FR167653 reduces obliterative airway disease in rats.
BACKGROUND
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.


METHODS
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.


RESULTS
Control allografts averaged 61% occlusion and 98% loss of epithelium at 14 days, whereas FR administration reduced luminal occlusion to 28% (p < 0.001) and epithelial loss to 71% (p < 0.001). 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 (p < 0.05) improvements relative to 14-day controls. NFkappa transactivation (p < 0.004) and TNF-alpha mRNA and protein expression were reduced dramatically by FR at 14 days.


CONCLUSIONS
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.
Department of Surgery, Division of Cardiothoracic Surgery, University of Washington Medical Center, 1959 NE Pacific Street, Seattle, WA 98195, USA. afarivar@u.washington.edu
Alexander S
AS
Farivar
Brendan
B
Mackinnon-Patterson
Steven
S
Woolley
Jane
J
Namkung
Akira
A
Shimamoto
Edward D
ED
Verrier
Michael S
MS
Mulligan
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001989:Bronchiolitis Obliterans / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000032:analysis; D016040:Lung Transplantation; D008297:Male; D023421:Models, Animal; D016328:NF-kappa B / Q000378:metabolism; D011183:Postoperative Complications / Q000628:therapy; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D000894:Anti-Inflammatory Agents, Non-Steroidal; C104334:FR 167653; D007375:Interleukin-1; D016328:NF-kappa B; D011720:Pyrazoles; D011725:Pyridines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases