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(Chest. 2006;129:1523-1530.)
© 2006 American College of Chest Physicians

Up-Regulated Membrane and Nuclear Leukotriene B4 Receptors in COPD*

Emanuela Marian, PhD; Simonetta Baraldo, PhD; Annalisa Visentin, MD; Alberto Papi, MD; Marina Saetta, MD; Leonardo M. Fabbri, MD, FCCP and Piero Maestrelli, MD

* From the Departments of Environmental Medicine and Public Health (Drs. Marian, Visentin, and Maestrelli), and Cardiothoracic and Vascularis Sciences (Drs. Baraldo and Saetta), University of Padova, Padova, Italy; the Department of Clinical and Experimental Medicine (Dr. Papi), University of Ferrara, Ferrara, Italy; and the Department of Medical, Oncological and Radiological Sciences (Dr. Fabbri), University of Modena, Modena, Italy.

Correspondence to: Piero Maestrelli, MD, Dipartimento di Medicina Ambientale e Sanità Pubblica, Università degli Studi di Padova, via Giustiniani, 2, 35128 Padova, Italy; e-mail: piero.maestrelli{at}unipd.it

Abstract

Study objectives: We investigated the role of two leukotriene B4 (LTB4) receptors, BLT1 and peroxisome proliferator-activated receptor (PPAR)-{alpha}, in conferring the susceptibility to develop COPD in smokers. Proinflammatory LTB4 activities are mediated by BLT1, while the inactivation of LTB4 is promoted by PPAR{alpha}.

Patients and methods: BLT1 and PPAR{alpha} proteins were quantified by immunohistochemistry in specimens obtained during lung surgery from 19 smokers with or without COPD and from 7 nonsmoking subjects.

Results: We have shown that the percentages of PPAR{alpha}-positive alveolar macrophages and PPAR{alpha}-positive cells in the alveolar wall were increased in COPD patients compared with control subjects. Moreover, the patients with COPD exhibited a significant increase of BLT1-positive alveolar macrophages compared with nonsmokers and an increased number of BLT1-positive cells in the alveolar walls compared with non-COPD smokers. In contrast, BLT1 and PPAR{alpha} immunoreactivity did not differ significantly between nonsmokers and non-COPD smokers. Most of BLT1-positive cells in the alveolar walls were neutrophils and CD8 cells. While the number of neutrophils infiltrating the lung parenchyma was similar among the three groups, the number of CD8 T cells was increased in COPD patients, but there was no evidence that BLT1 was up-regulated specifically on these cells in COPD patients.

Conclusion: The results demonstrated that BLT1 and PPAR{alpha} are detectable in alveolar macrophages and CD8 T cells in human lung tissue, and suggest that the dual LTB4 receptor system is up-regulated in the peripheral lungs of smokers who are susceptible to the development of COPD. This system might represent a novel target for therapeutic intervention in COPD patients.

Key Words: cigarette smoking • histology • immunohistochemistry • inflammation • macrophages

