Dexamethasone and Salbutamol Stimulate Human Lung Fibroblast Proliferation
© World Allergy Organization; licensee BioMed Central Ltd. 2011
Published: 14 December 2011
Asthma is characterized by bronchial hyperreactivity and airway remodeling. Subepithelial fibrosis, a feature of remodeling, is accompanied by activation of fibroblasts to myofibroblasts, with excessive proliferation and increased collagen, extracellular matrix protein, and profibrogenic cytokine production. Mast cells are important in the development of asthma and its fibrotic changes.
In this study, we aimed to investigate the direct effect of the drugs most frequently used in asthma, that is, glucocorticosteroids (dexamethasone) and shortacting β2-agonists (salbutamol), on human lung fibroblast proliferation when unstimulated or activated by mast cells or eotaxin.
Subconfluent human fetal lung or bronchial fibroblasts were incubated with different concentrations of the drugs (24 h) 6 activators, and [3H]-Thymidine was added (24 h) to measure their proliferation. IL-6 production in the supernatants of confluent mono-layers cultured in the presence of the drugs or forskolin (24 h) was analyzed by enzyme-linked immunosorbent assay.
Both drugs alone and in the presence of the activators enhanced fibroblast proliferation in a seemingly synergistic way for both fetal and bronchial fibroblasts. Dexamethasone was found to decrease IL-6 production, while salbutamol increased it.
These observations if corroborated by in vivo data may possibly account for the deleterious effect of long-term therapy with β2-bronchodilators and inhaled glucocorticosteroids on the natural history of asthma.
Asthma is a chronic inflammatory disease characterized by bronchial hyperreactivity and airway remodeling. Remodeling features are damage and shedding of airway epithelium, increased number of goblet cells, mucous gland hypertrophy, increased fibroblast/myofibroblast numbers, and increased airway smooth muscle mass and neovascularity [1–3]. Fibroblasts are thought to play a major role in the development of the structural changes in the airways by altering their phenotype from a quiescent cell into α-actin containing myofibroblasts that display enhanced proliferation, increased collagen and other extracellular matrix protein production, expression of adhesion molecules, and production of profibrotic and proinflammatory cytokines/chemokines and growth factors [1–4].
The early asthmatic response is typically initiated by activation of tissue-resident mast cells. The subsequent infiltration and activation of several additional inflammatory cells and notably that of the eosinophils account for the late phase of an asthma attack. Persistence of airway inflammation may explain the chronic disease. We and others have shown that mast cells and eosinophils are pivotal cells not only in initiating and maintaining airway inflammation in asthma but also in activation of fibroblasts to become myofibroblasts [5, 6]. The profibrotic effect of mast cells is due to several mediators, including histamine, tryptase, IL-6, nerve growth factor, eotaxin, TGF-β, TNF-α, and others [7–10].
Treatment of asthma usually includes short-acting β2-agonists for the relief of bronchoconstriction and, if needed, inhaled glucocorticosteroids to treat airway inflammation. Glucocorticosteroids have generally been considered to have antifibrotic activity based on data from in vitro studies carried out on fibroblasts from different anatomical origins. However, results obtained with lung fibroblasts have been inconclusive or contradictory because some have found that these drugs enhance fibroblast proliferation[11–14] and some have shown that they inhibit proliferation and production of profibrotic cytokines [12, 15]. Moreover, although very effective in reducing airway inflammation, the efficacy of glucocorticosteroids in attenuating airway fibrosis is still controversial [16–18]. Few studies have investigated the effect of short-acting β2-agonists on fibroblast proliferation and also with contrasting results [19, 20]. In this study, we were interested to examine the effect of salbutamol as a paradigm of short-acting β2-agonists and dexamethasone and as a paradigm of glucocorticosteroids and their combination on human fetal lung and adult bronchial fibroblast proliferation by themselves and in the presence of mast cells or eotaxin as stimulators.
