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Am J Physiol Lung Cell Mol Physiol 281: L1257-L1263, 2001;
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Vol. 281, Issue 5, L1257-L1263, November 2001

Prostaglandin E2 inhibits fibroblast chemotaxis

Tadashi Kohyama1, Ronald F. Ertl1, Vincenzo Valenti2, John Spurzem1,3, Masashi Kawamoto4, Yoichi Nakamura5, Tom Veys1,2, Luigi Allegra2, Debra Romberger1,2, and Stephen I. Rennard1

1 Pulmonary and Critical Care Medicine Section, University of Nebraska Medical Center, Omaha 68198-5125; 3 Veterans Affairs Medical Center, Omaha, Nebraska 68105; 2 University of Milan, Milan 20122, Italy; 4 First Department of Pathology, Nippon Medical School, Tokyo 113-0022; and 5 Third Department of Internal Medicine, University of Tokushima, Tokushima 770-8503, Japan


    ABSTRACT
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Fibroblasts are the major source of extracellular connective tissue matrix, and the recruitment, accumulation, and stimulation of these cells are thought to play important roles in both normal healing and the development of fibrosis. Prostaglandin E2 (PGE2) can inhibit this process by blocking fibroblast proliferation and collagen production. The aim of this study was to investigate the inhibitory effect of PGE2 on human plasma fibronectin (hFN)- and bovine bronchial epithelial cell-conditioned medium (BBEC-CM)-induced chemotaxis of human fetal lung fibroblasts (HFL1). Using the Boyden blind well chamber technique, PGE2 (10-7 M) inhibited chemotaxis to hFN 40.8 ± 5.3% (P < 0.05) and to BBEC-CM 49.7 ± 11.7% (P < 0.05). Checkerboard analysis demonstrated inhibition of both chemotaxis and chemokinesis. The effect of PGE2 was concentration dependent, and the inhibitory effect diminished with time. Other agents that increased fibroblast cAMP levels, including isoproterenol (10-5 M), dibutyryl cAMP (10-5 M), and forskolin (3 × 10-5 M) had similar effects and inhibited chemotaxis 54.1, 95.3, and 87.0%, respectively. The inhibitory effect of PGE2 on HFL1 cell chemotaxis was inhibited by the cAMP-dependent protein kinase (PKA) inhibitor KT-5720, which suggests a cAMP-dependent effect mediated by PKA. In summary, PGE2 appears to inhibit fibroblast chemotaxis, perhaps by modulating the rate of fibroblast migration. Such an effect may contribute to regulation of the wound healing response after injury.

eicosanoids; adenosine 3',5'-cyclic monophosphate; fibronectin; fibrosis; repair


    INTRODUCTION
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

FIBROBLAST MIGRATION from neighboring connective tissue into the site of inflammation plays an important role in tissue repair in response to injury. If the process is defective, abnormal repair may result. If the migration is excessive, however, the accumulation of fibroblasts and extracellular matrix within a tissue can lead to alteration of the tissue architecture and loss of function (6, 10, 14, 22). Many chronic disorders are characterized by the development of fibrosis; therefore, understanding the mechanisms that underlie and control fibrogenesis are important for understanding disease pathogenesis and potentially for developing therapeutic approaches.

Under normal circumstances, fibroblasts are not believed to be migratory. This is thought to be true despite the fact that many potential fibroblast chemoattractants are likely to be present even within the normal tissue milieu. This suggests that factors that could inhibit fibroblast chemotaxis may play important roles in normal tissues and may modulate response to injury. In this regard, prostaglandin E2 (PGE2) has been reported to inhibit several profibrotic responses including fibroblast proliferation (11), production of type I collagen (12, 15), and contraction of extracellular matrices (8, 25). In addition, PGE2 levels in bronchoalveolar lavage fluid have been found to be increased in chronic obstructive pulmonary disease (26), cystic fibrosis (16), and lung cancer (13).

The current study was therefore undertaken to evaluate the effect of PGE2 on fibroblast chemotaxis. For chemoattractant, the purified chemoattractant human plasma fibronectin (hFN) was used. In addition, bovine bronchial epithelial cell-conditioned medium (BBEC-CM), a complex mixture that contains several potential fibroblast chemoattractants as well as mediators that are able to modulate extracellular matrix production by human fibroblasts (15), was used. Finally, the mechanism by which PGE2 exerts its inhibitory effect was evaluated.