It has been established that the development of COPD is associated with an inflammatory process in the peripheral airways, including the accumulation of neutrophils, macrophages, and lymphocytes.1 The activation of neutrophils, producing proteases and oxygen-derived free radicals, is thought to be important in the pathogenesis of the disease, whereas the role of lymphocytes, particularly CD8 cells, remains more controversial.2 An important step in the recruitment of leukocytes is the local generation of chemoattractant signals, which mediate the trapping and adhesion on the microvascular endothelium followed by the migration of the cells to the tissue. Interleukin-8 and leukotriene B4 (LTB4) have been identified as important neutrophil chemoattractants in COPD patients.34 In particular, LTB4 seems to be the prominent chemotactic factor in patients with the most severe COPD5 and during acute exacerbations.67 In addition, studies8 have indicated that LTB4 is important for the recruitment of CD8 T cells to sites of inflammation. Whereas the infiltration of CD8 cells was demonstrated in several lung compartments of COPD patients,1910 the evidence of increased numbers of neutrophils in bronchial biopsy specimens and peripheral lung samples from COPD patients is often inconsistent.9101112 The present study focuses on the receptors that mediate LTB4 activity, peroxisome proliferator-activated receptor (PPAR)-{alpha} and BLT1. Proinflammatory LTB4 activities are mediated by binding to the BLT1 receptor, which is a high-affinity, G protein-coupled cell surface receptor of LTB4, expressed predominantly in leukocytes.13 LTB4 is inactivated through metabolic degradation by the microsomal {omega}-oxidation and peroxisomal ß-oxidation pathways. LTB4 has been reported14 to bind and activate PPAR{alpha}, resulting in the transcription of genes that promote fatty acid degradation. PPARs are a group of transcription factors that regulate the gene expression of enzymes that are associated with lipid homeostasis. Three PPAR subtypes have been identified ({alpha}, ß/{delta}, and {gamma}).15 Recent evidence has indicated a role for PPARs in the control of various types of inflammatory responses. Most of the antiinflammatory properties of the PPARs arise through their ability to antagonize the nuclear factor (NF)-{kappa}B and AP1 signaling pathways.16 It is well-established that the susceptibility of smokers to the development of COPD is associated with an exaggerated inflammatory response in the lungs to cigarette smoke.2 A different ability to mount an inflammatory response, due to diversity in the genes controlling inflammation, may explain the individual differences in the response to smoke, which lead to the characteristic pathologic lesions of COPD in some smokers.

The primary aim of this study was to investigate the expression of the two LTB4 receptors, PPAR{alpha} and BLT1, in the lungs of COPD patients. The immunoreactivity for PPAR{alpha} and BLT1 was quantified in alveolar macrophages and in the alveolar walls of 7 nonsmoking subjects, 9 smokers without COPD, and 10 smokers with COPD; the relationship with neutrophil and CD8 cell infiltration in the lung tissue was evaluated.

Materials and Methods

Subjects
Three groups of subjects undergoing lung resection for treatment of a solitary peripheral carcinoma or lung volume reduction surgery for treatment of emphysema were examined, as follows: 10 subjects with a smoking history of > 20 pack-years and fixed airway obstruction (subjects with COPD were defined according to the definition of the Global Initiative for Chronic Obstructive Lung Disease)17; 9 asymptomatic subjects with a smoking history of > 20 pack-years and normal lung function; and 7 asymptomatic nonsmoking subjects with normal lung function. Airway obstruction was defined as an FEV1/vital capacity ratio less than the predicted value minus a 1.64 residual SD and an FEV1 of < 50% predicted.18 Pulmonary function tests were performed within the week before patients underwent surgery. All subjects exhibited an increase in FEV1 of < 15% after the inhalation of 200 µg of salbutamol. Subjects with COPD had no exacerbations during the month preceding the study. All the subjects had been free of acute upper respiratory tract infections, and none had received oral or inhaled glucocorticoids or antibiotics within the month preceding surgery. They had negative skin test results for common allergen extracts and no history of asthma or allergic rhinitis. The study conformed to the Declaration of Helsinki, and informed written consent was obtained for each subject.

Immunohistochemistry
Tissue blocks were taken from the subpleural parenchyma, avoiding areas involved by tumor, were fixed in 4% formaldehyde, and were embedded in paraffin, as described elsewhere.19 Sections that were 5 µm thick were cut for immunohistochemical analysis.

