In addition to innate host-defense functions, surfactant protein A (SP-A) suppresses T cell-immune responses in vitro, and may be responsible for the hyporesponsive state of lung lymphocytes in vivo. Recent evidence indicate that donor T cells play a major role in the pathogenesis of non-infectious lung dysfunction after allogeneic bone marrow transplantation (BMT), also referred to as idiopathic pneumonia syndrome (IPS). IPS accounts for up to 40 percent of non-GVHD deaths in allogeneic BMT patients. In a murine IPS model that simulates the human condition, lung dysfunction is dependent on infusion of allogeneic T cells. The most severe lung injury is observed during the generation of severe oxidative/nitrative stress in BMT mice given both allogeneic T cells and cyclophosphamide, a commonly used conditioning drug known to deplete antioxidant defenses. Oxidative/nitrative stress inhibits SP-A production, and can damage SP-A structure and function. Keratinocyte growth factor (KGF), a mediator of epithelial cell-proliferation, enhances SP-A expression and prevents experimental lung injury, but the protective mechanisms are incompletely understood. The role of SP-A and KGF-derived SP-A and the effects of reactive oxygen/nitrogen species on T cell-dependent inflammation and IPS injury in vivo have not been thoroughly investigated. We hypothesize that SP-A protects the lung in vivo from IPS injury by inhibiting allogeneic donor T cell-immune responses. We further hypothesize that injection of cyclophosphamide into T cell-recipient mice injures SP-A-producing cells and prevents upregulation of SP-A expression by the generation of peroxynitrite (ONOO), a potent oxidant and nitrating species. Our hypothesis has been formulated based on strong preliminary data showing that exogenous SP-A downregulates alveolar inflammation in vivo. The rationale for the proposed research is that, once the role of SP-A in T cell-dependent inflammation and repair is established, new and innovative anti-inflammatory and antioxidant approaches to limit IPS injury can be developed. Using our BMT model in normal and gene targeted irradiated mice infused with donor T cells from normal and knockout mice, our hypothesis will be tested by completing the following specific aims: 1. Establish the role and mechanism of SP-A in regulation of alveolar inflammation and IPS injury; 2. Determine the mechanism by which allogeneic T cells and cyclophosphamide increase oxidative/nitrative stress; 3. Define the role of SP-A and oxidative/nitrative stress in the immuno-modulatory effects of keratinocyte growth factor after allogeneic marrow transplantation. Completion of aims will establish whether exogenous SP-A and upregulation of endogenous SP-A may be utilized as therapeutic options for the treatment of IPS and, potentially, other life-threatening inflammatory lung diseases.