    METHODS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Materials. PGE2 and indomethacin were purchased from Sigma (St. Louis, MO) and dissolved in 100% ethanol. Calphostin, forskolin, dibutyryl cAMP (DBcAMP), substance P, and vasoactive intestinal peptide (VIP) were purchased from Sigma. KT-5720 and prostaglandin F2alpha (PGF2alpha ) were purchased from Calbiochem (San Diego, CA), and Rp-8-(p- chlorophenylthio)guanosine 3',5'-cyclic monophosphothioate (Rp-8-pCPT-cGMPS) was purchased from BIOMOL (Plymouth Meeting, PA). Calphostin and KT-5720 were dissolved in DMSO at 10-2 M. Indomethacin, Rp-8-pCPT-cGMPS, VIP, PGF2alpha , and forskolin were dissolved in ethanol at 10-2, 10-2, 10-4, 10-3 M, and 5 × 10-3 M, respectively. PGE2, isoproterenol, substance P, DBcAMP, and PGF2alpha were dissolved in sterile distilled water at 10-3, 10-2, 10-2, 10-3, and 10-3 M, respectively.

Human fetal lung fibroblasts. Human fetal lung fibroblasts (HFL1) were obtained from the American Type Culture Collection (Manassas, VA). The cells were cultured in 100-mm tissue culture dishes (Falcon, Becton Dickinson Labware, Lincoln Park, NJ) in Dulbecco's modified Eagle's medium (DMEM, GIBCO BRL, Grand Island, NY) supplemented with 10% FCS, 50 U/ml penicillin G sodium, 50 µg/ml streptomycin sulfate (penicillin-streptomycin, GIBCO BRL), and 1 µg/ml amphotericin B (Parma-Tek, Huntington, NY) in a humidified atmosphere at 37°C and 5% CO2-95% air. The fibroblasts were routinely passaged every 4 or 5 days, and cells were used between passages 13 and 20 in all experiments. Confluent fibroblasts were removed from the dishes by treatment with 0.05% trypsin in 0.53 mM ethylenediaminetetraacetic acid and resuspended in DMEM without serum.

Conditioned medium of BBECs. BBECs were prepared as previously described (24) by modification of the methods of Wu and Smith (27). Briefly, bronchi from bovine lungs obtained from a local slaughterhouse were cut into pieces. The bronchi were then trimmed of connective tissue and put into DMEM that contained 0.1% protease (type XIV, Sigma). After overnight incubation at 4°C, the bronchial lumens were washed with DMEM containing 10% FCS (BioFluids, Rockville, MD) to detach the BBECs. LHC basal medium (BioFluids) was supplemented to make LHC-9 as previously described (17). The BBECs were filtered through 100-µm Nitex mesh (Tetko, Elmsford, NY) and resuspended in a 1:1 mixture of LHC-9 and RPMI 1640 medium (LHC-9-RPMI; GIBCO BRL) at 1 × 106 cells/ml, plated on 100-mm tissue culture dishes, and incubated at 37°C in 5% CO2-95% air. The BBECs reached confluence within 7 days. The culture medium was changed and the cell layers were rinsed twice with DMEM that contained 440 µg/ml L-glutamine (Fisher Scientific, Pittsburgh, PA), penicillin-streptomycin, and Fungizone (GIBCO BRL) but no serum. The cells were cultured for 24 h, and the BBEC-CM was harvested, divided into aliquots, and stored at -80°C until used.

Human fibronectin. hFN was prepared from human plasma by gelatin-Sepharose affinity chromatography as previously described (9). After elution with 4 M urea, the hFN was further purified by heparin-agarose affinity chromatography and eluted with 500 mM NaCl.

HFL1 cell chemotaxis. HFL1 cell chemotaxis was assessed by the Boyden blind well chamber technique (5) using a 48-well chamber (Nuclepore, Cabin John, MD). HFL1 cells (1.0 × 106 cells/ml in DMEM without serum) were loaded into the upper well of the chamber with the desired concentration of PGE2 or other additives. PGE2 concentration levels used in the current study have been found to be active in cell-based assays (2, 11).

Chemoattractants were placed in the bottom chamber. In some experiments, PGE2 was also added to the lower chamber. The two wells were separated by an 8-µm pore filter (Nuclepore, Pleasanton, CA) coated with 0.1% gelatin (Bio-Rad, Hercules, CA), and the chamber was incubated at 37°C in a moist 5% CO2-95% air atmosphere. Except as designated, chambers were incubated for 6 h, after which the cells on the top of the filter were removed by scraping. The filter was then fixed, stained with Protocol (Biochemical Science, Swedesboro, NJ), and mounted on a glass microscope slide. Migration was assessed by counting the number of cells in five high-power fields with a light microscope. Triplicate wells were prepared in each experiment for every condition. Replicate experiments were performed with separate cultures of cells on separate occasions.

