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Am. J. Respir. Crit. Care Med., Volume 164, Number 8, October 2001, 1487-1494

Regulation of Peroxisome Proliferator-activated Receptor gamma  Expression in Human Asthmatic Airways
Relationship with Proliferation, Apoptosis, and Airway Remodeling

LAURENT BENAYOUN, SÉVERINE LETUVE, ANNE DRUILHE, JORGE BOCZKOWSKI, MARIE-CHRISTINE DOMBRET, PATRICIA MECHIGHEL, JÉRÔME MEGRET, GUY LESECHE, MICHEL AUBIER, and MARINA PRETOLANI

Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 408, Faculté de Médecine Xavier Bichat, Paris; Service de Chirurgie Thoracique, Hôpital Beaujon, Clichy, France




    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Airway inflammation and alterations in cellular turnover are histopathologic features of asthma. We show that the expression of peroxisome proliferator-activated receptor gamma  (PPARgamma ), a nuclear hormone receptor involved in cell activation, differentiation, proliferation, and/or apoptosis, is augmented in the bronchial submucosa, the airway epithelium, and the smooth muscle of steroid-untreated asthmatics, as compared with control subjects. This is associated with enhanced proliferation and apoptosis of airway epithelial and submucosal cells, as assessed by the immunodetection of the nuclear antigen Ki67, and of the cleaved form of caspase-3, respectively, and with signs of airway remodeling, including thickness of the subepithelial membrane (SBM) and collagen deposition. PPARgamma expression in the epithelium correlates positively with SBM thickening and collagen deposition, whereas PPARgamma expressing cells in the submucosa relate both to SBM thickening and to the number of proliferating cells. The intensity of PPARgamma expression in the bronchial submucosa, the airway epithelium, and the smooth muscle is negatively related to FEV1 values. Inhaled steroids alone, or associated with oral steroids, downregulate PPARgamma expression in all the compartments, cell proliferation, SBM thickness, and collagen deposition, whereas they increase apoptotic cell numbers in the epithelium and the submucosa. Our findings have demonstrated that PPARgamma (1) is a new indicator of airway inflammation and remodeling in asthma; (2) may be involved in extracellular matrix remodeling and submucosal cell proliferation; (3) is a target for steroid therapy.



    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Keywords: nuclear antigens; airway smooth muscle; bronchial epithelium; corticosteroids

Asthma is classically defined as a chronic inflammatory disease of the airways characterized by reversible airflow obstruction. Nevertheless, alterations in the structure of the airway wall, defined as airway remodeling, are now also recognized as regular features of asthma (1). These alterations include extensive epithelial damage, collagen deposition, thickness of the subepithelial basement membrane (SBM), subepithelial fibrosis and airway smooth muscle hypertrophy, and/or hyperplasia (1).

Bronchial inflammation and airway structural abnormalities involve an altered expression and/or function of a large variety of proinflammatory cytokines, growth factors and their receptors, as well as a dysregulation in the differentiation, proliferation, and apoptosis of multiple cell types. These include infiltrating leukocytes, particularly eosinophils, and structural cells responsible for the maintenance of airway tissue integrity such as mesenchymal cells and bronchial epithelial and smooth muscle cells (3, 4).

Peroxisome-proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor superfamily of ligand-activated transcriptional factors, which include receptors for steroids, thyroid hormone, vitamin D, and retinoic acid (5). Among them, PPARgamma was originally characterized as a regulator of adipocyte differentiation and lipid metabolism (6) and, more recently, of cellular turnover (7). Indeed, several lines of evidence indicate that PPARgamma profoundly affects cell cycle, differentiation and apoptosis (7). Thus, PPARgamma activation by natural or synthetic ligands such as the cyclooxygenase metabolite 15-deoxy-Delta 12,14 PGJ2, polyunsaturated fatty acids, different nonsteroidal anti-inflammatory drugs, and the oral antidiabetic agents thiazolidinediones favor macrophage differentiation and prevent colorectal, prostate, and breast cancer by inhibiting cell growth and accelerating apoptosis (7). Fibroblast, synoviocyte, macrophage, endothelial and T-cell apoptotic death in response to thiazolidinediones has also been documented (8).

