Allograft Airway Fibrosis in the Pulmonary Milieu: A Disorder of Tissue Remodeling

Abstract

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.

The Role of Intrapulmonary De Novo Lymphoid Tissue in Obliterative Bronchiolitis after Lung Transplantation

“…To overcome the challenge, we used an animal model of OB in which the allograft airway is exposed to the pulmonary milieu (22). In the model, we observed a larger number of lymphoid tissues in the lung after allograft transplantation compared with that of isografts (Fig.…”

“…For rat specimens, the following primary Abs reported to react with rat tissue were used: rabbit anti-human CD3 (DakoCytomation) and mouse anti-human CD79a (Abcam) for formalin-fixed paraffin-embedded or frozen sections; and mouse anti-rat mucosal addressin cell adhesion molecule (MAd-CAM)-1 (BD Biosciences), rabbit anti-human von Willebrand factor (Millipore), and anti-rat RT1A u (OX27; Serotec) for frozen sections. Immunofluorescence labeling was conducted as described previously (22).…”

“…A rat intrapulmonary tracheal transplant model of OB is an animal model of OB that reflects the influences of the pulmonary milieu (20,22). This model enables examination of the pulmonary immune system's reaction to allogenic stimuli.…”

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

“…Attempts to simulate airway fibrosis in the in vivo lung environment have also been made by placing the tracheal graft in the lung tissue through a transthoracic approach termed the intrapulmonary tracheal transplant model (61,106,107). Another potentially powerful model takes advantage of humanized mice by transplanting human airways and peripheral blood mononuclear cells into an immunodeficient mouse (108,109).…”

Obliterative Airway Remodeling

“…These changes demonstrate divergent histologic and radiologic findings, various potencies to progress to additional compartments of the lung, and different clinical outcomes. 1,2 At histologic analysis, two major variants can be distinguished. The first is varying degrees of discontinuous submucosal collagenous deposits that narrow the lumen of the bronchioli up to the point of total obliteration, referred to as "constrictive bronchiolitis."…”