The long-term success of lung transplantation has been challenged by chronic graft dysfunction, which
is manifested as obliterative bronchiolitis (OB). We demonstrated that allograft airway fibrosis is a
dynamic process of tissue remodelling, in which cellular and matrix components dynamically change
before or after complete obliteration of the airway lumen. This dynamic process was associated with
changes in expression and activity of matrix metalloproteinases (MMPs). The early inflammatory
phase was associated with MMP-dependent migration of blood-borne fibrocytes, which highly express
MMP-9 and MMP-12. ‘Established’ fibrosis was associated with MMP-2 and MMP-14 expressed by
myofibroblasts in both human OB lesions and their animal models. In established allograft airway
fibrosis, general MMP inhibition resulted in apoptosis of myofibroblasts in vivo and in vitro, while
low-doses of MMP-inhibitor treatment induced upregulation of MMP-2, increased collagenolytic
activity, and significantly decreased myofibroblasts and collagen.
The dynamic process of tissue remodelling in established allograft airway fibrosis was supported by
underlying continuous alloimmune responses, in particular, direct T-cell-myofibroblast contact.
iii
Modulation of tissue remodelling using a low-dose MMP inhibitor in combination with cyclosporine
induced partial regression of fibrosis after its establishment.
We further demonstrated the mechanism of alloimmune responses unique to the lung. Human and
animal studies demonstrated that bronchioles develop de novo lymphoid tissue characterized by
formation of high endothelial venules and homing of effector memory T-cells. A following study
demonstrated the important role of local immunological memory maintained by the intrapulmonary
lymphoid tissue in exerting effector function in allograft rejection.
Collectively, the present studies support the hypothesis that tissue remodelling is an important
mechanism of allograft airway fibrosis. Regulation of tissue remodelling and underlying tissue injury is
important not only to arrest aberrant remodelling of allograft airways but likely to reverse aberrant
remodelling and to regenerate normal tissue architecture in airways after lung transplantation.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/17484 |
| Date | 30 July 2009 |
| Creators | Sato, Masaaki |
| Contributors | Keshavjee, Shaf |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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