Materials and methods
Mast Cells and Mast Cell Sonicates
The human mast cell leukemia cell line HMC-1 (donated by Dr J. Butterfield, Mayo Clinic, Rochester, MN) was used as a source of mast cells . HMC-1 cells were cultured in Iscove's medium (Biological Industries) supplemented with 10% FCS containing Fe , 50 U/mL penicillin, 0.05 mg/mL streptomycin, and 160 mL/L (1.2 mM) monothioglycerol. Cells were passaged twice a week.
HMC-1 cells were centrifuged (120 g, 5 min) and resuspended in 2 to 5 mL in DMEM/2% FCS (0.75-1:75 × 105/mL) and bath sonicated (2 min, 0°C; Heat Systems/Ultrasonic 380W, duty cycle 5 s; output power, 50%). Sonicates were then microcentrifuged for 5 minutes at 4°C, 120 g (Hettich Ultracentrifuge; Hettich Zentrifugen, Tuttlingen, Germany) to remove cell debris. The debris-free sonicate supernatant ("sonicate") was collected into aliquots and stored at -80°C.
Fibroblast Proliferation Assay
Fibroblast proliferation was assessed using the [3H]-Thymidine incorporation assay. Fibroblasts were plated in 96-well plates (3-4 × 103 cells per well in 200 μL DMEM/10% FCS). After incubation for 24 hours, the wells were rinsed twice with DMEM/2% FCS, and dexamethasone (Sigma Chemicals, St Louis, MO) (stock solution 10-2 M in ethanol) or salbutamol (stock solution 10-4 M in phosphate buffered saline; Sigma), at different concentrations or mast cell sonicates (15 × 103), or eotaxin/CCL11 (500 ng/mL) (R&D, Minneapolis, MN) was added in 200 μL DMEM/2% FCS in 3 to 4 wells for each treatment. Treatment with TGF-β (10 ng/mL) (R&D) was used as a positive control. After an additional incubation for 24 hours, 1 μL of [3H] Thymidine (2 or 5 mC/well) (DuPont NEN, Boston, MA) was added to each well, and the cells were incubated for an additional 24 hours. At the end of the incubation, cells were washed with cold phosphate buffered saline, fixed with methanol, and precipitated with 5% trichloroacetic acid (Merck, Darmstadt, Germany). The cells were lysed with 0.1% NaOH, transferred to scintillation vials, and counted in a β-counter (LKB 1211 Rackbeta; Pharmacia, Uppsala, Sweden). The results were obtained as counts per minute per well and are presented as the percentage of change (increase or decrease) in the fibroblast proliferation after the treatment compared with the cells that were incubated with medium alone:
To evaluate the presence of IL-6 released in the culture medium, an ELISA kit (PeptroTech, Rocky Hill, NJ) with sensitivity of 32 to 2000 pg/mL was used. For these experiments, fibroblasts were cultured in 24-well plates (3 × 103 cells per well in 200 μL DMEM/10% FCS) until confluent. At this point, the wells were rinsed twice with DMEM/5% FCS and dexamethasone, salbutamol, or forskolin (stock solution 5 mg/mL in ethanol; Sigma) at different concentrations was added in 200 μL DMEM/5% FCS. After an 18-hour incubation, supernatants were collected and kept frozen at -80°C until assayed.
Each experiment was performed in at least triplicates for 3 or 4 times. The results are presented as the mean ± standard error of the mean and were analyzed by the unpaired Student t test or analysis of variance test as appropriate for each case. P values of < 0.05 were considered significant.
Dexamethasone and Salbutamol Increase Fetal Lung Fibroblast Proliferation Alone and When Stimulated by Mast Cells
Influence of Mast Cell Numbers on Dexamethasone and Salbutamol Increase in Fibroblast Proliferation
Increase in Fibroblast Proliferation (%)
Mast Cell per Well
15 × 103
349 ± 37*
348 ± 39*
25 × 103
352 ± 36*
405 ± 58*
35 × 103
387 ± 41*
566 ± 76*
Dexamethasone and Salbutamol Increase Human Bronchial Fibroblast Proliferation Alone and When Stimulated by Either Mast Cells or Eotaxin
Dexamethasone and Salbutamol Influence Differently IL-6 Production From Fetal Lung Fibroblasts
Influence of Dexamethasone, Salbutamol, and Forskolin on IL-6 Release From Fetal Lung Fibroblasts
Change in IL-6 production
↓72 ± 1%*
↓79 ± 4%*
↓60 ± 5%†
↑138 ± 6%*
↑144 ± 4%*
↑150 ± 1%†
↑149 ± 4%*
↑151 ± 4%*
It is well accepted that there is an increase in the number of fibroblasts in the airways of patients with asthma that correlates with thickness of lamina reticularis and disease severity. Moreover, fibroblast activation and differentiation to myofibroblasts are also evident [1–4].
