title: Therapeutic attenuation of pulmonary fibrosis via targeting of IL-4- and IL-13-responsive cells.
abstract: Severe forms of idiopathic interstitial pneumonia (IIP), such as usual interstitial pneumonia, can be impervious to modern steroid and immunosuppressive treatment regimens, thereby emphasizing the need for novel effective therapies. Consequently, research attention has been directed toward understanding the cytokine networks that may affect fibroblast activation and, hence, the progression of certain IIPs. This led us to investigate whether the specific targeting of resident lung cells responsive to IL-4 and IL-13 exerted a therapeutic effect in an experimental model of IIP, namely the bleomycin-induced model of pulmonary fibrosis. IL-4, IL-13, and their corresponding receptor subunits, IL-4Ralpha, IL-13Ralpha1, and IL-13Ralpha2, were maximally expressed at the mRNA and protein levels in whole lung samples on day 21 or 28 after an intratracheal bleomycin challenge. The intranasal administration of an IL-13 immunotoxin chimeric molecule (IL13-PE) from days 21-28, but not for 1-wk periods at earlier times, after bleomycin challenge had a significant therapeutic effect on histological and biochemical parameters of bleomycin-induced pulmonary fibrosis compared with the control group. The intranasal IL13-PE therapy significantly reduced the numbers of IL-4 and IL-13 receptor-positive mononuclear cells and macrophages and the levels of profibrotic cytokine and chemokine in the lungs of bleomycin-challenged mice on day 28. Thus, this study demonstrates that IL-4- and/or IL-13-binding cells are required for the maintenance of pulmonary fibrosis induced by bleomycin and highlights the importance of further investigation of antifibrotic therapeutics that target these cells during pulmonary fibrosis.
authors.affiliation: Department of Pathology, University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, MI 48109, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Jakubzick
authors.forename: Esther S
authors.initials: ES
authors.lastname: Choi
authors.forename: Bharat H
authors.initials: BH
authors.lastname: Joshi
authors.forename: Michael P
authors.initials: MP
authors.lastname: Keane
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: Raj K
authors.initials: RK
authors.lastname: Puri
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001761:Bleomycin / Q000008:administration & dosage; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D018390:Gene Targeting / Q000379:methods; D000922:Immunotoxins / Q000008:administration & dosage / Q000627:therapeutic use; D018793:Interleukin-13 / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics / Q000627:therapeutic use; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D011347:Procollagen / Q000096:biosynthesis / Q000235:genetics; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control / Q000628:therapy*; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: D018925:Chemokines; D016207:Cytokines; C508183:Il13ra1 protein, mouse; D000922:Immunotoxins; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D011347:Procollagen; D021122:Protein Subunits; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4; D001761:Bleomycin; D015847:Interleukin-4