Herpesvirus in Idiopathic Pulmonary Fibrosis

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DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic, pulmonary disease with no proven effective treatment. Spontaneous remissions do not occur and death usually ensues within 3 to 5 years of diagnosis. The pathogenesis of IPF is complex and not fully delineated. However, a critical pathogenic event in the development of IPF is ongoing injury of lung epithelium. The cause of this injury remains unknown although chronic viral infection of the lungs, particularly with herpesvirus, is garnering increasing interest as a potential cause of the in jury. Studies from us and others that use lung tissue from humans with IPF show the presence of one or more herpesviruses in the lungs of IPF patients. In addition, we found that mice with a T helper(Th)-2 phenotype inoculated with murine herpesvirus develop chronic lung epithelial infection and many histologic features reminiscent of IPF. Based on these data, our concept is that herpesvirus does not normally infect the lung but in a susceptible host, herpesvirus infects lung epithelium and the infected epithelium expresses cytokines and growth factors which directs the fibrogenic response leading to the development of IPF. Our long term goal is to prove that there is a causal link between herpesvirus infection of the lung and the development of IPF. A critical step in reaching that goal is to develop strategies to eradicate herpesvirus infection in the lung and then show amelioration of IPF. The purpose of the current proposal is two-fold. First is to provide sufficient evidence for a potential role of herpesvirus in the pathogenesis of IPF to justify an antiviral therapeutic trial in IPF. Second is to gather information on the viral replication cycle in the IPF lung in order to design the most effective antiviral strategy for such a trial. Therefore, we propose the following specific aim. In lung tissue from patients with IPF: i. Identify which herpesviruses are present in the lung using PCR; ii. Identify cellular sites of herpesvirus infection using immunohistochemical and immunofluorescent analysis for detection of viral proteins; iii. Determine whether herpesviruses are primarily latent in the infected cells or whether lytic replication is occurring; and iv. Determine whether cells infected with herpesvirus, or neighboring uninfected cells, express host proteins known to be involved in the pathogenesis of IPF. Control lung tissue from patients with chronic lung diseases not associated with progressive fibrosis will be examined.