FR167653 reduces obliterative airway disease in rats

Autor: Michael S. Mulligan, Jane Namkung, Brendan C. Mackinnon-Patterson, Steven M Woolley, Akira Shimamoto, Edward D. Verrier, Alexander S. Farivar
Rok vydání: 2004
Předmět:
Male
Pulmonary and Respiratory Medicine
Pathology
medicine.medical_specialty
Time Factors
Transcription
Genetic
Pyridines
medicine.medical_treatment
Bronchiolitis obliterans
Electrophoretic Mobility Shift Assay
p38 Mitogen-Activated Protein Kinases
Andrology
Transactivation
Postoperative Complications
medicine
Animals
Transplantation
Homologous
Lung transplantation
RNA
Messenger
Respiratory system
Bronchiolitis Obliterans
Transplantation
Lung
Reverse Transcriptase Polymerase Chain Reaction
Tumor Necrosis Factor-alpha
business.industry
Anti-Inflammatory Agents
Non-Steroidal
NF-kappa B
Interleukin
medicine.disease
Immunohistochemistry
Rats
medicine.anatomical_structure
Rats
Inbred Lew
Models
Animal
Pyrazoles
Surgery
Tumor necrosis factor alpha
Cardiology and Cardiovascular Medicine
business
Interleukin-1
Lung Transplantation
Zdroj: The Journal of Heart and Lung Transplantation. 23:985-992
ISSN: 1053-2498
DOI: 10.1016/j.healun.2004.04.008
Popis: Obliterative bronchiolitis (OB) is the main cause of late mortality among long-term survivors of lung transplantation. Although p38 kinase is functional in multiple acute inflammatory injury models, its role in chronic lung rejection is undefined. p38 regulates the expression of the cytokines tumor necrosis (TNF)-alpha and interleukin (IL)-1beta, 2 mediators involved in the development of OB in a tracheal transplant model. These studies assessed whether specific inhibition of p38 with FR167653 (FR) protects against the development of OB in rat tracheal allografts.Rat airways were heterotopically transplanted from Brown-Norway donors into Lewis recipients, and animals were sacrificed on day 14 (6 per group). Treated animals received 10 mg/kg daily of FR intraperitoneally beginning either immediately or at day 7 after transplant. Allografts were assessed by computerized morphometry, and tracheas were processed for TNF-alpha mRNA and protein expression by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry, respectively. Electrophoretic mobility shift assays evaluated nuclear factor kappa beta (NFkappaB) transactivation.Control allografts averaged 61% occlusion and 98% loss of epithelium at 14 days, whereas FR administration reduced luminal occlusion to 28% (p0.001) and epithelial loss to 71% (p0.001). Delayed treatment beginning on day 7 slowed progression of disease, as tracheal occlusion averaged 44% and epithelial loss averaged 80%, both of which were significant (p0.05) improvements relative to 14-day controls. NFkappa transactivation (p0.004) and TNF-alpha mRNA and protein expression were reduced dramatically by FR at 14 days.A specific p38 inhibitor, FR 167653, ameliorates obliterative airway disease in rat tracheal allografts via attenuated NFkappaB transactivation, which ultimately results in diminished TNF-alpha mRNA and protein expression.
Databáze: OpenAIRE
Externí odkaz: