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Obliterative bronchiolitis (OB) is thought to be a form of chronic allograft rejection. However, immunosuppressive therapy is not effective once fibrosis has developed. We hypothesize that disordered tissue remodeling is a mechanism for the pathogenesis of OB. We examined allograft airway fibrosis in an intrapulmonary tracheal transplant model of OB. Allograft airways were completely obliterated at day 21 by fibrotic tissue; however, tissue remodeling continued thereafter, as demonstrated by the change of collagen deposition density, shift from type I to type III collagen, shift from fibroblasts to myofibroblasts and shift of expression profiles and activities of matrix metalloproteinases (MMPs). We then used a broad-spectrum MMP inhibitor, SC080, to attempt to manipulate tissue remodeling. Administration of the MMP inhibitor from day 0 to day 28 reduced airway obliteration, without inhibiting T-cell activation. MMP inhibition from day 14 to day 28 showed similar effects on airway obliteration. MMP inhibition from day 21 to day 35 did not reverse the airway obliteration, but significantly reduced the collagen deposition, type III collagen and myofibroblasts in the lumen. We conclude that tissue remodeling plays a critical role in the development and maintenance of fibrosis after transplantation.

Heme oxygenase-1 (HO-1) has been found to be a cytoprotective protein, and has recently been identified as a graft survival gene. This study demonstrates that HO-1 expression is increased in human lung allografts with acute cellular rejection and obliterative bronchiolitis. HO-1 expression was correlated with increased tissue iron and/or ferritin expression and increased inflammatory/oxidant load as measured by myeloperoxidase expression. Although the trigger for increased HO-1 expression in this setting is unknown, it may be related to hemorrhage and/or oxidative stress associated with rejection.

The main cause of mortality following lung transplantation is chronic rejection, manifesting morphologically as obliterative bronchiolitis (OB). It has been suggested that damage to the respiratory epithelium initiates proliferation of mesenchymal cells, leading to dense collagenous scarring in small airways. Inducible nitric oxide synthase (iNOS) is strongly expressed in the damaged epithelium in human OB, along with high levels of peroxynitrite, suggesting that endogenous NO mediates the epithelial destruction. To examine further the role of iNOS in this process, heterotopic airway implants were studied in rats, an acknowledged disease model. Specimens of iso- or allografted trachea, collected 3-60 days after implantation, were processed for histology and immunocytochemistry for iNOS and, as a marker of peroxynitrite formation, nitrotyrosine. In both iso- and allografts at the earliest stage (day 3), ischaemia was associated with severe epithelial damage or loss. These changes progressed until day 7 and were accompanied by strong expression of iNOS and nitrotyrosine in epithelial cells. In isografts, epithelial recovery was seen, with abundant iNOS immunoreactivity but little nitrotyrosine. In contrast, the epithelium in allografts did not regenerate and progressive inflammation and fibroproliferation occurred until complete obliteration of the tracheal lumen at day 60. The fibroproliferation was associated with changes in morphology of fibroblasts that were accompanied by alterations in their iNOS expression. iNOS immunoreactivity was dense in the plump fibroblasts of early lesions, in some cases as early as post-operative day 5, but very weak in elongated fibroblasts in totally occluded grafts. The intensity of immunoreactivity for nitrotyrosine corresponded to that of iNOS. These results indicate a dual role for NO in the airway obliteration that follows transplantation, through destruction of epithelium and stimulation of fibroblast activity., (Copyright 2000 John Wiley & Sons, Ltd.)