In adult organisms, cells localized primarily in the bone marrow and in low number in other organs have the ability to differentiate into multiple cell phenotypes. One current of repair of injured tissue invokes mobilization and homing of these progenitor cells to sites of injury and their differentiation into organ parenchymal cell types. However, progenitor cells have also been implicated in promoting fibrogenesis by differentiating into lung fibroblasts. Based on our and others studies, we hypothesize that bone marrow derived progenitor cells may promote either lung repair or fibrosis, depending on the nature of the injury and the immune proclivity of the host. In this project we propose to clarify the roles of bone marrow derived stem cells in acute and chronic lung injury. We will conduct studies in a novel rodent model, a genetically modified T-bet deficient mice will be treated chronically with bleomycin to induce progressive pulmonary fibrosis. Therefore, we propose the following hypothesis: 1. In response to a single episode of injury, mesenchymal stem cells contribute to effective repair of the injured lung by modulating the inflammatory response, favoring transient fibrogenesis essential to remodeling and differentiating into lung parenchymal cells. 2. Prolonged or repeated lung injury provokes a maladaptive repair response in which mesenchymal stem cells promote fibrogenesis by favoring a persistent Th2 type immune response and by localizing in the lungs and differentiating into fibroblasts that contribute directly to the fibrosis. 3. A persistent Th2 bias of CD4+ T lymphocytes promotes a maladaptive response to lung injury. Administration of mesenchymal stem cells to Th2 biased animals will exaggerate the fibrotic response to bleomycin . To test these hypothesis, we propose the following specific aims: 1. Using an animal model of progressive pulmonary fibrosis, to compare responses of the lungs to single and multiple intratracheal instillations of bleomycin. 2. To determine effects of mesenchymal stem cell transfer on repeated bleomycin induced lung injury. 3. In vitro and in vivo to determine the role of chemoattractant factors (SDF-1) and Th2 cytokines (IL-4 and IL-13) and TGFf31, in the processes of localization, proliferation and differentiation of bone marrow derived mesenchymal stem cells in the lungs after continues injury.