In the present study, we aimed to investigate the in vitro effect of glucocorticosteroids and short-acting β2-agonists widely used as first-line antiasthmatic drugs on human lung fibroblast proliferation and IL-6 production. We specifically choose to evaluate fibroblast proliferation because this is the first hallmark of fibrosis taking place. IL-6 was selected among a plethora of proinflammatory profibrotic cytokines produced by the fibroblast that mainly influences the inflammatory response [23, 24].
We found that dexamethasone and salbutamol alone and in combination increase both human fetal lung and human bronchial fibroblast proliferation. Moreover, we demonstrate for the first time that when the fibroblasts are preincubated with either drug and then with an activator such as mast cell sonicate or eotaxin, fibroblast proliferation is further increased. In contrast, the production of the proinflammatory and profibrotic cytokine IL-6 by confluent fibroblast monolayers was found to be decreased by dexamethasone, while it was increased in the presence of salbutamol. When the 2 drugs were added together, dexamethasone was still able to slightly decrease IL-6 production.
We have previously shown that mast cells enhance proliferation of human lung fibroblasts, an effect also seen with histamine and to a lesser extent with tryptase . In a more recent study, we have also defined the profibrotic properties of eotaxin/CCL11,  a central mediator of asthma that can also be produced by mast cells .
In that study, we did not find significant differences between the human fetal lung fibroblast line and human bronchial fibroblasts regarding their proliferative responses to eotaxin/CCL11. This was explained by the fact that they were found to express similar levels of surface CCR3. Similarly, in the present study, we did not observe significant differences in the response of the fetal lung and the bronchial fibroblasts toward the proliferative effects of either the drugs or the stimulants. This is an interesting observation because fibroblasts from cell lines and primary cultures might behave differently. The fact that we did not detect major differences between these 2 sources of fibroblasts might be due to the fact that primary cells did not need to be cultured and subcultured for extensive time and when used were not senescent.
Many studies have been carried out to investigate the effects of glucorticosteroids on several sources of fibroblasts such as human fetal lines, or primary human lung, asthmatics endobronchial biopsies, human nasal polyps derived or mouse 3T3 and rat lung and even adipose tissue derived providing sometimes similar and sometimes contrasting results. We opted for the most commonly used source of human lung fibroblasts, the cell line MRC-5 and primary human bronchial fibroblasts.
Regarding our data, it is interesting to note that generally in the absence of the mast cell sonicate, dexamethasone effect was always greater than that of salbutamol. In this work, we showed for the first time that salbutamol caused a further increase in fibroblast proliferation in a dose-dependent fashion in fibroblasts treated with eotaxin. This proliferative event is probably carried out by the interaction of eotaxin with its receptor and by salbutamol with β2-receptors.
Glucocorticosteroids in general and specifically dexamethasone are known to decrease gene expression of proinflammatory cytokines. Several studies have found that dexamethasone decreases cytokine secretion by fibroblasts, among them IL-6 . The results of our study correlate with these findings. But also this decreasing effect is not universally detected and depends on the exposure duration and the cytokine under study . Studies that tested the effect of β2-agonists on IL-6 secretion on different cell types found that these drugs enhanced IL-6 secretion . As far as we know, the effect of β2-agonists on IL-6 secretion from lung fibroblasts has not yet been studied. We found that salbutamol increased slightly IL-6 production. Cyclic adenosine monophosphate (cAMP) is known as an IL-6 secretion enhancer (airway smooth muscle cells, 3T3 fibroblasts, and gingival fibroblasts), even though it has been reported that lung fibroblast cell line had an inverse relationship between the amount of cAMP and the amount of IL-6 secreted from the cell .
