Simultaneous LFA-1 and CD40 Ligand Antagonism Prevents Airway Remodeling in Orthotopic Airway Transplantation: Implications for the Role of Respiratory Epithelium as a Modulator of Fibrosis

Abstract

Airway remodeling is a prominent feature of certain immune-mediated lung diseases such as asthma and chronic lung transplant rejection. Under conditions of airway inflammation, the respiratory epithelium may serve an important role in this remodeling process. Given the proposed role of respiratory epithelium in nonspecific injury models, we investigated the respiratory epithelium in an immune-specific orthotopic airway transplant model. MHC-mismatched tracheal transplants in mice were used to generate alloimmune-mediated airway lesions. Attenuation of this immune injury and alteration of antidonor reactivity were achieved by the administration of combined anti-LFA-1/anti-CD40L mAbs. By contrast, without immunotherapy, transplanted airways remodeled with a flattening of respiratory epithelium and significant subepithelial fibrosis. Unopposed alloimmune injury for 10 days was associated with subsequent epithelial transformation and subepithelial fibrosis that could not be reversed with immunotherapy. The relining of donor airways with recipient-derived epithelium was delayed with immunotherapy resulting in partially chimeric airways by 28 days. Partial epithelial cell chimerism was sufficient to prevent luminal fibrosis. However, epithelial chimerism was also associated with airway remodeling. Therefore, there appears to be an intimate relationship between the morphology and level of chimerism of the respiratory epithelium and the degree of airway remodeling following alloimmune injury.

Adenovirus-mediated HIF-1α gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection

“…In these OTT studies, acute rejection is simply defined as the inflammatory phase that progresses to chronic rejection in the absence of early intervention with immunosuppression. Chronic rejection, which follows untreated acute rejection, is characterized by relatively less inflammation, increasing subepithelial fibrosis, and the development of a flattened, dysplastic epithelium (8,24). In our prior study (8), we further demonstrated that after prolonged ischemia, which begins on day 10, the airways eventually become neovascularized and that by day 28, there is evidence of partial restoration of blood flow.…”

Microvascular destruction identifies murine allografts that cannot be rescued from airway fibrosis

“…Allogeneic OTTs have previously been used as a model of lymphocytic bronchitis, the large airway correlate of BOS, developing both epithelial metaplasia and subepithelial fibrosis (9). In the present study, we delineate the interactions of host and recipient blood vessels after OTT and demonstrate that the resultant time-dependent loss of vascular perfusion in allografts corresponds to the presence of tissue hypoxia.…”

“…Data from this study suggest that a functional microvasculature is critical in the maintenance of normal airway architecture and may be a critical mechanistic link between inflammation and therapy-resistant rejection leading to fibrosis. Loss of CD31 + endothelium after 10 days of airway rejection is synchronous with columnar epithelial sloughing and dysplastic columnar epithelial replacement, a finding that has already been correlated to alloimmune airway fibrosis (9). Following complete revascularization of syngrafts and allografts by 6 days via connection of recipient vessels to preexisting donor vessels in the graft, allografts exhibit complement deposition and undergo immunologically mediated vessel destruction.…”

“…H&E-stained axial sections were used to measure the ratio of subepithelial height to epithelial height. This measure has been validated previously as correlating strongly with chronic rejection histologic scoring (9). Syngeneic grafts that were retransplanted maintained a normal ratio of approximately 1.…”

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

“…Although obliterative lesions are not observed, OTTs develop lymphocytic bronchitis (a large airway precursor of BOS) as well as subepithelial fibrosis (103). Findings from the OTT studies have been cautiously extrapolated to explain how occlusive fibrosis may evolve following rejection in higher generation bronchioles (77,80,83,104,105).…”