In addition, PPARgamma activation downregulates the synthesis and release of immunomodulatory cytokines from various cell types (12).

Although these findings support a major role for PPARgamma in immune disorders characterized by tissue inflammation and remodeling, there is no evidence, as yet, of PPARgamma expression in human asthmatic airways.

The present study was aimed at investigating the localization of PPARgamma in bronchial biopsies from control subjects and asthmatic patients and at determining whether changes in its expression correlate with cell proliferation and apoptosis, with the expression of markers of airway remodeling and with steroid therapy.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Patients

Thirty-four nonsmoker asthmatic patients, mainly atopic, and fulfilling the criteria of the Guidelines for the Diagnosis and Management of Asthma of the National Heart, Lung, and Blood Institute (NHLBI) (15) were recruited (Table 1). All patients did not experience exacerbations within the 2 mo preceding the bronchoscopy. A flow-volume curve was performed in all subjects and FEV1, FVC, and the ratio FEV1/FVC were assessed before and after the inhalation of 200 µg of salbutamol.

                              
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TABLE 1

 DEMOGRAPHIC CHARACTERISTICS OF CONTROL AND ASTHMATIC SUBJECTS*

The 34 asthmatics were distributed into three groups as follows: 13 asthmatics who were receiving intermittent inhaled short-acting beta 2 agonists, taken as needed; 12 asthmatics who were treated with short- and long-acting beta 2 agonists and inhaled steroids (=< 800 µg/d of budesonide or 1,000 µg/d of beclomethasone dipropionate, or 500 µg/d of fluticasone propionate); 9 asthmatics who received long-acting beta 2 agonists, inhaled steroids and 10 to 60 mg/d of regular oral prednisone (Table 1).

A group of eight healthy volunteers receiving no medication was also studied (Table 1).

Fiberoptic Bronchoscopy, Biopsy Processing and Immunohistochemistry

The bronchoscopy was performed according to the guidelines outlined by the American Thoracic Society (16), as described (17). The Bichat Hospital Ethics Committee approved the experimental protocol for fiberoptic bronchoscopy, and all subjects gave their written consent to participate.

Immunohistochemistry was performed on 5-µm sections from endobronchial biopsies, as described (17), using the following antibodies or their corresponding isotypes: antihuman PPARgamma (SC7196, 10 µg/ml; Santa Cruz Biotechnologies, Santa Cruz, CA), anti-CD3 (clone Leu-4, 10 µg/ml; Sigma Chemical, St. Louis, MO), anti-CD68 (clone EBM11, 4 µg/ml; Dako, Trappes, France), anti-ECP (clone EG2, 10 µg/ml; Pharmacia, Uppsala, Sweden), anti-Ki67 (clone B56, 1 µg/ml; PharMingen, Becton Dickinson, San Diego, CA), an anticleaved subunit of caspase-3 of 20 kD Ab (clone C92-605, 2.5 µg/ml; PharMingen). Mouse or rabbit alkaline phosphatase antialkaline phosphatase (APAAP) antibodies were used next.

Immunofluorescence double staining was performed using rhodamine-labeled goat F(ab')2 to rabbit Ig and fluorescein-conjugated goat F(ab')2 to mouse IgG1 (Immunotech, Marseille, France).

A minimum of two serial sections from the same biopsy, or sections from three to five different biopsies, were analyzed. PPARgamma -, Ki67-, and caspase-3 expression in the bronchial mucosa, the airway epithelium, and the smooth muscle were evaluated as described (17).

Assessment of Airway Remodeling

SBM thickening was quantified by computer-assisted image analysis (Microvision Instruments, Histolab, Evry, France), as described (18). Final results were the means of 20 to 50 measurements performed from each biopsy specimen, and two biopsies from each patient were analyzed.