Statistical analysis. The data were analyzed for significance using single or two-factor ANOVA and Student's t-test for paired data. Data are expressed as means ± SE.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Chemotaxis of HFL1 cells was measured to either purified hFN or conditioned medium harvested from cultured BBEC in the blind well assay system. Both stimuli triggered HFL1 cell migration concentration dependently, although more cells migrated in response to BBEC-CM (Fig. 1). PGE2 (10-7 M) added to the fibroblasts immediately before the cells were placed in the top wells of the chemotaxis chamber inhibited chemotaxis of fibroblasts to both stimuli (Fig. 1). The inhibitory effect of PGE2 was concentration dependent (Fig. 2).


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  		Fig. 1.   Inhibition of fibroblast chemotaxis by prostaglandin E2 (PGE2). Chemotaxis of human fetal lung fibroblasts (HFL1) was measured with the Boyden blind well assay system using either various concentrations of purified human fibronectin (hFN; A) or various dilutions of conditioned medium harvested from cultured bovine bronchial epithelial cells (BBEC-CM; B) as chemoattractant. Chemotaxis values were compared between the presence and absence of PGE2 (10-7 M) at each concentration of hFN or dilution of BBEC-CM. Data are means ± SE for triplicate cultures, each measured for chemotaxis in triplicate.



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  		Fig. 2.   Inhibition of fibroblast chemotaxis by PGE2: concentration dependence. Chemotaxis of HFL1 cells was assayed with the Boyden blind well chamber assay system. hFN (20 µg/ml; A) and BBEC-CM (1:4 dilution; B) were used as the chemoattractants. PGE2 was added to the fibroblasts at various concentrations immediately before the cells were placed in the top wells of the chemotaxis chamber. Chemotaxis values were compared between control and indicated concentrations of hFN (A) or dilutions of BBEC-CM (B). Data are means ± SE for triplicate cultures, each assayed for chemotactic activity in triplicate.

The number of fibroblasts that accumulated on the bottom of the chemotaxis chamber increased as a function of time. The effect of PGE2 was relatively greater at earlier time points. With increasing time, the number of migrated fibroblasts was observed to increase for all concentrations tested. Sterility of cell cultures was preserved for as long as 24 h. Because the number of migrated fibroblasts was still increasing at this time point, it would appear that PGE2 has a significant effect on the rate of fibroblast migration (Fig. 3).


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  		Fig. 3.   Inhibition of fibroblast chemotaxis by PGE2: time course at various concentrations. Migration of HFL1 cells was assayed with the Boyden blind well chamber assay system. hFN (20 µg/ml; A) and BBEC-CM (1:4 dilution; B) were used as chemoattractants. PGE2 was added to the fibroblasts in the top wells at various concentrations. Chambers were incubated and after varying times were removed for staining and counting. Data are means ± SE for triplicate cultures, each assayed for chemotaxis in triplicate.

Because the chemotaxis chamber has two parts, it was of interest to determine whether it mattered if PGE2 was added to the top or the bottom of the filter. PGE2 added either above or below the membrane inhibited fibroblast chemotaxis with nearly equal effectiveness. PGE2 added to both sides of the membrane, however, was much more potent in inhibiting fibroblast chemotaxis (Fig. 4).


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  		Fig. 4.   Effect of adding PGE2 to different sides of the chemotaxis membrane. Fibroblast chemotaxis was performed to hFN in the Boyden blind well chamber assay system. PGE2 in various concentrations was added either to the top of each well (with the target fibroblasts), to the bottom of each well (with the chemoattractant), or to both sides of the filter. Data are means ± SE for triplicate cultures, each assayed for chemotaxis in triplicate.

To determine whether PGE2 inhibited either chemotaxis, chemokinesis, or both, various concentrations of hFN and BBEC supernatant medium were placed both above and below the filter. This allowed migration to be measured in the presence of increasing concentrations both in the absence of a gradient (chemokinesis, shown by the diagonal lines in Fig. 4) and in the presence of a gradient (chemotaxis, shown by the vertical lines in Fig. 4). The number of cells migrating increased as the concentration of either hFN or BBEC-CM increased in the absence of a gradient, which indicated that chemokinesis was present. Similarly, the number of migrated cells increased when a gradient was present, which indicated that chemotaxis was also present toward both stimuli. PGE2 inhibited both chemotaxis and chemokinesis in a concentration-dependent manner (Tables 1 and 2).