Rabbit polyclonal antibodies against PPAR{alpha} and PPAR{gamma} (anti-PPAR{alpha} and anti-PPAR{gamma}; Santa Cruz Biotechnology; Santa Cruz, CA) and BLT1 (anti-BLT1; Cayman Chemical; Ann Arbor, MI) were labeled with biotinylated swine antirabbit Igs (E0353; Dako; Glostrup, Denmark) followed by streptavidin biotinylated alkaline phosphatase complex and Fast Red staining (Dako).19 Mouse monoclonal antibody was used to identify neutrophils (antielastase, M752; Dako) and CD8 T cells (M7103; Dako), and was detected with the alkaline phosphatase antialkaline phosphatase method (APAAP kit system K670; Dako) and Fast-Red substrate (Dako).910 Mouse monoclonal antibody against inducible nitric oxide synthase (iNOS) [sc7271; Santa Cruz Biotechnology] were used as previously described.20 The slides were observed using light microscopy (DMLB; Leica; Cambridge, UK) at x630 magnification in a blinded fashion. Immunostaining for PPAR-{alpha}, PPAR-{gamma}, BLT1, and iNOS was quantified in alveolar walls and alveolar macrophages, while that for elastase and CD8 cells was quantified in the alveolar walls only. At least 20 high-power fields (hpfs) of lung parenchyma were randomly selected for each section, and at least 100 macrophages inside the alveoli were evaluated.20 Alveolar macrophages were defined as mononuclear cells with well-represented cytoplasm present in the alveolar spaces and not attached to the alveolar wall. The results were expressed as a percentage of PPAR-{alpha}-positive, PPAR-{gamma}-positive, or BLT1-positive macrophages per hpf. The number of positively stained cells within the alveolar walls was computed as previously described.19 Negative controls for nonspecific binding incubated with rabbit or mouse Ig as a primary antibody were processed and revealed no signal. The results were expressed as the number of cells per millimeter of alveolar wall.

Double immunostaining was performed in order to determine the cell type staining positively for BLT1. CD68 (macrophages), CD8, and neutrophil elastase-positive cells were studied. Slides were double-stained with antibodies anti-CD68 (mouse monoclonal M814; Dako), or anti-CD8, or antielastase, and anti-BLT1. The BLT1 primary antibody was detected using biotinylated swine antirabbit Igs (E353; Dako) followed by avidin-biotin complex and Fast Red staining. Slides were then incubated with anti-CD68, anti-CD8, or antielastase, and bound antibodies were labeled (EnVision+ method, K4000; Dako) and developed with diaminobenzidine. Control slides were obtained by performing double staining in which one of the primary antibodies was not added or using appropriate mouse and/or rabbit control IgG as the primary antibodies.

Statistical Analysis
Differences between groups were analyzed using the analysis of variance for clinical data and the Kruskal-Wallis test for histologic data. The Mann-Whitney U test was carried out after the Kruskal-Wallis test when appropriate. At least three replicated measurements of immunostained slides were performed by the same observer in at least 10 randomly selected slides to assess the intraobserver reproducibility.21 The intraclass correlation coefficients were 0.98 to 0.99. Probability values of p < 0.05 were accepted as significant.

Results

Table 1 shows the characteristics of the subjects examined. The three groups of subjects were similar with regard to age. There was no significant difference in smoking history between smokers with or without COPD. COPD patients exhibited lower values of arterial oxygen tension (p < 0.01). As expected from the selection criteria, subjects with COPD had significantly lower values of FEV1 percent predicted and FEV1/FVC ratio compared to smokers with normal lung function and nonsmokers.


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  		Table 1. Characteristics of the Subjects*

 
PPAR{alpha} and PPAR{gamma} were constitutively expressed by bronchiolar epithelial cells. In the alveolar compartment, PPAR{alpha} and PPAR{gamma} immunoreactivity was observed in alveolar macrophages and alveolar walls. Figure 1 shows examples of the PPAR{alpha} immunostaining of lung specimens in a patient with COPD (Fig 1, top left, a) and in a nonsmoking control subject (Fig 1, top right, b). Immunostaining for BLT1 was present in alveolar macrophages, in the alveolar wall (Fig 1, bottom left, c, and bottom right, d), and in some bronchiolar epithelial cells.


Figure 1
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  		Figure 1. Immunohistochemistry study of human lung specimens are shown: the alveolar wall and macrophages stained for PPAR{alpha} in a patient with COPD (top left, a) and in a nonsmoking control subject (top right, b); and the alveolar wall and macrophages stained for BLT1 in a patient with COPD (bottom left, c) and in a nonsmoking control subject (bottom right, d). Formalin-fixed, paraffin-embedded sections were processed for immunohistochemistry using polyclonal antibodies against PPAR{alpha} and BLT1 followed by staining with streptavidin biotinylated alkaline phosphatase complex and Fast Red stain. All sections were counterstained with hematoxylin (original x 630).

