ANNALS OF RESPIRATORY MEDICINE
REVIEW ARTICLE
Role of Leukotriene B4 Receptor Antagonist in Pulmonary Fibrosis Takehiro Izumo, Mitsuko Kondo, Naoki Arai and Atsushi Nagai Affiliation: First Department of Medicine, Tokyo Women’s Medical University School of Medicine, Shinjuku-ku, Tokyo, Japan
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Leukotrienes (LTs) are important chemoattractants for leukocytes and play a pivotal role in the pathogenesis of inflammatory and immune disease, and recent evidence suggests that LTs also play an important role in pulmonary fibrosis. The synthesis of leukotriene B4 (LTB4) and cysteinyl leukotriene (cysLT) is catalyzed by 5-lipoxygenase. Elevated levels of LTB4 in bronchial alveolar lavage fluid have been reported in allergic diseases and pulmonary fibrosis. Recent reports using LTB4 receptor (BLTR) antagonists have revealed that ligation of BLTR by LTB4 is important for the activation and recruitment of inflammatory cells including neutrophils, eosinophils, monocyte/macrophages, and T cells to inflamed tissues in inflammatory diseases. Although it is about 30 years since LTB4 was discovered in 1979, recent research about BLTR antagonists has revealed the important roles of the LTB4/BLTR pathway in the pathophysiology of pulmonary diseases, such as bronchial asthma and pulmonary fibrosis. We reported recently that BLTR antagonists inhibited the development of bleomycin-induced pulmonary fibrosis in mice by decreasing the inflammation and altering transforming growth factor b, interleukin (IL)-6, IL-13, and interferon c. Current therapy for pulmonary fibrosis is ineffective, and the disease has a poor outcome and is associated with severe morbidity. Corticosteroid therapy for pulmonary fibrosis is not effective and does not prevent progression. Targeting of the LTB4/BLTR pathway may be an important strategy in the treatment of pulmonary fibrosis. Keywords: pulmonary fibrosis, leukotriene B4, leukotriene B4 receptor (BLTR), leukotriene B4 receptor antagonist, cysteinyl leukotriene Correspondence: Takehiro Izumo, First Department of Medicine, Tokyo Women’s Medical University, School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan. Tel: (81)-3-3353-8111; Fax: (81)-3-5379-5457; e-mail:
[email protected]
critical to the development of rejection and obliterative bronchiolitis after lung transplantation by mediating airway fibroproliferation [8]. However, the role of BLTR in pulmonary fibrosis has remained unclear. We reported recently that a BLTR antagonist inhibits inflammation by a decrease in inflammatory cells including neutrophils, macrophages, and lymphocytes, and inhibits the development of bleomycin-induced pulmonary fibrosis [9].
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INTRODUCTION
Although the prototypic fibroproliferative lung diseases are diffuse disorders of the pulmonary parenchyma such as idiopathic pulmonary fibrosis (IPF), many new aspects of their pathogenesis are shared by remodeling diseases involving other compartments of the lung. Leukotrienes (LTs) are metabolites of arachidonic acid by the 5-lipoxygenase (5-LO) pathway. Recent reports have suggested that LTs are important regulators of pulmonary fibrosis [1,2] (Figure 1). LTB4 is a chemoattractant for leukocytes and plays a pivotal role in the pathogenesis of inflammatory and immune disease such as bronchial asthma, sepsis, atherosclerosis, and fibrosis [1]. IPF is a deleterious disease with very poor prognosis despite all known methods of treatment [3]. The pathological features of IPF are fibroblast proliferation, increased amounts of extracellular matrix, and varying degrees of persistent inflammation of the alveolar septa [2,3]. LTB4 is thought to be a cause of various inflammatory disorders, and it is produced by alveolar cells in patients with IPF [4,5]. There are two LTB4 receptor (BLTR) subtypes, BLT1 and BLT2, and both subtypes are G protein-coupled receptors and present on the cell surface [4,6]. BLT1 mediates LTB4induced T helper type 1 (Th1) and Th2 cell chemotaxis and firm adhesion to endothelial cells exposed to flow, and mediates CD4+ and CD8+ T-cell recruitment into the airway in an asthma model [7]. BLT1-mediated T-cell trafficking is
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This review focuses on leukotriene metabolism, LTB4 receptor and LTB4 receptor antagonists, and the role of LTB4 in pulmonary fibrosis.