Collagen deposition was evaluated through staining of bronchial sections using the picrosirius red technique (19) and it was measured at regular intervals with a calibrated image analyzer (Microvision Instruments). Results were expressed as a percentage of picrosirius-stained area over the total biopsy area.

Statistical Analysis

Results are expressed as means ± SEM. A one-way analysis of variance followed by the nonparametric Mann-Whitney U test for unpaired values were used to determine significance among groups. Correlation coefficients (r') were calculated using Spearman's nonparametric rank-order method; p values of =< 0.05 were considered significant.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

PPARgamma Expression in Bronchial Biopsies from Control Subjects and Asthmatics and Modulation by Steroid Therapy

Control subjects showed only rare PPARgamma positive cells in their bronchial submucosa and a weak or no expression of PPARgamma in the bronchial epithelium and the airway smooth muscle (Figures 1 and 2). PPARgamma expression was significantly augmented in all compartments in steroid-untreated asthmatics (Figures 1 and 2).



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  		Figure 1.   Immunohistochemical analysis of PPARgamma expression in the bronchial tissue from control subjects, from corticosteroid-untreated asthmatics (CS-untreated), and from asthmatic patients treated with inhaled steroids alone (ICS) or in association with oral steroids (ICS + OCS). PPARgamma -expressing cells were evaluated in the bronchial mucosa (A), in the airway epithelium (B) and in the smooth muscle (C ). Results are expressed as numbers of PPARgamma -positive cells per millimeter of basement membrane (in the case of the bronchial mucosa), or as a scoring system (in the case of epithelium and airway smooth muscle) where scores 0, 1, 2, and 3 correspond to the absence or the presence of a red staining of weak, moderate, or high intensity, respectively. Values were compared by a one-way analysis of variance followed by a Mann-Whitney U test.



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  		Figure 2.   Immunohistochemical localization of PPARgamma in bronchial biopsies from control subjects and steroid-untreated and -treated asthmatic patients. Contrary to the control subject (A), who shows no staining in the airway epithelium and the smooth muscle (ASM), a marked expression of PPARgamma associated with these two structures is noted in the epithelium and the airway smooth muscle of steroid- untreated asthmatics (B, C, and D). This is accompanied by an intense infiltration of PPARgamma -positive cells, particularly near the subepithelial basement membrane (arrows, B and C ). These features are much less intense in an inhaled and oral steroid-treated asthmatic (E ). Cryostat sections were incubated with a specific rabbit antihuman PPARgamma polyclonal Ab, followed by APAAP (red deposits) and light Mayer hematoxylin counterstaining. Magnification: ×300.

Treatment with inhaled steroids was associated with a decrease in PPARgamma expression in the bronchial submucosa (70%, p < 0.001) (Figure 1), in the airway smooth muscle (92%, p < 0.001) (Figure 1), and, to a lesser extent, in the bronchial epithelium (42%, difference not statistically significant) (Figure 1). In the inhaled and oral steroid-treated group, the increase in PPARgamma expression was significantly reduced in the three compartments analyzed (Figure 1 and Figure 2E).

By immunofluorescence, we established that PPARgamma - expressing cells in the bronchial submucosa were eosinophils and macrophages, whereas T lymphocytes were consistently negative (Figure 3). Furthermore, in several biopsy specimens, particularly from steroid-untreated asthmatics, we observed increased numbers of subepithelial cells expressing PPARgamma and showing a fibroblastlike morphology (Figure 2B and C). However, the intense spontaneous trapping of fluorescence by connective tissue, which was frequently observed in these areas, prevented double staining to be assessed.



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  		Figure 3.   Immunofluorescence staining for the localization of PPARgamma on eosinophils, macrophages, and T lymphocytes in human bronchial biopsies. Sections were reacted with the following couples of Abs: mouse EG2/rabbit anti-PPARgamma (A, B ), mouse anti-CD68/rabbit antiPPARgamma (C, D), and mouse antiCD3/rabbit antiPPARgamma (E, F ). FITC-conjugated antimouse Ig and rhodamine-labeled antirabbit Ig were used as revelation systems. The same microscopy field was photographed twice, first with a filter specific for FITC (A, C, E ) and next with one for rhodamine (B, D, F ). Double-positive cells are indicated by the arrows. Magnification: ×600.

PPARgamma Expression in Relation to Cell Proliferation and Apoptosis

To determine cell proliferation and apoptosis, the immunohistochemical detection of the Ki67 nuclear antigen (20) and of the cleaved form of caspase-3 (21), respectively, were assessed.

Although these markers were distributed to different degrees along the airway epithelium and the bronchial submucosa in both control subjects and asthmatics, the airway smooth muscle was consistently negative, irrespective of the patient group (data not shown).

Control subjects showed low numbers of Ki67-positive cells in their bronchial epithelium and submucosa (Figure 4A and B and Figure 5). A significant increase in the number of proliferating epithelial and mucosal cells was observed in steroid-untreated asthmatics (Figure 4A and B and Figure 5). Inhaled steroids decreased cell proliferation rate in the epithelium without modifying significantly that of mucosal cells (Figure 4). In the inhaled and oral steroid-treated group, the number of Ki67-positive cells in both the epithelium and the bronchial submucosa decreased down to the levels of control patients (Figures 4 and 5).



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  		Figure 4.   Immunohistochemical detection of cell proliferation and apoptosis in bronchial biopsies from control, from corticosteroid-untreated asthmatics (CS-untreated) and from asthmatic patients treated with inhaled steroids alone (ICS) or in association with oral steroids (ICS + OCS). Proliferation (A and C ) and apoptotic death (B and D) were analyzed in the bronchial epithelium (A and B) and in the submucosa (B and D) using murine antihuman Ki67 and rabbit antihuman caspase-3 active form of 20 kD Abs, respectively, followed by APAAP Abs. Results are expressed as numbers of Ki67-expressing cells per 100 total epithelial cells and of caspase-3-positive cells over the total numbers of epithelial cells in each biopsy, or as numbers of Ki67-, or caspase-3-positive cells per millimeter of basement membrane. Values were compared by a one-way analysis of variance followed by a Mann-Whitney U test.



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  		Figure 5.   Immunohistochemical analysis of proliferation (A, C, E ) and apoptosis (B, D, F ) in bronchial epithelium from control subjects (A and B) and steroid-untreated (C and D) and -treated (E and F ) asthmatic patients. Cell proliferation and apoptosis were detected by incubating the cryostat sections with specific murine antihuman Ki67 and rabbit antihuman caspase-3 active form Abs, respectively, followed by APAAP (red deposits) and light Mayer hematoxylin counterstaining. Magnification: ×300.

Very few caspase-3-positive cells were enumerated in the bronchial epithelium and the submucosa of control subjects (Figure 4B and D and Figure 5). A significant increment in these numbers was noted in both compartments in steroid-untreated, in inhaled steroid- and in inhaled and oral-treated asthmatics, as compared with control subjects (Figure 4B and D and Figure 5).

To avoid confounding effects of steroid treatment when interpreting the association between the extent of PPARgamma expression and the number of proliferating and apoptotic cells in the different compartments, only control subjects and steroid-untreated asthmatics were considered. The individual intensities of PPARgamma expression in the airway epithelium failed to correlate with the number of Ki67- or caspase-3-positive cells (r' = 0.03 and r' = 0.116, respectively, n = 21, not significant). In contrast, the number of PPARgamma -expressing cells in the bronchial submucosa positively correlated with that of proliferating cells (r' = 0.62, n = 21, p < 0.001), but not with that of apoptotic cells (r'= 0.13, n = 21, not significant).

PPARgamma Expression in Relation to Airway Remodeling and to the Degree of Bronchial Obstruction

Morphometric and histochemical analysis of bronchial biopsies from control subjects showed an absence or a moderate thickness of the SBM and collagen deposition (Figure 6). SBM thickening was markedly augmented in steroid-untreated asthmatics (Figure 6A). Treatment with inhaled or inhaled and oral steroids was associated with a significant inhibition in SBM thickness (40.6 and 71.4%, p < 0.01 and p < 0.001, respectively) (Figure 6A).



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  		Figure 6.   Assessment of airway remodeling in control and in corticosteroid-untreated (CS-untreated) and -treated (inhaled, ICS, or inhaled and oral, ICS + OCS) asthmatics. The thickness of the subepithelial membrane (SBM) (A) and collagen deposition (B) were evaluated by morphometry and by picrosirius red staining, respectively. Results are expressed in micrometers for SBM and as % of picrosirius-stained area over the total biopsy area for collagen deposition.

A trend toward an increase in collagen deposition was also noted in steroid-untreated asthmatics, as compared with control subjects, but the high degree of variability precluded the results from achieving statistical significance (Figure 6B). In the inhaled and inhaled and oral steroid-treated group, collagen deposition was reduced by 50.5 and 71.4%, respectively, although the differences were not statistically significant (p > 0.05).

The association between PPARgamma expression, SBM thickness, collagen deposition and FEV1 values in control subjects and steroid-untreated asthmatics was then examined.

The intensities of PPARgamma expression in the bronchial submucosa and the airway epithelium and smooth muscle correlated positively with SBM thickness (r' = 0.49, p < 0.001; r' = 0.29, p < 0.01 and r' = 0.67, p < 0.001, respectively, n = 21) and was negatively related to the individual FEV1 values (Figure 7). Epithelium-associated PPARgamma expression also correlated positively with collagen deposition (r' = 0.30, n = 21, p < 0.05).



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  		Figure 7.   Correlation analysis between the individual intensities of PPARgamma expression in the bronchial submucosa (A), the airway epithelium (B ), and the airway smooth muscle (C ), and the values of FEV1 in control subjects and in steroid-untreated asthmatic patients. Correlation coefficients (r') were calculated using Spearman's nonparametric rank- order method.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

In the present study, we have demonstrated for the first time the localization of the nuclear antigen PPARgamma in human airways. This expression was augmented in asthmatics as compared with control subjects, particularly in airway epithelium and smooth muscle. Although we have been able to identify the PPARgamma protein in association with eosinophils and macrophages, a rise in the numbers of subepithelial cells expressing PPARgamma and showing a fibroblastlike morphology was also noted. In keeping with these observations, we detected high levels of PPARgamma by immunoblot in protein extracts from unstimulated primary cultured human lung fibroblasts (unpublished results). These findings parallel those recently reported showing the presence of PPARgamma protein in human synovial fibroblasts and in hepatic myofibroblasts (8, 22).

T lymphocytes in the bronchial mucosa failed to express PPARgamma , an observation in contrast with previous reports demonstrating the constitutive expression of the PPARgamma gene and protein by murine helper T-cell clones and by freshly isolated murine T lymphocytes (11, 23). Because no additional data are available in the literature concerning PPARgamma expression in human T cells, either in peripheral blood or in lymphoid and inflamed tissues, it is difficult at this stage to find an explanation for this discrepancy. Nevertheless, we confirmed the absence of PPARgamma immunostaining associated with T cells using frozen sections from human tonsils and lung lymph nodes (data not shown).

