Graft protective effects of heme oxygenase 1 in mouse tracheal transplant-related obliterative bronchiolitis.
BACKGROUND
Heme oxygenase (HO)-1, long believed to be a cytoprotective protein, has recently been identified as a graft survival gene. This study evaluates the role of HO-1 in a murine heterotopic tracheal allograft model for obliterative bronchiolitis.


METHODS
Mice with deficient or experimentally enhanced HO-1 expression underwent subcutaneous implantation of murine tracheal isografts and allografts. Grafts were excised after 9, 16, or 21 days and evaluated by histologic examination, immunohistochemistry for HO-1 and interleukin (IL)-10 proteins, and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling. To evaluate the relationships between IL-10 and HO-1, the effects of modulation of HO-1 expression on IL-10 expression were evaluated and HO-1 expression was examined in tracheal transplants from IL-10 null mice.


RESULTS
Isografts demonstrated normal histology with minimal HO-1 staining, whereas allografts showed features of human airway rejection (loss of respiratory epithelium, luminal granulation tissue, lymphocytic tracheitis) with increased HO-1 staining in macrophages and mesenchymal cells. HO-1-deficient mice demonstrated a more rapid progression of the tracheal allograft injury as compared with control allografts, and this was associated with a decrease in the anti-inflammatory cytokine, IL-10. Tracheal transplants using IL-10-deficient mice also resulted in a more severe injury, and this was accompanied by a decrease in HO-1 staining.


CONCLUSIONS
HO-1 protein expression is increased in murine heterotopic airway rejection, and deficiency of HO-1 accelerates the development of the obliterative bronchiolitis-like lesion. IL-10 protein expression parallels expression of HO-1, suggesting that IL-10 may participate in the genesis of HO-1's effects on the inflammatory processes triggered by allotransplantation.
Visner
Gary A
GA
Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA. visnega@peds.ufl.edu.
Lu
Fuhua
F
Zhou
Hailan
H
Latham
Christopher
C
Agarwal
Anupam
A
Zander
Dani S
DS
D000818:Animals; D001989:Bronchiolitis Obliterans / Q000517:prevention & control*; D003094:Collagen / Q000378:metabolism; D006084:Graft Rejection; D006419:Heme Oxygenase (Decyclizing) / Q000032:analysis / Q000502:physiology*; D051547:Heme Oxygenase-1; D020287:In Situ Nick-End Labeling; D016753:Interleukin-10 / Q000502:physiology; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D014132:Trachea / Q000201:enzymology / Q000637:transplantation*; D014184:Transplantation, Homologous
D008565:Membrane Proteins; D016753:Interleukin-10; D003094:Collagen; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse