Obliterative bronchiolitis (OB) is a process of chronic rejection after lung transplantation and is a major challenge for long-term survival. In fact, if there was effective therapy for OB then lung transplantation might be considered a potentially curative procedure. OB is characterized by an inflammatory response and fibrosing intraluminal granulation tissue in small airways leading to airflow obstruction and death. Increased levels of matrix metalloproteinase-8 (MMP-8) have been reported in OB but the biological role of MMP-8 in OB is not known. MMP-8 is an interstitial collagenase, highly expressed by polymorphonuclear cells (PMNs), and also present in fibroblasts. The central hypothesis of this proposal is that MMP-8 promotes accumulation of PMNs in OB lesions by promoting their migration through the extracellular matrix protein barriers, and facilitates fibroblast migration by processing mediators that regulate fibrosis. Preliminary data in support of these hypotheses shows that MMP-8 null mice are protected against OB in a heterotopic airway transplant model with less luminal obliteration, PMN recruitment, and fibrosis. Further, anti-fibrotic cytokine interteron gamma-inducible protein 10kD (IP-10) is processed by MMP-8 and increased levels are present in MMP-8 -/- mice compared to wild-type mice. The primary goal of this study is to delineate the molecular mechanisms by which MMP-8 modulates inflammatory and fibrotic responses in OB. The secondary goal is to develop a novel in vivo transgenic mouse model of OB. To date, the only reported mouse model of OB is the heterotopic airway transplant model, as the small size of the mouse lung precludes lung transplantation.
The Specific Aims of this project are to 1) identify the molecular mechanisms for recruitment of PMNs into the airway lumen of MMP-8-/- mice in a heterotopic airway transplant model of OB, 2) elucidate the molecular mechanisms for reduced fibrosis in MMP-8-/- mice in OB and 3) generate a novel in vivo model of chronic rejection in the lung as a model of OB. In this model MHC class I disparate molecules will be targeted specifically to the small airways of mice, to non-surgically generate the equivalent of a lung transplant in the mouse. This work will clarify the role of MMP-8 in the pathophysiology of OB and may suggest new insights into MMP-8-blockade as a novel therapeutic target to ameliorate OB.
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