                              
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  		Table 1.   Checkerboard analysis of cell migration by hFN against PGE2


                              
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  		Table 2.   Checkerboard analysis of cell migration by BBEC-CM against PGE2

Because a major effect of PGE2 on many cells is to increase cAMP, other agents that can also increase cAMP were evaluated for possible effects on fibroblast chemotaxis. Isoproterenol (10-5 M), forskolin (3 × 10-5 M), DBcAMP (10-5 M), and PGE2 (10-6 M) all inhibited the effects of fibroblast chemotaxis to both hFN and BBEC-CM (Fig. 5). VIP (10-9 M) had a minimal effect. By way of further comparison, PGF2alpha (10-6 M) and substance P agents (10-9 M), which do not primarily act by increasing cAMP, were also assessed. Substance P had a minimal inhibitory effect that did not achieve statistical significance. PGF2alpha inhibited chemotaxis to BBEC-CM by 32.7%, which was statistically significant (P < 0.0014).


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  		Fig. 5.   Effects of other reagents on fibroblast chemotaxis. Fibroblast chemotaxis was performed in the Boyden blind well chamber assay system. Isoproterenol (10-6 M), forskolin (3 × 10-5 M), dibutryryl cAMP (DBcAMP, 10-5 M), and vasoactive intestinal peptide (VIP, 10-9 M) were added to the top of each well. For comparison, indomethacin (10-6 M), prostaglandin F2alpha (PGF2alpha , 10-6 M), and substance P (10-6 M) were also evaluated. hFN (A) and BBEC-CM (1:4 dilution; B) were used as chemoattractants. Data are means ± SE for triplicate cultures, each assayed for chemotaxis in triplicate.

To determine whether the PGE2 effect was mediated by the cAMP-dependent protein kinase (PKA), HFL1 cells were treated with the PKA inhibitor KT-5720 for 1 h before being harvested for the chemotaxis assay. KT-5720 elevated the chemotaxis of HFL1 cells to hFN under control conditions and blocked inhibition mediated by both PGE2 and DBcAMP (Fig. 6).


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  		Fig. 6.   Effect of inhibition of protein kinase A (PKA). HFL1 cells were preincubated with the PKA inhibitor KT-5720 in monolayer culture and harvested. hFN (20 g/ml) was used as the chemoattractant for chemotaxis. PGE2 (10-7 M) or DBcAMP (10-5 M) was added to the fibroblasts in the top wells. Data are means ± SE for triplicate cultures, each assayed for chemotaxis in triplicate.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The current study demonstrates that PGE2 is capable of inhibiting fibroblast chemotaxis to both purified hFN and BBEC-CM. The inhibition of chemotaxis by PGE2 was concentration dependent. Cell migration continued over time, which suggests that the effect of PGE2 was to decrease the rate of migration. Both chemotaxis and chemokinesis were affected. Isoproterenol and forskolin (agents that increase cAMP) and DBcAMP had an inhibitory effect similar to PGE2, and the effect of PGE2 was blocked by an inhibitor of PKA. These results suggest that the inhibitory effect of PGE2 is mediated through cAMP and PKA.

The accumulation of fibroblasts is likely an important event in tissue response to injury. Accumulation of fibroblasts can occur via chemotactic recruitment of cells and local proliferation. It is likely that both mechanisms play important roles. In addition to wound healing, many disorders are also characterized by the accumulation of fibroblasts. When accumulation is excessive, the resulting fibrosis can result in distortion of tissue architecture and loss of function (14). It is likely that a large number of cells produce mediators that can drive fibroblast recruitment. In this regard, several mediators capable of causing fibroblast chemotaxis have been described (19-21).

The current study demonstrated that PGE2, by inhibiting fibroblast chemotaxis, could serve as a downregulatory signal for the amplitude of a fibrotic response. PGE2 can also inhibit fibroblast proliferation (11), fibroblast production of type I collagen (12, 15), and fibroblast contraction of extracellular matrices (8, 25). All of these functions are also consistent with a potential downregulatory effect on the fibrotic response.

