Abstract
It has been suggested that alveolar and interstitial macrophages play a key role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) by producing proinflammatory and/or fibrogenic cytokines. We showed that inflammatory macrophages expressed folate receptor beta (FRbeta) while resident macrophages in normal tissues expressed no or low levels of FRbeta. In the present study, we examined the distribution of FRbeta-expressing macrophages in the lungs of patients with usual idiopathic pulmonary fibrosis (UIP) and mice with bleomycin-induced pulmonary fibrosis (PF) and tested whether the depletion of FRbeta-expressing macrophages could suppress bleomycin-induced PF in mice. Immunostaining with anti-human or -mouse FRbeta monoclonal antibody (mAb) revealed that FRbeta-expressing macrophages were present predominantly in fibrotic areas of the lungs of patients with UIP and mice with bleomycin-induced PF. Intranasal administration of a recombinant immunotoxin, consisting of immunoglobulin heavy and light chain Fv portions of an anti-mouse FRbeta mAb and truncated Pseudomonas exotoxin A, increased survival significantly and reduced levels of total hydroxyproline and fibrosis in bleomycin-induced PF. In immunohistochemical analysis, decreased numbers of tumour necrosis factor-alpha-, chemokines CCL2- and CCL12-producing cells were observed in the immunotoxin-treated group. These findings suggest a pathogenic role of FRbeta-expressing macrophages in IPF. Thus, targeting FRbeta-expressing macrophages may be a promising treatment of IPF.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADP Ribose Transferases / administration & dosage
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ADP Ribose Transferases / genetics
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ADP Ribose Transferases / pharmacology
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ADP Ribose Transferases / therapeutic use*
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Animals
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Antibodies, Monoclonal / genetics
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Antibodies, Monoclonal / immunology
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Antigens, CD / metabolism
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Antigens, Differentiation, Myelomonocytic / metabolism
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Bacterial Toxins / administration & dosage
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Bacterial Toxins / genetics
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Bacterial Toxins / pharmacology
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Bacterial Toxins / therapeutic use*
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Bleomycin / pharmacology*
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Carrier Proteins / immunology*
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Carrier Proteins / metabolism
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Chemokine CCL2 / metabolism
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Exotoxins / administration & dosage
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Exotoxins / genetics
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Exotoxins / pharmacology
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Exotoxins / therapeutic use*
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Folate Receptors, GPI-Anchored
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Humans
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Hydroxyproline / metabolism
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Idiopathic Pulmonary Fibrosis / pathology
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Immunoglobulin Fragments / genetics
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Immunotoxins / administration & dosage
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Immunotoxins / pharmacology
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Immunotoxins / therapeutic use*
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Lung / metabolism
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Lung / pathology
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Macrophages / drug effects
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Macrophages / metabolism
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Macrophages / pathology
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Macrophages, Alveolar / drug effects
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Macrophages, Alveolar / metabolism
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Macrophages, Alveolar / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Monocyte Chemoattractant Proteins / metabolism
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Pseudomonas aeruginosa Exotoxin A
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Pulmonary Fibrosis / chemically induced*
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Pulmonary Fibrosis / drug therapy*
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Pulmonary Fibrosis / pathology
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Receptors, Cell Surface / immunology*
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Receptors, Cell Surface / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / pharmacology
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Recombinant Fusion Proteins / therapeutic use
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Survival Analysis
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Transforming Growth Factor beta1 / metabolism
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Treatment Outcome
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Tumor Necrosis Factor-alpha / metabolism
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Virulence Factors / administration & dosage
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Virulence Factors / genetics
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Virulence Factors / pharmacology
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Virulence Factors / therapeutic use*
Substances
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Antibodies, Monoclonal
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Antigens, CD
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Antigens, Differentiation, Myelomonocytic
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Bacterial Toxins
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CD68 antigen, human
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Carrier Proteins
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Ccl12 protein, mouse
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Ccl2 protein, mouse
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Chemokine CCL2
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Exotoxins
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Folate Receptors, GPI-Anchored
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Immunoglobulin Fragments
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Immunotoxins
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Monocyte Chemoattractant Proteins
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Receptors, Cell Surface
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Recombinant Fusion Proteins
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Transforming Growth Factor beta1
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Tumor Necrosis Factor-alpha
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Virulence Factors
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Bleomycin
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ADP Ribose Transferases
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Hydroxyproline