title: The Selective JAK1/3-Inhibitor R507 Mitigates Obliterative Airway Disease Both With Systemic Administration and Aerosol Inhalation.
abstract: The efficacy of selective Janus kinase 1/3 inhibitor R507 to prevent obliterative airway disease was analyzed in preclinical airway transplantation models.
  
  
  
  Orthotopic trachea transplantations were performed between Lewis donors and Brown Norway rat recipients. Oral everolimus (4 mg/kg once per day) or oral respective inhaled R507 (60 mg/kg twice per day, each) was used for immunosuppression. Grafts were retrieved after 6 or 60 days. Toxicity and anti-inflammatory effects of R507 were analyzed on human airway epithelial cells.
  
  
  
  In 6-day animals, oral and inhaled R507 more potently diminished mononuclear graft infiltration than everolimus and preserved ciliated pseudostratified columnar respiratory epithelium. Everolimus and R507 similarly suppressed systemic cellular and humoral immune activation. In untreated rats, marked obliterative airway disease developed over 60 days. Oral and inhaled R507 was significantly more effective in reducing airway obliteration and preserved the morphology of the airway epithelium. Luciferase-positive donors revealed that a substantial amount of smooth muscle cells within the obliterative tissue was of donor origin. Only everolimus but not R507, adversely altered kidney function and lipid profiles. The R507 aerosol did not show airway toxicity in vitro but effectively suppressed activation of inflammatory signaling pathways induced by IL-1β.
  
  
  
  The Janus kinase 1/3 inhibitor R507 is a very well-tolerated immunosuppressant that similarly diminished obliterative airway disease with systemic or inhaled administration.
authors.affiliation: 1 TSI Laboratory, University Heart Center Hamburg, Hamburg, Germany. 2 Cardiovascular Research Center Hamburg (CVRC) and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, Hamburg, Germany. 3 Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany. 4 Department of Surgery, TSI Laboratory, University of California San Francsico (UCSF), San Francsico, CA. 5 Cardiovascular Medicine and Stanford Cardiovascular Institute, Stanford University, Stanford, CA. 6 Department of Anaesthesiology, University Hospital Hamburg, Hamburg, Germany. 7 Rigel Pharmaceuticals, South San Francisco, CA. 8 Aerogen Ltd, Galway, Ireland. 9 Department of Clinical Chemistry, University Medical Center Hamburg, Hamburg, Germany. 10 Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden. 11Department of Cardiothoracic Surgery, Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Deuse
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Hua
authors.forename: Mandy
authors.initials: M
authors.lastname: Stubbendorff
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Spin
authors.forename: Evgenios
authors.initials: E
authors.lastname: Neofytou
authors.forename: Vanessa
authors.initials: V
authors.lastname: Taylor
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Gary
authors.initials: G
authors.lastname: Park
authors.forename: James B
authors.initials: JB
authors.lastname: Fink
authors.forename: Thomas
authors.initials: T
authors.lastname: Renne
authors.forename: Martina
authors.initials: M
authors.lastname: Kiefmann
authors.forename: Rainer
authors.initials: R
authors.lastname: Kiefmann
authors.forename: Hermann
authors.initials: H
authors.lastname: Reichenspurner
authors.forename: Robert C
authors.initials: RC
authors.lastname: Robbins
authors.forename: Sonja
authors.initials: S
authors.lastname: Schrepfer
mesh_terms: D000280:Administration, Inhalation; D000284:Administration, Oral; D000336:Aerosols / Q000737:chemistry; D000818:Animals; D001989:Bronchiolitis Obliterans / Q000517:prevention & control*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism; D000068338:Everolimus / Q000008:administration & dosage; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors*; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008856:Microscopy, Fluorescence; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction; D014132:Trachea / Q000637:transplantation*; D016896:Treatment Outcome
chemical_list: D000336:Aerosols; D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; D000068338:Everolimus; D007770:L-Lactate Dehydrogenase; C507905:Jak1 protein, mouse; C507935:Jak3 protein, mouse; D053613:Janus Kinase 1; D053616:Janus Kinase 3