PGE2 is capable of interacting with several receptors that can initiate several signal transduction pathways (4). Of these, stimulation of adenylate cyclase with increased levels of cAMP is believed to play an important role in many PGE2 actions. The current study supports a cAMP-dependent mechanism for PGE2 inhibition of fibroblast chemotaxis. Consistent with this, several other agents that also increase cAMP were observed to inhibit chemotaxis. In addition, the cAMP analog DBcAMP inhibited chemotaxis. Finally, cAMP exerts many of its actions by activating PKA. KT-5720, an inhibitor of PKA, was able to block the inhibitory effect of both PGE2 and DBcAMP, which confirms the dependence of cAMP on PGE2 inhibition.

Regulation of fibroblast recruitment in vivo is likely to depend on both chemotactic factors [of which many have been described (19-21)] and inhibitors (1). The current study supports an inhibitory role for PGE2 and suggests that other agents that can increase cAMP could have a similar effect. Other mechanisms could also inhibit fibroblast chemotaxis. In this regard, PGF2alpha , a mediator that acts primarily via phospholipase C rather than by activating adenylate cyclase, had a small inhibitory effect. Interestingly, the inhibitory effect of PGF2alpha on fibroblast chemotaxis was statistically significant when BBEC-CM was used as the chemoattractant.

Accumulation of fibroblasts in the airway is believed to support normal airway repair and also plays a pathogenic role in the tissue remodeling that characterizes both asthma and chronic bronchitis. The development of peribronchiolar fibrosis and the associated contraction of fibrotic tissue can lead to airway narrowing and compromised airflow. It is of interest, therefore, that airway epithelial cells have been reported to produce several fibroblast chemoattractants including fibronectin (23), insulin-like growth factor I (28), endothelin-1 (3), platelet-derived growth factor, and transforming growth factor-beta (TGF-beta ) (28). In the current study, both the purified chemoattractant (hFN) and BBEC-CM, which likely contains a multiplicity of chemotactic factors, were assessed. PGE2 was able to inhibit chemotaxis to both the purified hFN and the complex conditioned medium. That PGF2alpha appeared to be somewhat more effective than the complex mixture at inhibiting chemotaxis suggests the possibility that different chemoattractants may cause inhibition via different mechanisms.

PGE2 is likely present at sites of inflammation. Two enzymes, cyclooxygenase-1 and -2 (COX-1 and COX-2, respectively), regulate its production. COX-2 in particular is upregulated by proinflammatory cytokines such as interleukin-1 and tumor necrosis factor-alpha . TGF-beta , a mediator believed to play an important role in modulating repair responses, has been reported to upregulate COX-1 (7). A role for PGE2 in modulating the inflammatory response has been suggested. With regard to chemotaxis, PGE2 can inhibit transendothelial migration of both human T lymphocytes (18) and human neutrophils (2). Interestingly, the inhibition of neutrophil chemotaxis appears to occur by mechanisms that are independent of cAMP (2).

The mechanisms by which PGE2 and increased cAMP lead to decreased fibroblast chemotactic migration remain to be defined. The number of cells that migrated, however, increased with time, which suggests a primary effect on the rate of migration. The rate of migration of a cell depends on several interacting factors, including the ability of the cell to 1) polymerize cytoskeletal elements (which causes protrusion of cytoplasmic processes at the cell edge), 2) adhere to subjacent matrix at the leading edge, and 3) detach from substrate at the trailing edge. The effects of any or all of these processes could result in a decreased rate of migration.

In summary, the current study demonstrates that PGE2, in addition to its other inhibitory effects on profibrotic responses, can also inhibit fibroblast chemotaxis. Through such a mechanism, PGE2 could contribute to the modulation of profibrotic stimuli and therefore play an important role in controlling fibrotic responses. It is possible, therefore, that PGE2-mediated pathways could be a therapeutic target to augment impaired healing or to block the development of excessive fibrosis.


    ACKNOWLEDGEMENTS

We acknowledge the helpful discussions with Dr. Todd Wyatt and also thank Mary Tourek and Lillian Richards for manuscript preparation.


    FOOTNOTES

This work was supported in part by the Larson Endowment at the University of Nebraska Medical Center (Omaha, NE) and a grant from SmithKline Beecham.

Address for reprint requests and other correspondence: S. I. Rennard, Pulmonary and Critical Care Medicine Section, Univ. of Nebraska Medical Center, 985125 Nebraska Medical Center, Omaha, NE 68198-5125 (E-mail: srennard{at}unmc.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 27 February 2001; accepted in final form 9 July 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Lung Cell Mol Physiol 281(5):L1257-L1263
1040-0605/01 $5.00 Copyright © 2001 the American Physiological Society


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