Effects of Aging and Respiratory Syncytial Virus Infection on the uPA/Plasmin System in Pulmonary Fibrosis

Abstract

RationaleIdiopathic pulmonary fibrosis (IPF) is a serious disease often resulting in death. Aging, infection, pulmonary type 2 (Th2) immune responses and impaired fibrolytic activity play central roles in IPF. We hypothesize that aging and viral infection reduces lung urokinase (uPA) levels and increases uPA inhibitor PAI‐1 and that this leads to altered immune responses and TGF‐beta signaling, resulting in worsened fibrosis.MethodsWe compared the severity of bleomycin‐induced pulmonary fibrosis (BLM‐IPF) in mice deficient for uPA (uPA‐/‐) and its receptor (uPAR‐/‐) to wild type (WT) young and aged mice in the presence or absence of RSV infection.ResultsWT mice have diminished uPA expression following infection and BLM challenge, uPA activity levels and uPA total antigen levels diminished in the serum and lung tissues of infected BLM challenged WT aged mice compared to young mice. Whereas the PAI‐1 expression was significantly higher in uPA‐/‐ or uPAR‐/‐ aged BLM challenged mice compared to the WT mice. uPA or uPAR deficient viral infected and BLM treated mice showed increased fibrosis compared to WT as shown by hydroxyproline, total lung collagen, lung histology, and increased TGF‐beta expression. Lung T cells from infected uPA‐/‐ or uPAR‐/‐ aged mice produced lower levels of Th1, Th17 and higher levels of Th2 cytokines compared to WT mice.ConclusionsThis novel study provided both in vivo and in vitro data that showed how age‐infection‐related changes in the uPA/plasmin system impact the development of IPF. Supported by a VA Merit Review Grant (MRG.)