Beyond Chronic Rejection: Tissue Remodelling in Obliterative Bronchiolitis after Lung Transplantation
Year: 2009
Type: dissertation
Abstract: The long-term success of lung transplantation has been challenged by chronic graft dysfunction, which\nis manifested as obliterative bronchiolitis (OB). We demonstrated that allograft airway fibrosis is a\ndynamic process of tissue remodelling, in which cellular and matrix components dynamically change\nbefore or after complete obliteration of the airway lumen. This dynamic process was associated with\nchanges in expression and activity of matrix metalloproteinases (MMPs). The early inflammatory\nphase was associated with MMP-dependent migration of blood-borne fibrocytes, which highly express\nMMP-9 and MMP-12. ‘Established’ fibrosis was associated with MMP-2 and MMP-14 expressed by\nmyofibroblasts in both human OB lesions and their animal models. In established allograft airway\nfibrosis, general MMP inhibition resulted in apoptosis of myofibroblasts in vivo and in vitro, while\nlow-doses of MMP-inhibitor treatment induced upregulation of MMP-2, increased collagenolytic\nactivity, and significantly decreased myofibroblasts and collagen.\nThe dynamic process of tissue remodelling in established allograft airway fibrosis was supported by\nunderlying continuous alloimmune responses, in particular, direct T-cell-myofibroblast contact.\niii\nModulation of tissue remodelling using a low-dose MMP inhibitor in combination with cyclosporine\ninduced partial regression of fibrosis after its establishment.\nWe further demonstrated the mechanism of alloimmune responses unique to the lung. Human and\nanimal studies demonstrated that bronchioles develop de novo lymphoid tissue characterized by\nformation of high endothelial venules and homing of effector memory T-cells. A following study\ndemonstrated the important role of local immunological memory maintained by the intrapulmonary\nlymphoid tissue in exerting effector function in allograft rejection.\nCollectively, the present studies support the hypothesis that tissue remodelling is an important\nmechanism of allograft airway fibrosis. Regulation of tissue remodelling and underlying tissue injury is\nimportant not only to arrest aberrant remodelling of allograft airways but likely to reverse aberrant\nremodelling and to regenerate normal tissue architecture in airways after lung transplantation.
Source: TSpace (University of Toronto)
Author: Masaaki Sato
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2499197682