In our study, salbutamol and forskolin that increase cAMP production, both increased IL-6 secretion from the fibroblasts. These findings strengthen the assumption that the mechanism through which salbutamol affects the increase in IL-6 secretion is cAMP dependent. Interestingly, when dexamethasone and salbutamol were added together, the decrease in IL-6 production was smaller than the one obtained in the presence of dexamethasone alone.
Many mediators, including growth factors, IL-6, and other cytokines, are involved in fibroblast proliferation regulation. In a previous study, we found that when added to fetal lung fibroblasts, IL-6 increased their proliferation up to 140% (data not published). Therefore, we might speculate that salbutamol can influence lung fibroblast proliferation by causing IL-6 production. The effect of β2-agonists in general and specifically of salbutamol on fibroblast proliferation has almost not been studied. Agarwal and Glasel described the effect of treatment with opioid and β-adrenergic agonists on cell proliferation . They found that although both receptors increase cAMP production, opioid agonists lowered the level of proliferation, while a β2-agonist (procaterol) increased cell proliferation. Silvestri et al found that salmeterol decreased fetal lung line fibroblast proliferation induced by bFGF. The source of the cells is indeed similar to the cells in our study, but salmeterol is a long-acting β2-agonist as opposed to salbutamol .
Another important difference is that the study by Silvestri et al,  and other studies, tested the drug's effect on proliferation of cells that were incubated with a growth factor (in this case basic fibroblast growth factor). It is difficult to determine whether the drug's effect is independent of the tested growth factor and whether this can be compared with our research in which salbutamol's effect on fibroblasts was assessed either without additional treatment or in the presence of mast cells or eotaxin.
It is difficult to speculate how the dexamethasone carries out its profibrogenic response. Several mechanisms have been suggested regarding the fashion in which the glucocorticosteroids enhance fibroblast proliferation. For example, they can either enhance or decrease the activity of different growth factors (among them, insulin growth factor-1 and fibroblast growth factor) and their receptors (ie, platelet derived growth factor) or their production (ie, connective tissue growth factor). The time of drug addition to the cultures can make a difference. When it is added after the cells reached confluence, it causes enhancement of proliferation, while drug administration during the exponential growth phase usually causes a decrease . In our protocol, we added dexamethasone to subconfluent monolayer and still it had a profibrogenic effect.
It is interesting to point out that the literature on the effect of drug combination on fibroblast proliferation presents a complex picture. Many researches describe an additive and a synergistic effect of glucocorticosteroids and β2-agonists. On the other hand, other studies have found classes of the two drugs to have antagonistic effects. Peters et al reported that β2-agonists, among them salbutamol, have the ability to lower the steroid effect on gene transcription by inhibiting the binding to the glucocorticosteroid responsive element on the DNA. On the other hand, salbutamol and salmeterol have been described as having the ability to activate the receptor by a mechanism related to cAMP increase .
Our findings obtained in vitro show that whatever the underlying mechanism(s) is, the drugs have a direct fibrogenic effect and a synergistic effect with central players, such as mast cell-derived mediators in the asthmatic process. If these in vitro observations are found to be true also in the in vivo complexity of the asthmatic patient with airway remodeling and fixed airway obstruction, it is then possible to speculate that this may not only be part of the natural course of the disease but a complication of the accepted drug treatment and a product of the drugs' interactions with the inflammation mediators. Therefore, if the profibrogenic effect of glucocorticosteroids and β2-agonists is reconfirmed in vivo, the combination of the remodeling and the drugs' effect can be dangerous. In conclusion, more in vivo studies are warranted to clarify what the risks and benefits are of monotherapy versus combination of inhaled glucocorticosteroids and short- and long-acting β2-agonists on airway remodeling in asthma.
Partially funded by a research grant from the Aimwell Charitable Trust to F. Levi-Schaffer.
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