 
Alveolar Macrophages
The number of alveolar macrophages per hpf counted in COPD patients was significantly higher (median, 155 cells; interquartile range [IQR], 119 to 193 cells) than in control smokers (median, 104 cells; IQR, 95 to 118 cells; p < 0.05) and in nonsmokers (median, 92 cells; IQR, 85 to 95 cells; p < 0.01). The quantification of immunoreactivity for PPAR{alpha} indicated that the percentages of alveolar macrophages that were positive for this LTB4 intracellular receptor was significantly increased in subjects with COPD compared with non-COPD smokers and nonsmoking control subjects (Table 2 ). The percentages of alveolar macrophages that were positive for the membrane LTB4 receptor BLT1 was significantly higher in subjects with COPD compared with nonsmoking control subjects. Non-COPD smokers exhibited percentages of BLT1-positive macrophages that were intermediate between those of the other two groups, but the differences were not significant (Table 2). The percentages of iNOS-positive macrophages was significantly higher in smokers with or without COPD compared with nonsmokers (Table 2).


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  		Table 2. Comparison of PPAR{alpha}-Positive, PPAR{gamma}-Positive, BLT1 Receptor-Positive, and iNOS-Positive Alveolar Macrophages*

 
Double immunostaining indicated that the majority of cells in alveolar spaces counted as alveolar macrophages were CD68-positive (94%; IQR, 88 to 98%). Most of the BLT1-positive cells in alveolar spaces were CD68-positive (86%; IQR, 69 to 96%). The percentages of CD68-positive cells exhibiting immunoreactivity for BLT1 increased significantly from those of nonsmokers (66%; IQR, 58 to 69%), non-COPD smokers (78%; IQR, 73 to 98%), and COPD patients (94%; IQR, 88 to 97%; p < 0.01). These results are consistent with those shown in Table 2 where the identification of alveolar macrophages was performed by morphologic criteria.

Alveolar Wall
The number of PPAR{alpha}-positive cells (Fig 2 ) and the number of BLT1-positive cells in the alveolar wall were increased in COPD subjects compared with subjects in the other two groups who had normal lung function (Table 3 ). Nonsmokers exhibited the same median numbers of BLT1-positive cells as non-COPD smokers. However, the higher variability of BLT1 immunoreactivity in the former group prevented the detection of a significant difference with COPD subjects (Fig 3 ).


Figure 2
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  		Figure 2. Comparison of individual values of PPAR{alpha}-positive cells in the alveolar wall among nonsmoking control subjects, non-COPD smokers, and patients with COPD.

 

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  		Table 3. Comparison of PPAR{alpha}-Positive, PPAR{gamma}-Positive, BLT1 Receptor-Positive, iNOS-Positive, Neutrophil Elastase-Positive, and CD8-Positive Cells in the Alveolar Wall*

 

Figure 3
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  		Figure 3. Comparison of individual values of LTB4 receptor (BLT1)-positive cells in the alveolar wall among nonsmoking control subjects, non-COPD smokers, and patients with COPD.

 
Immunostaining for neutrophil elastase in the alveolar wall did not show significant differences among the three groups, whereas the number of CD8 T cells in the alveolar wall was significantly increased in COPD patients compared to the other groups of subjects (Table 3). The number of iNOS-positive cells in the alveolar wall was significantly higher in COPD subjects vs nonsmokers (Table 3).

In the alveolar wall, the double immunostaining of BLT1 with CD68 cells, CD8 cells, and neutrophils was detected (Table 4 , Fig 4 ). CD8 cells and neutrophils accounted for most of BLT1 receptor-positive cells, without significant differences among the three groups of patients. A trend for a lower expression of BLT1 in alveolar wall macrophages was observed in smokers with and without COPD compared with nonsmokers, but the differences were not statistically significant (Table 4).


