Bronchiolitis obliterans (BO) following lung transplantation is a chronic disease associated with increased morbidity and mortality. The disease results in progressive respiratory failure and is characterized by airway epithelial cell injury, airway inflammation and fibrous obliteration of the airway lumen. We have recently demonstrated antecedent respiratory viral infection is a distinct risk factor for the subsequent development of death and bronchiolitis obliterans syndrome (BOS), the functional manifestation of BO. Our long-term research objective is to examine the role of airway epithelial cell injury-response cytokines in mediating viral-dependent allograft dysfunction. For this application, we propose respiratory viral infection of the allograft results in enhanced epithelial cell injury and increased expression of epithelial injury-response cytokines. In turn, these injury-response cytokines initiate inflammatory cascades that culminate in allograft dysfunction. To investigate this proposal, we examined the role of respiratory viral infection in a mouse transplant model. Respiratory viral infection in combination with transplantation resulted in allograft dysfunction manifested as exaggerated epithelial injury, macrophage- predominant inflammation and fibrous obliteration of the allograft. We next demonstrated viral infection and transplantation resulted in a synergistic increase in the expression of the epithelial cell injury-response cytokine IL-12 p80 (p80), a macrophage chemoattractant. Additional experiments using mouse strains that enhanced or blocked p80 function confirmed p80 was a central effector of allograft dysfunction. Collectively, these results suggested expression of p80 may also mediate allograft dysfunction in humans. In support of this possibility, transplant recipients with excessive airway inflammation, a known risk factor for subsequent BOS, demonstrated elevated bronchoalveolar lavage levels of p80 that correlated with increased macrophage accumulation in the allograft. Accordingly, the aims of this proposal are to determine the effects of p80 in viral-dependent allograft dysfunction, determine the role of p80 on the immune response in viral-dependent allograft dysfunction, and perform a prospective cohort study of human lung transplant recipients to characterize the role for viral-driven p80 expression in BOS. These studies will provide insight into the viral-dependent pathophysiologic mechanisms that result in chronic allograft dysfunction, and exploitation of this knowledge may be used to identify therapeutic strategies aimed to prevent disease onset or delay its progression. In lay terms, we have previously shown that the common cold, or a respiratory viral infection, is associated with chronic lung disease in people that have had a lung transplant. In particular, these viral infections increase the risk of chronic lung rejection and death. This research will study how these viruses cause chronic lung rejection so that treatments for this condition can be developed.
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