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LEUKOTRIENE B4 BIOSYNTHESIS LTB4 is a potent lipid inflammatory mediator derived from phospholipids by the sequential actions of cytosolic phospholipase A2 , 5-LO, and LTA4 hydrolase (Figure 1). LTB4 was discovered by Borgeat and Samuelsson [10], and found to be a potent neutrophil chemoattractant by Ford-Hutchinson et al [11]. The LTs are formed in different cell types as well as via transcellular metabolism involving multiple cells such as neutrophils, platelets, and vascular cells [12–14]. Macrophages and monocytes also synthesize both LTB4 and the cysteinyl (cys) LTs. The major function of LTB4 is as a chemoattractant for leukocytes, and it plays a pivotal role in the pathogenesis of inflammatory and immune diseases such 1
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Figure 1. Studies of eicosanoid synthesis and receptors in bleomycin-induced pulmonary fibrosis. Arachidonic acid is released from membrane phospholipids by cytosolic phospholipase A2 (cPLA2) metabolized by the 5-lipoxygenase (5-LO) pathway to produce leukotriene (LT), or by cyclooxygenase (COX) to produce prostaglandin (PG) and thromboxane (TX). The numbers show the references.
as bronchial asthma, sepsis, atherosclerosis, and fibrosis [1]. LTB4 and the peptide chemokines mediate their function through the receptors, the G protein-coupled seven-transmembrane domain receptor superfamily.
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studies of human BLT1 cDNA demonstrated that BLT1 expression is the highest in peripheral blood leukocytes and is present in much lower amounts in spleen, thymus, bone marrow, lymph nodes, heart, skeletal muscle, brain, and liver [19,20]. The expression of human BLT1 protein has been confirmed by flow cytometry using anti-BLT1 monoclonal antibodies on CD15+ peripheral blood granulocytes, and on HL-60 cells when differentiated into neutrophil-like cells by treatment with dimethyl sulfoxide (DMSO). The study of murine BLT1 cDNA demonstrated that BLT1 expression is predominantly in activated leukocytes, neutrophils, macrophages, and eosinophils [16]. These findings were consistent with the notification that LTB4 is a local inflammatory mediator. Murine BLT1 was highly expressed in T-cell lymphomas that spontaneously arose in c-myc transgenic mice homozygous for p53-null alleles, suggesting that T cells can express BLT1. Recent reports have suggested that LTB4 also acts as an important attractant for differentiated T cells. BLT1 mediates LTB4-induced Th1 and Th2 cell chemotaxis and mediates CD4+ and CD8+ T-cell recruitment into the airway in an asthma model [7].
LEUKOTRIENE B4 RECEPTOR AND LEUKOTRIENE B4 RECEPTOR ANTAGONIST
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Although, molecular identification of the LTB4 receptor eluded investigators for many years, Yokomizo et al [15] successfully cloned the human high-affinity LTB4 receptor in 1997, and Huang et al [16] also cloned the mouse LTB4 receptor. This receptor was initially named BLTR, and Yokomizo et al [15] renamed BLT1 when a second LTB4 receptor (BLT2) was identified [6]. Membrane fractions of COS-7 cells transfected with BLT1 showed a high affinity for LTB4 with a Kd of 0.154 nM, comparable to that observed in retinoic acid-differentiated HL-60 cells. Human BLT1 is 352 amino acid residues in length, and mouse BLT1 is 351 amino acids, similar to the lengths of other chemoattractant receptors [17]. The primary structures of human and mouse BLT1 are 78% identical at the amino acid level. Both BLT1 and BLT2 are G protein-coupled receptors and present on the cell surface [6]. BLT1 is expressed primarily on leukocytes, whereas BLT2 is expressed more ubiquitously [1]. LTB4 was classically described as a chemoattractant for myeloid leukocytes, and BLT1 was shown to be expressed on granulocytes, macrophages, monocytes, and eosinophils, and to a lesser extent, on native lymphocytes [18]. The AoRM 2010; 000:(000). Month 2010
BLT2, another G protein-coupled LTB4 receptor, was independently identified by Yokomizo et al [6]. They identified human BLT2 while analyzing the promoter of BLT1. Northern and dot blot analyses have revealed that the distribution of BLT2 expression differs significantly from that of BLT1. Membrane fractions of HEK 293 cells transfected with cloned human BLT2 sequence demonstrated specific and saturable 2
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Leukotriene B4 receptor antagonist in pulmonary fibrosis
LTB4 binding with a Kd of 22.7 nM, approximately 20-fold higher than human BLT1 transfectants. The two LTB4 receptor genes form a cluster in both human and mouse genomes [21]. The human BLT2 gene is located about 3 kb 59 of the human BLT1 gene [21]. The mouse BLT2 gene is similarly located about 4 kb 59 of the BLT1 coding sequence [21]. The expression of human and mouse BLT1 is mainly in leukocytes, but human BLT2 is expressed more ubiquitously. BLT2 expression is present in most human tissues, mainly in spleen, liver, ovary, and peripheral blood leukocytes [22–24]. In contrast, the expression of mouse BLT2 has not been detected as BLT2 mRNA in murine neutrophils, macrophages, T cells, lymph node, spleen, or lung. The biological roles of BLT2 have not been clarified. BLT1 binds LTB4 with significantly greater specificity than BLT2. A recent report showed that 12(S)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid (12-HHT) is a natural ligand for BLT2 [25].