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  		Table 4. BLT1 Receptor-Positive Cells Double Stained for CD68, CD8, and Neutrophil Elastase in the Alveolar Wall*

 

Figure 4
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  		Figure 4. Human lung specimens that were double-stained for BLT1 as red staining, and CD68 (macrophages) or CD8 as brown staining. Shown are a negative control section of double staining with mouse and rabbit normal IgG used as the primary antibodies (top left, a), the CD68 antibody alone (top right, b), the CD8 antibody and normal rabbit IgG (middle left, c), BLT1 antibody and normal mouse IgG (middle right, d), alveolar spaces and wall stained with either CD8 and BLT1 antibodies (arrows) in a COPD subject (bottom left, e), and the alveolar wall stained with either CD68 and BLT1 antibodies (arrows) in a COPD subject (bottom right, f) [original x 630].

 
In contrast to the data of the LTB4 receptors, the differences in the expression of PPAR{gamma} among the three groups of patients were not significant in alveolar macrophages and the alveolar wall (Table 2 and 3), although the PPAR{gamma} immunostaining in alveolar macrophages tended to be greater in non-COPD smokers and COPD patients.

Discussion

In this study, we have demonstrated for the first time the localization of the nuclear receptors PPAR{alpha} and PPAR{gamma}, and of the BLT1 receptor in peripheral human lung tissue. The immunoreactivity for the two LTB4 receptors, PPAR{alpha} and BLT1, was augmented in alveolar macrophages and the alveolar wall of subjects with a history of smoking and airflow obstruction.

There is abundant evidence from the analysis of sputum and exhaled breath condensate samples that levels of LTB4 are increased in the airway lumen of COPD patients.3456722 A study of BAL fluid23 demonstrated a significantly increased concentration of LTB4 in former smokers with emphysema compared with smokers without emphysema. No information is available on the LTB4 content of the lung parenchyma in COPD patients. We provide some indirect evidence of enhanced LTB4 activity in the peripheral lung tissue of COPD patients (ie, at the site where the predominant lesions of COPD occur). LTB4 is one of the few ligands that utilize a dual-receptor system.24 The proinflammatory effects of LTB4 are thought to be triggered by high-affinity binding to the BLT1 receptor on immune cells. Our findings are consistent with the observations that BLT1 is inducible in macrophages in vitro and its expression is up-regulated in animal models of inflammation.1325

There is an apparent discrepancy of BLT1 expression between the alveolar space and alveolar wall macrophages. However, the trend toward a lower expression of BLT1 in the alveolar wall macrophages of COPD patients was not statistically significant. In addition, double-staining data showed that the contribution of macrophages to BLT1-positive cells in the alveolar wall is minimal. Most of BLT1-positive cells in this compartment were indeed neutrophils and CD8 cells. We had no evidence that BLT1 was up-regulated on neutrophils or CD8 cells in COPD patients. Therefore, the increased BLT1 immunoreactivity in the alveolar walls of COPD patients may reflect the increased number of these inflammatory cells that are infiltrating the lung tissue. A more precise quantification of the degree of up-regulation of the receptor would be of importance, but it is not feasible by immunostaining. On the other hand, we could not apply immunoblot techniques for protein measurement because the available tissue in this study was formalin-fixed and paraffin-embedded.

Originally identified as a chemoattractant for neutrophils, LTB4 has been demonstrated to be a potent chemoattractant for CD8 T cells.8 LTB4-induced chemotaxis mediated by BLT1 might represent one of the mechanisms that is responsible for the increased number of CD8 T cells in the lung tissue of COPD patients.1910 However, this hypothesis could not be elucidated by this study of human lung specimens, given its observational nature. Neutrophilic inflammation has been described in the airway lumen and epithelium, and in the mucous glands of patients with COPD,262728 but less consistently in bronchial biopsy specimens and lung parenchyma.9101112 We confirmed that the number of neutrophils was not significantly different in the alveolar wall of COPD patients compared with non-COPD smokers.910 The increased accumulation of neutrophils in the airways appears to be restricted to the most severe manifestation of COPD.129 We cannot exclude that our COPD patients had airway neutrophilia, since the histologic examination of a section of lung parenchyma only identifies one time point during the transition of the cells from the circulation to the airways. A single study30 detected an absolute increase in the number of neutrophils in the peripheral lung of patients undergoing lung volume reduction surgery for the treatment of severe COPD. The discrepancy with our observations may be explained by differences in the methodology used and in the characteristics of the subjects. First, Retamales and coworkers30 quantified the inflammatory cells in alveolar walls and alveolar spaces, whereas we measured elastase-positive cells in the alveolar wall only. Second, their patients had greater cigarette consumption and more severe disease than our subjects.

