Graft protective effects of heme oxygenase 1 in mouse tracheal transplant-related obliterative bronchiolitis1

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Abstract
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.

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