LEUKOTRIENE METABOLISM IN PULMONARY FIBROSIS
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LTs are metabolites of arachidonic acid by the 5-LO pathway. Recent reports have suggested that LTs are important regulators of pulmonary fibrosis [1,2] (Figure 1). Patients with IPF produce excessive amounts of LTB4 and cysLTs in their lungs [5], and lower amounts of collagen and hydroxyproline are observed in the 5-LO gene knockout mice after administration of bleomycin [37]. The LT level in bronchoalveolar lavage fluid (BALF) increases in bleomycin-treated mice, and the cysLTs levels, in particular, are much higher than the levels of the other eicosanoids [38]. Furthermore, the increase in inflammatory cells in BALF and lung tissues in bleomycin-treated 5-LO gene knockout mice and cytosolic phospholipase A2 gene knockout mice are much lower than in wildtype mice, suggesting that cysLTs and cysLT receptors may be involved in the inflammatory process of bleomycin-induced pulmonary fibrosis. Because LTs have a direct effect on migration, proliferation, and matrix protein synthesis by fibroblasts, LTs may play an important role in pulmonary fibrosis [39,40]. LTs also activate macrophages to release other proinflammatory mediators, such as tumor necrosis factor, interleukin (IL)-6, and IL-8, and growth factors, such as fibroblast growth factor [41]. LTs are known to stimulate fibroblast proliferation, collagen synthesis, and myofibroblast differentiation. CysLTs promote the proliferation of murine and human bone marrow-derived fibrocytes, which participate in tissue remodeling and repair [42]. The BAL fluid from patients with IPF contains higher levels of LTB4 than that from control subjects [43]. The homogenates of the lung tissue from IPF patients have 15-fold higher levels of LTB4 and fivefold higher levels of LTC4 than those of control subjects, reflecting constitutive activation of the 5-LO enzyme in alveolar macrophages [5]. Increased lung LT levels have also been observed in mice after intratracheal administration of bleomycin [37]. We reported previously finding that montelukast, one of the cysLT1 receptor antagonists that have been widely used in the treatment of bronchial asthma, inhibits the development of bleomycininduced pulmonary fibrosis [44].
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BLT1 and BLT2 are distinguished pharmacologically. Multiple LTB4 receptor antagonists have been developed, including CP-105,696 [26], U-75302 [27], LY255283 [28], LY29311 [29], CP-195,543 [26], LTB019 [30], ZK158252, and ONO-4057 [31]. Some of these agents selectively antagonize BLT1 and BLT2, whereas others antagonize both receptors. CP-105,696 and U-75302 compete with LTB4 binding in a dose-dependent manner to membrane fractions of CHO cells expressing human BLT1 but not human BLT2. LY255283 competes with LTB4 binding to human BLT2 but not human BLT1. ZK158252, CP-195,543, LY29311, ONO-4057, and LTB019 compete with LTB4 binding to both receptors [32].The association of elevated LTB4 with human inflammatory diseases, suggesting a causal role for LTB4, has been demonstrated in animal models of inflammatory diseases. LTB4 receptor antagonists have inhibited the recruitment of leukocytes. Administration of the LTB4 receptor antagonist LY255283 significantly ameliorated systemic arterial hypotension, pulmonary arterial hypertension, pulmonary edema, and arterial hypoxemia in a porcine model of shock and acute respiratory distress syndrome [33]. Administration of CP-105,696 markedly blocked the massive influx of inflammatory cells into subsynovial connective tissue, and abrogated the destruction of articular cartilage and erosion of bone in the murine collagen arthritis model of rheumatoid arthritis [34]. In the murine allergic encephalitis model, the administration of CP-105,696 blocked the recruitment of eosinophils into the spinal cord and completely inhibited the development of paralysis [35]. Administration of CP-105,696 significantly prevented the development of airway hyperresponsiveness in a primate model of asthma, and inhibited recruitment of neutrophils into airways early after antigen challenge [36]. Administration of LTB019 prevented LTB4induced upregulation of CD11b/18 on human neutrophils and in accordance with its anti-neutrophil action in animals [30]. We reported recently that ONO-4057 inhibited pulmonary inflammation by a decrease in inflammatory cells including neutrophils, macrophages, and lymphocytes, and inhibited the development of bleomycin-induced pulmonary fibrosis in mice [9].
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An imbalance of Th1/Th2 cytokines is a key feature of pulmonary fibrosis. Several recent papers have suggested that LTB4 functions not only as a local inflammatory mediator, but also as an important chemoattractant for T cells as well as neutrophils [1]. In an asthma model, BLT1 mediates LTB4induced Th1 and Th2 cell chemotaxis, forms adhesion to endothelial cells exposed to flow, and mediates CD4+ and CD8+ T-cell recruitment into the airway. Although the role of lymphocytes in the pathogenesis of the pulmonary fibrotic response has not been fully clarified, several studies have emphasized the importance and diverse roles of these cells in the fibrotic process [7].
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ROLE OF LEUKOTRIENE B4 RECEPTOR ANTAGONIST IN BLEOMYCIN-INDUCED PULMONARY FIBROSIS Bleomycin-induced pulmonary fibrosis has been widely used in C57BL/6 male mice by a single intratracheal injection 3
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of saline containing bleomycin. ONO-4057 is a non-selective BLTR antagonist that predominantly antagonizes BLT1, and has been reported to inhibit human neutrophil aggregation, chemotaxis, and degranulation induced by LTB4 [6,45]. We reported recently that ONO-4057 decreased the LTB4 level in BALF and ameliorated bleomycin-induced pulmonary inflammation and fibrosis. The neutrophil number and the LTB4 level in BALF were decreased by ONO-4057 [9], indicating that neutrophil chemotaxis, aggregation, and degranulation were suppressed. LTB4 and active transforming growth factor (TGF)-b1 levels in BALF were inhibited by ONO-4057. Neutrophils and epithelial cells immunostained positive for TGF-b, suggesting that these cells are the main source of TGF-b production. ONO-4057 probably inhibits neutrophiland macrophage-mediated inflammation by suppressing BLTRs on neutrophils and macrophages, and as a result inhibited TGF-b production especially by neutrophils. ONO4057 reduced the IL-13 level but not IL-4, and increased interferon-c in BALF. These results suggest that ONO-4057 may improve Th1/Th2 balance. However, compared with these cytokines, the IL-6 level in BALF was extremely elevated in our bleomycin-induced mouse model, and ONO-4057 clearly reduced IL-6. Several studies have demonstrated that IL-6 has both proinflammatory and anti-inflammatory properties [46]. IL-6 also exhibits negative feedback on the process of fibrosing. In fact, the IL-6 level of BALF is greatly increased in patients with IPF and in the bleomycin-induced model of pulmonary fibrosis [46]. High IL-6 levels are correlated with alveolar hypercellularity and neutrophil counts in IPF [47]. Recently, IL-6-deficient mice demonstrated attenuation in bleomycin-induced lung injury and fibrosis [48]. Therefore, one of the mechanisms for the inhibition of inflammation and fibrosis by ONO-4057 may be associated with the decrease in IL-6.
Corticosteroid therapy for pulmonary fibrosis is not effective and does not prevent the progression of fibrosis. Targeting of the LTB4/BLTR pathway may be an important strategy in the treatment of pulmonary fibrosis. Disclosure: The authors declare no conflict of interest. Acknowledgment: This work was supported, in part, by the Nagao Memorial Fund and a Hisako Yamakawa Award.
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ONO-4057 inhibited inflammation by a decrease in inflammatory cells including neutrophils, macrophages, and lymphocytes. The decrease in Ashcroft score and lung hydroxyproline content, the decrease in active TGF-b1 level in BALF, and the reduced TGF-b expression detected immunohistochemically in the lung sections indicated that ONO-4057 mitigated the development of fibrosis.
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CONCLUSION
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LTs have been shown to be important regulators in the development of pulmonary fibroproliferation. LTs directly influence inflammatory cells and alveolar cells, and exert indirect effects by modulating chemokines. Although it is about 30 years since LTB4 was discovered in 1979, recent research on BLTR antagonists has revealed the important roles of the LTB4/BLTR pathway in the pathophysiology of pulmonary diseases, such as bronchial asthma and pulmonary fibrosis [1,2,9]. Further understanding of the roles of multiple receptors for individual chemoattractants, such as BLT1 and BLT2, may give valuable insights into the complex regulation of inflammatory responses. Current therapy for pulmonary fibrosis is ineffective, and the disease has a poor outcome and is associated with severe morbidity. AoRM 2010; 000:(000). Month 2010
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