Although the PPAR target genes were generally associated with lipid homeostasis, it has been shown experimentally that all three PPAR isotypes can participate in the regulation of the inflammatory response. Most of the studies that have been carried out have come to the conclusion that PPAR activation can negatively regulate the induction of the inflammatory response.16 LTB4 would effectively control its own degradation by initiating the up-regulation of the fatty acid oxidation pathways. This catabolic inactivation of the eicosanoid is facilitated by the direct interaction and activation of PPAR{alpha}, which is a nuclear receptor for LTB4.15 However, the involvement of PPARs may result in a different response outcome depending on the experimental conditions. There is evidence in murine macrophages that PPAR{alpha} agonists, including LTB4, enhance the inducible isoform of nitric oxide synthase (ie, iNOS).31 It has been shown that iNOS expression is increased in patients with severe COPD, and the excess of nitric oxide (NO), which is produced by iNOS, is thought to have proinflammatory effects.20 It remains to be elucidated whether PPAR{alpha} up-regulation in COPD patients promotes the NO production pathway, but the association of enhanced iNOS and PPAR{alpha} immunoreactivity in patients with the disease is consistent with this hypothesis.

The role of PPAR{gamma} in the regulation of the inflammatory response is even less clear than that of PPAR{alpha}. In animal models, PPAR{gamma} has been shown to decrease the severity of some inflammatory diseases, including colitis, arthritis, and asthma.323334 In contrast, PPAR{gamma} expression was increased in the bronchial submucosa, airway epithelium, and smooth muscle cells from asthmatic patients and was directly correlated with the severity of airflow obstruction.35 PPAR{gamma} agonists have been shown to inhibit the production of inflammatory cytokines, such as tumor necrosis factor and interleukin-8, the recruitment of neutrophils, the inducible production of NO, and the expression of matrix metalloprotease-91636 which are thought to be relevant in the pathophysiology of COPD.2 These properties of PPAR{gamma} arise through its ability to inhibit the NF-{kappa}B and AP1 signaling pathways. Although the increased expression of NF-{kappa}B has been reported in bronchial biopsy specimens from smokers and patients with COPD,37 we were unable to demonstrate significantly different levels of PPAR{gamma} among the three groups of patients. An up-regulation of PPARs in COPD patients was therefore selective for isoform 2. From our PPAR{gamma} immunoreactivity data, it can be argued that this nuclear receptor has no role in COPD. However, given the reported mutual antagonism between PPAR{gamma} and NF-{kappa}B, our results might indicate a defect in the ability of these patients to suppress inflammation through PPAR{gamma} up-regulation.

In conclusion, our results demonstrated that the dual LTB4 receptor system, BLT1 and PPAR{alpha}, is up-regulated in the alveolar macrophages and lung parenchyma in COPD. It is difficult at this stage to predict the roles of BLT1 and PPARs in the development of the exaggerated inflammatory response to inhaled noxious stimuli causing COPD and in the progression of the disease. It may be hypothesized that the up-regulation of the two LTB4 receptors contributes to inflammation of lung parenchyma by inducing iNOS via PPAR{alpha}, and recruiting CD8 T cells and neutrophils via BLT1. These results may have an implication for the therapeutic strategy used in treating COPD patients, since the efficacy of current drugs for the treatment of COPD is far from satisfactory. The LTB4 receptors, which are expressed in the peripheral lung, might represent an attractive alternative therapeutic target for COPD.35

Footnotes

Abbreviations: hpf = high-power field; iNOS = inducible nitric oxide synthase; IQR = interquartile range; LTB4 = leukotriene B4; NF = nuclear factor; NO = nitric oxide; PPAR = peroxisome proliferator-activated receptor

This research was supported by the Italian Ministry of University and Research (PRIN 2003), by the University of Padova, and by Associazione Ricerca Cura Asma, Padova, Italy.

Received for publication July 28, 2005. Accepted for publication December 13, 2005.

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