title: The Causal Role of IL-4 and IL-13 in Schistosoma mansoni Pulmonary Hypertension.
abstract: BACKGROUND
  The etiology of schistosomiasis-associated pulmonary arterial hypertension (PAH), a major cause of PAH worldwide, is poorly understood. Schistosoma mansoni exposure results in prototypical type-2 inflammation. Furthermore, transforming growth factor (TGF)-β signaling is required for experimental pulmonary hypertension (PH) caused by Schistosoma exposure.
  
  
  OBJECTIVE
  We hypothesized type-2 inflammation driven by IL-4 and IL-13 is necessary for Schistosoma-induced TGF-β-dependent vascular remodeling.
  
  
  METHODS
  Wild-type, IL-4(-/-), IL-13(-/-), and IL-4(-/-)IL-13(-/-) mice (C57BL6/J background) were intraperitoneally sensitized and intravenously challenged with S. mansoni eggs to induce experimental PH. Right ventricular catheterization was then performed, followed by quantitative analysis of the lung tissue. Lung tissue from patients with schistosomiasis-associated and connective tissue disease-associated PAH was also systematically analyzed.
  
  
  RESULTS
  Mice with experimental Schistosoma-induced PH had evidence of increased IL-4 and IL-13 signaling. IL-4(-/-)IL-13(-/-) mice, but not single knockout IL-4(-/-) or IL-13(-/-) mice, were protected from Schistosoma-induced PH, with decreased right ventricular pressures, pulmonary vascular remodeling, and right ventricular hypertrophy. IL-4(-/-)IL-13(-/-) mice had less pulmonary vascular phospho-signal transducer and activator of transcription 6 (STAT6) and phospho-Smad2/3 activity, potentially caused by decreased TGF-β activation by macrophages. In vivo treatment with a STAT6 inhibitor and IL-4(-/-)IL-13(-/-) bone marrow transplantation also protected against Schistosoma-PH. Lung tissue from patients with schistosomiasis-associated and connective tissue disease-associated PAH had evidence of type-2 inflammation.
  
  
  CONCLUSIONS
  Combined IL-4 and IL-13 deficiency is required for protection against TGF-β-induced pulmonary vascular disease after Schistosoma exposure, and targeted inhibition of this pathway is a potential novel therapeutic approach for patients with schistosomiasis-associated PAH.
authors.affiliation: 1 Program in Translational Lung Research, Department of Medicine, Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kumar
authors.affiliation: 1 Program in Translational Lung Research, Department of Medicine, Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mickael
authors.affiliation: 1 Program in Translational Lung Research, Department of Medicine, Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Jacob
authors.initials: J
authors.lastname: Chabon
authors.affiliation: 1 Program in Translational Lung Research, Department of Medicine, Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Liya
authors.initials: L
authors.lastname: Gebreab
authors.affiliation: 1 Program in Translational Lung Research, Department of Medicine, Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Alleluiah
authors.initials: A
authors.lastname: Rutebemberwa
authors.affiliation: 1 Program in Translational Lung Research, Department of Medicine, Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Alexandra Rodriguez
authors.initials: AR
authors.lastname: Garcia
authors.affiliation: 1 Program in Translational Lung Research, Department of Medicine, Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Koyanagi
authors.affiliation: 1 Program in Translational Lung Research, Department of Medicine, Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Linda
authors.initials: L
authors.lastname: Sanders
authors.affiliation: 1 Program in Translational Lung Research, Department of Medicine, Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Aneta
authors.initials: A
authors.lastname: Gandjeva
authors.affiliation: 2 Department of Medicine, National Jewish Health, Denver, Colorado.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Kearns
authors.affiliation: 2 Department of Medicine, National Jewish Health, Denver, Colorado.
authors.forename: Lea
authors.initials: L
authors.lastname: Barthel
authors.affiliation: 2 Department of Medicine, National Jewish Health, Denver, Colorado.
authors.forename: William J
authors.initials: WJ
authors.lastname: Janssen
authors.affiliation: 3 Department of Pathology, Sao Paulo University Medical School, Sao Paulo, Brazil; and.
authors.forename: Thais
authors.initials: T
authors.lastname: Mauad
authors.affiliation: 4 Department of Medicine, Memorial S. Jose Hospital, Universidade de Pernambuco, Recife, Brazil.
authors.forename: Angela
authors.initials: A
authors.lastname: Bandeira
authors.affiliation: 1 Program in Translational Lung Research, Department of Medicine, Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Eric
authors.initials: E
authors.lastname: Schmidt
authors.affiliation: 1 Program in Translational Lung Research, Department of Medicine, Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
authors.affiliation: 1 Program in Translational Lung Research, Department of Medicine, Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Graham
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000276:immunology*; D007249:Inflammation; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology*; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology*; D053662:Interleukin-4 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D050800:STAT6 Transcription Factor / Q000276:immunology / Q000378:metabolism; D012550:Schistosoma mansoni; D012555:Schistosomiasis mansoni / Q000150:complications / Q000276:immunology*; D051899:Smad2 Protein / Q000276:immunology / Q000378:metabolism; D051900:Smad3 Protein / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology; D066253:Vascular Remodeling
chemical_list: D015815:Cell Adhesion Molecules; C504000:IL4R protein, human; D036341:Intercellular Signaling Peptides and Proteins; D018793:Interleukin-13; D053662:Interleukin-4 Receptor alpha Subunit; C512835:POSTN protein, human; C486574:RETNLB protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C494100:Stat6 protein, mouse; D016212:Transforming Growth Factor beta; D015847:Interleukin-4
keywords: Th2 cells; pulmonary hypertension; schistosomiasis; transforming growth factor-β