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The Selective JAK1/3-Inhibitor R507 Mitigates Obliterative Airway Disease Both With Systemic Administration and Aerosol Inhalation.
- Source :
-
Transplantation [Transplantation] 2016 May; Vol. 100 (5), pp. 1022-31. - Publication Year :
- 2016
-
Abstract
- Background: The efficacy of selective Janus kinase 1/3 inhibitor R507 to prevent obliterative airway disease was analyzed in preclinical airway transplantation models.<br />Methods: 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.<br />Results: 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.<br />Conclusions: The Janus kinase 1/3 inhibitor R507 is a very well-tolerated immunosuppressant that similarly diminished obliterative airway disease with systemic or inhaled administration.
- Subjects :
- Administration, Inhalation
Administration, Oral
Aerosols chemistry
Animals
Cells, Cultured
Epithelial Cells metabolism
Everolimus administration & dosage
Humans
L-Lactate Dehydrogenase metabolism
Microscopy, Fluorescence
Oligonucleotide Array Sequence Analysis
Rats
Rats, Inbred Lew
Signal Transduction
Treatment Outcome
Bronchiolitis Obliterans prevention & control
Immunosuppressive Agents administration & dosage
Janus Kinase 1 antagonists & inhibitors
Janus Kinase 3 antagonists & inhibitors
Protein Kinase Inhibitors administration & dosage
Trachea transplantation
Subjects
Details
- Language :
- English
- ISSN :
- 1534-6080
- Volume :
- 100
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Transplantation
- Publication Type :
- Academic Journal
- Accession number :
- 26910327
- Full Text :
- https://doi.org/10.1097/TP.0000000000001110