Broad-spectrum chemokine inhibition ameliorates experimental obliterative bronchiolitis.
BACKGROUND
Obliterative bronchiolitis (OB) affects over half of all long-term survivors after lung transplantation. Respiratory epithelial cell injury, peribronchial inflammation, and proliferation of fibrovascular connective tissue causing airway occlusion characterize this lesion. Several chemokines participate in experimental OB, and singular blockade is only partially effective. We hypothesized that a broad-spectrum chemokine inhibitor would be an effective intervention in preventing the progression of OB in an established heterotopic tracheal transplantation model.


METHODS
Tracheas from Brown-Norway or Lewis rats were transplanted subcutaneously into Lewis recipients. Treated, allogeneic recipients received either a broad-spectrum chemokine inhibitor in its active (NR58.3.14.3) or inactive (NR58.3.14.4) form at a dose of 30 mg/kg daily. Luminal obstruction, epithelial loss, leukocytic infiltrates, and inflammatory cytokine mRNA levels were assessed in explanted tracheal samples 14 days after transplantation.


RESULTS
After 14 days, allografts receiving the inactive chemokine inhibitor demonstrated marked peribronchial inflammation, near complete loss of respiratory epithelium, and extensive intraluminal proliferation of fibrovascular connective tissue, with a mean 84% +/- 5% reduction in airway lumen cross-sectional area. Isografts showed limited inflammation, with minimal loss of epithelium and luminal occlusion. Allogeneic recipients treated with the active chemokine inhibitor showed a significant preservation of respiratory epithelium, minimal peribronchial inflammation, and a marked decrease in the loss of airway cross-sectional area (23% +/- 1%) (p < 0.001).


CONCLUSIONS
These findings further characterize the participation of chemokines in OB, and suggest that broad-spectrum chemokine inhibition may potentially be a useful therapeutic tool in slowing the progression of this disease.
Naidu
Babu V
BV
Division of Cardiothoracic Surgery, Department of Surgery, University of Washington, Seattle, Washington, USA.
Farivar
Alexander S
AS
Krishnadasan
Baiya
B
Woolley
Steven M
SM
Grainger
David J
DJ
Verrier
Edward D
ED
Mulligan
Michael S
MS
D000818:Animals; D001989:Bronchiolitis Obliterans / Q000188:drug therapy* / Q000517:prevention & control; D018925:Chemokines / Q000037:antagonists & inhibitors* / Q000502:physiology; D018450:Disease Progression; D008297:Male; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000627:therapeutic use*; D011183:Postoperative Complications / Q000188:drug therapy / Q000517:prevention & control; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D014132:Trachea / Q000473:pathology / Q000637:transplantation
D018925:Chemokines; D010456:Peptides, Cyclic; C411952:cyclo(cysteinyl-glutaminyl-isoleucyl-tryptophyl-lysyl-glutaminyl-lysyl-prolyl-aspartyl-leucyl-cysteinyl-amide)