry showed that matrix metalloproteinase-9 was principally localized to vascular endothelial cells, however, methylprednisolone treatment caused matrix metalloproteinase-9 expression also in alveolar septal cells, which was prevented by the broad-spectrum matrix metalloproteinase inhibitor GM6001.

Glucocorticoids have been shown to decrease the amount of matrix metalloproteinase-9 protein in sputum samples (14) and the expression of matrix metalloproteinase-9 in bronchial epithelium (13) of patients with asthma. Directionally, these findings are different from our results because we demonstrate that methylprednisolone treatment increases the number of cells that express matrix metalloproteinase-9. Apparently, there are species- and cell-specific differences in the response of matrix metalloproteinases to steroids—for example, it has been shown that rat and human vascular smooth muscle cells responded differently to dexamethasone with regard to cell migration and matrix metalloproteinase-2 activity (19).

We treated rats with a high dose of methylprednisolone (2 mg/kg), as is common in the treatment of patients with exacerbations of chronic obstructive pulmonary disease (20).

However, the implications of our animal data for the treatment of human disease are not clear at present. The natural history of chronic obstructive pulmonary disease is incompletely understood and different phenotypes of patients with chronic obstructive pulmonary disease may respond differently to various drugs.

Our animal model is of interest as a proof of concept in the context of the protease/antiprotease hypothesis of emphysema (2, 21), and because of the observation of increased expression of gelatinase and collagenases in the lungs from patients with chronic obstructive pulmonary disease (22), and the demonstration of the release of matrix metalloproteinase-9 by alveolar macrophages from patients with chronic obstructive pulmonary disease (23). Although it had been previously recognized that glucocorticoids can affect the alveolarization in animal experiments (24–27), our finding that glucocorticoid treatment increases the activity of a gelatinase in the lung tissue provides new mechanistic information. Our observation that a broad-spectrum inhibitor of metalloproteinases (GM6001) prevented the methylprednisolone-induced emphysema in the adult rats indicates that proteolytic processes are indeed involved in the lung parenchyma destruction in this particular model. The precise cellular and molecular targets of the active protease (or proteases) in the lung in this model and whether methylprednisolone causes lung cell apoptosis deserve further investigations.

In summary, we observed that chronic treatment of adult rats with methylprednisolone results in an increase of the number of cells that express matrix metalloproteinase-9 and an increase of the activity of matrix metalloproteinase-9 in the lung tissue and pulmonary emphysema. We believe that an extrapolation of the data derived from this rodent model to the condition of patients with chronic obstructive pulmonary disease is premature at present; however, we wonder whether the well-recognized side effect of chronic steroid treatment, osteoporosis, has a pulmonary correlate in susceptible individuals.


   FOOTNOTES
 
Supported by the Hart-Family Chair for Emphysema Research, National Institutes of Health grants 1RO1 HL60195-01 (R.M.T.) and 1RO1 HL60913-01 (N.F.V.).

Received in original form October 21, 2002; accepted in final form January 8, 2003


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 METHODS
 RESULTS
 DISCUSSION
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Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2003 American Thoracic Society