Up-regulation of inducible nitric oxide synthase in fibroblasts parallels the onset and progression of fibrosis in an experimental model of post-transplant obliterative airway disease

The main cause of mortality following lung transplantation is chronic rejec tion, manifesting morphologically as obliterative bronchiolitis (OB), it ha s been suggested that damage to the respiratory epithelium initiates prolif eration of mesenchymal cells, leading to dense collagenous scarring in smal l 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 exa mine further the role of iNOS in this process, heterotopic airway implants were studied in rats, an acknowledged disease model. Specimens of iso- or a llografted trachea, collected 3-60 days after implantation, were processed for histology and immunocytochemistry for iNOS and, as a marker of peroxyni trite formation, nitrotyrosine. In both iso- and allografts at the earliest stage (day 3), ischaemia was associated with severe epithelial damage or l oss. These changes progressed until day 7 and were accompanied by strong ex pression of iNOS and nitrotyrosine in epithelial cells, In isografts, epith elial recovery was seen, with abundant iNOS immunoreactivity but little nit rotyrosine. In contrast, the epithelium in allografts did not regenerate an d progressive inflammation and fibroproliferation occurred until complete o bliteration of the tracheal lumen at day 60. The fibroproliferation was ass ociated with changes in morphology of fibroblasts that were accompanied by alterations in their iNOS expression. iNOS immunoreactivity was dense in th e plump fibroblasts of early lesions, in some cases as early as post-operat ive day 5, but very weak in elongated fibroblasts in totally occluded graft s. The intensity of immunoreactivity for nitrotyrosine corresponded to that of iNOS. These results indicate a dual role for NO in the airway obliterat ion that follows transplantation, through destruction of epithelium and sti mulation of fibroblast activity, Copyright (C) 2000 John Wiley & Sons, Ltd.