A relevant experimental model for human bronchiolitis obliterans syndrome.
BACKGROUND
The long-term success of human lung transplantation is limited by the development of bronchiolitis obliterans syndrome. Acute rejection episodes and infections are important risk factors and seem to play major pathogenic roles. We established a relevant experimental model that mimics important aspects of human bronchiolitis obliterans syndrome.


METHODS
The Fischer 344-to-Lewis rat strain combination was used for orthotopic left lung transplantation. Isogeneic transplantations were performed in the Lewis rat. Recipients were treated with ciclosporin for 10 days. Lipopolysaccharide or vehicle was instilled into the airways 28 days after transplantation. Grafts were monitored by computed tomography, and recipients were euthanized on Days 28-90. The messenger RNA expression of selected chemokines and their receptors was measured on Days 28, 29, 33, 40 after transplantation. Graft histopathology on Day 90 was compared with lungs from patients who underwent re-transplantation due to end-stage allograft dysfunction.


RESULTS
Lung allografts treated with ciclosporin and vehicle only sporadically displayed tissue remodeling. In contrast, lipopolysaccharide treatment induced severe inflammation. In the long-term, severe vascular remodeling, lung fibrosis, and fibroproliferative remodeling of airways were found that closely resemble the histopathologic changes in grafts from human patients with bronchiolitis obliterans syndrome. Chronic damage was virtually absent from pulmonary isografts and native right lungs. Chemokine (C-C motif) ligand 5 and chemokine (C-X-C motif) ligand 9-11, and their receptors, were over-expressed in allografts.


CONCLUSIONS
Our experimental model mirrors key aspects of human bronchiolitis obliterans syndrome. It will be useful to elucidate its pathogenesis and to develop therapeutic approaches improving the long-term outcome of human lung transplantation.
Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, Giessen, Member of the German Center for Lung Research (DZL).
Srebrena
S
Atanasova
Markus
M
Hirschburger
Danny
D
Jonigk
Martin
M
Obert
Kathrin
K
Petri
Alena
A
Evers
Andreas
A
Hecker
Jessica
J
Schmitz
Andreas
A
Kaufmann
Jochen
J
Wilhelm
Trinad
T
Chakraborty
Gregor
G
Warnecke
Jens
J
Gottlieb
Winfried
W
Padberg
Veronika
V
Grau
D000818:Animals; D001989:Bronchiolitis Obliterans / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007165:Immunosuppression Therapy; D008070:Lipopolysaccharides / Q000009:adverse effects; D008168:Lung / Q000378:metabolism / Q000473:pathology; D016040:Lung Transplantation; D011183:Postoperative Complications / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D012307:Risk Factors; D013577:Syndrome; D051193:Toll-Like Receptors / Q000378:metabolism
D018925:Chemokines; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors
chemokines; chronic allograft damage; cytokines; lipopolysaccharide; lung transplantation; pulmonary vascular remodeling