Upregulation of PPARgamma expression in airway epithelium and smooth muscle of asthmatics reported in this study is reminiscent of previous observations showing an augmented PPARgamma immunostaining associated with the colonic epithelium in mice with an inflammatory bowel disease (24), in rat neointima after balloon injury and in early human atheroma (25). This enhanced PPARgamma expression may reflect an inflammatory response of different cell types and structures to natural PPARgamma ligands generated within the airways during the allergic reaction. Although the nature of these stimuli in the lung is unknown, it is well established that a range of naturally occurring substances, including polyunsaturated fatty acids, the 15-lipoxygenase metabolite, 15-hydroxyeicosatetranoic acid (15-HETE), or cytokines such as IL-4, are potent PPARgamma expression-promoting agents (12, 26, 27). In particular, 15-HETE and IL-4 are produced in the airways of asthmatics by different inflammatory and immune cells (28) and contribute to eosinophilic inflammation, mucus secretion, and narrowing (33). The possibility that 15-HETE and IL-4 also operate in airway inflammation by inducing and/or activating PPARgamma in different pulmonary cells remains to be established.

Structural abnormalities characteristic of the remodeling response in asthma involve, at least in part, a dysregulation in the proliferation and apoptosis of different cell types responsible for the maintenance of airway integrity (36). Of note, synthetic and naturally occurring PPARgamma ligands greatly ameliorate different features of tissue remodeling, including the thickening of the bowel wall in mice with inflammatory bowel diseases (24) and arterial restenosis after endothelial injury in rats (37). These beneficial effects may be related to the ability of PPARgamma ligands to inhibit cell migration, proliferation, and proinflammatory and toxic mediator production (24, 37) and to promote apoptotic cell death (8).

These observations led us to determine whether changes in PPARgamma expression related to the proliferating and apoptotic status of the different cell types analyzed and to SBM thickening and submucosal collagen deposition, two histopathologic features of airway remodeling (3).

When compared with control subjects, asthmatic patients showed an enhanced proliferation and apoptosis in the epithelium and the bronchial submucosa, as assessed by the increment in the number of cells expressing the nuclear antigen Ki67 and the cleaved form of caspase-3, respectively.

As previously reported (3, 40, 41), a remodeling response characterized by SBM thickening and collagen deposition was also noted in steroid-untreated asthmatics as compared with control subjects. Together, these observations argue for an increased cellular turnover, probably in response to different mitogens, growth factors, and toxic products chronically released within the inflammatory airways.

The intensity of PPARgamma expression in the airway epithelium is related to SBM thickening and to collagen deposition, but not to proliferation or apoptosis. In contrast, the number of PPARgamma -positive cells in the bronchial submucosa significantly correlated with SBM thickening and with the number of Ki67-, but not of caspase-3-expressing cells. These results suggest that PPARgamma may be involved in the regulation of extracellular matrix deposit and of submucosal cell proliferation, rather than in epithelial cell turnover.

Finally, the intensities of PPARgamma expression in the bronchial submucosa, the airway epithelium, and the smooth muscle of steroid-treated asthmatics and the individual values of FEV1 significantly correlated, suggesting that high levels of PPARgamma in the airways may represent a marker of the severity of airflow obstruction.

Corticosteroids offer clinical improvement in airway function most likely by reducing airway inflammation, as a result of an inhibition of many transcription genes involved in the synthesis of proinflammatory lipid mediators and cytokines (42). Here we demonstrated that PPARgamma expression in the bronchial mucosa, the airway epithelium, and the smooth muscle was also downregulated in inhaled- and, to a higher extent, in oral steroid-treated asthmatics. These results indicate that the anti-inflammatory and immunomodulatory properties of these drugs may extend to the regulation of PPARgamma expression in target cells. However, the possibility that long-lasting beta 2-agonists, which are regularly administered to most of the asthmatic patients in combination with inhaled or oral steroids, would also interfere with PPARgamma expression cannot be ruled out. This particularly in view of substantial clinical data showing a synergistic benefit of these two therapies in reducing airway inflammation and in improving symptoms, probably as a result of their complementary modes of action (43).

Our observations showing lower levels of PPARgamma in steroid-treated asthmatics are in apparent contradiction with some in vitro findings showing upregulation by dexamethasone of PPARgamma gene expression in human adipocytes (44). Because no additional information is available in the literature concerning the modulation by corticosteroids, alone or in association with long-lasting beta 2-agonists, of PPARgamma gene and protein expression in human tissues, it is difficult to find an explanation for this discrepancy. Further studies with primarily cultured bronchopulmonary cells will certainly help to clarify this matter.

The mechanisms by which steroid therapy may decrease the levels of PPARgamma are presently unclear. It may be hypothesized that corticosteroids suppress the synthesis and release of PPARgamma expression-promoting agents from different cell types present in asthmatic airways. This would be the case for IL-4, whose gene expression is markedly reduced in bronchial biopsies of steroid-treated asthmatics (45). The production of the lipoxygenase metabolite, 15-HETE is also downregulated by corticosteroids, although at very high doses, in cultured human bronchial epithelial cells and dermal fibroblasts (46, 47).

Similarly to what we have observed for PPARgamma expression in the bronchial epithelium and in the submucosa, inhaled, and, to a greater extent, oral steroid therapy, inhibited cell proliferation, SBM thickness, and collagen deposition, whereas they enhanced apoptotic death. Several in vitro and in vivo findings have shown the ability of corticosteroids to prevent epithelial cell proliferation (48) and to induce apoptosis of different mucosal cells, including eosinophils (19, 49, 50) and T lymphocytes (53). In contrast, the efficacy of these drugs in modulating extracellular matrix alterations is a matter of controversy. Thus, in some studies inhaled steroids decreased SBM thickening and collagen deposition (53), whereas other studies have not been able to detect this benefit (56).

In conclusion, our results identify PPARgamma as a new factor expressed in high levels by submucosal and structural cells during the inflammatory and remodeling response in asthma. It is difficult at this stage to anticipate a role for PPARgamma in human asthmatic airways. In view of the results from the literature showing the inhibitory properties of this nuclear antigen against cell differentiation, proliferation, and activation (12), it may be hypothesized that its upregulation in asthma would represent a self-regulatory mechanism aimed at preventing further cell activation and expansion, thus contributing to the cessation of airway inflammatory and remodeling, as proposed for other pathologic conditions (8, 12, 24, 25, 60). However, this classic view may be contradicted by our findings demonstrating a clear association between an augmented PPARgamma expression, the presence of features of airway remodeling, and the increase in bronchial obstruction. These observations, together with the efficacy of steroid therapy in downregulating PPARgamma expression, may lead to consider this nuclear antigen as a new mediator with proinflammatory and fibrogenic activities. This hypothesis is consistent with the expression of high levels PPARgamma within the atherosclerotic plaques of mice and humans (25, 61) and with the recent debate concerning the potential atherogenic properties of endogenously produced PPARgamma (60).

Future studies with tissue-specific PPARgamma -deficient mice, or the use of PPARgamma agonists in experimental animal models and in isolated cells are thus required to gain better insight of the functional properties of PPARgamma and of the possibility of using its ligands as alternative or additional therapeutic strategies to resolve airway inflammation and remodeling in asthma.


    Footnotes

Correspondence and requests for reprints should be addressed to Marina Pretolani, PhD, INSERM U408, Faculté de Médecine Xavier Bichat, 16, rue Henri Huchard, 75018 Paris, France. E-mail: mpretol{at}bichat.inserm.fr

(Received in original form January 17, 2001 and accepted in revised form July 12, 2001).

Dr. Benayoun is a fellow of the Fondation de France.
Dr. Letuve is a fellow of the Fondation pour la Recherche Médicale.

Acknowledgments: The writers wish to thank Dr. Pierre Desreumaux for interesting discussion, Mireille Autré for kind assistance in collecting clinical data concerning the patients, and Isabelle Poirier and Gabrielle Beuve for expert technical help during fiberoptic bronchoscopy.

Supported by the Fonds de Recherche Hoechst Marion Roussel and by Grant No. 5367 from the Association pour la Recherche sur le Cancer.


    References
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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