Acute lung injury (ALI) is characterized by pulmonary cellular infiltration and edema resulting from endothelial cell (EndoC) and epithelial cell (EpiC) injury, the mechanism of which remains unclear. ALI can also lead to acute respiratory distress syndrome (ARDS), which is often lethal. It occurs in several disorders affecting ~150,000 patients per year in US with a mortality rate of ~50%. One of the common features of ALI is the inflammation in the lungs and the production of cytokines. In the current investigation, we will use a mouse model of superantigen such as staphylococcal enterotoxin-induced ALI to delineate the immunopathogenesis mechanisms involved. Staphylococcal enterotoxins and other related exotoxins have been classified by the Center for Disease Control as potential biological warfare agents. It is well established that staphylococcal enterotoxins activate a large percentage of T cells expressing an invariant T cell receptor. Preliminary studies from our lab have demonstrated that staphylococcal enterotoxin B (SEB) treatment of mice led to marked upregulation of CD44 expression on lymphocytes, which migrate to the lungs and cause vascular leak by using CD44 as an effector molecule. We have shown that CD44 knock out (KO) mice are more resistant to SEB-induced pulmonary damage and furthermore, treatment of CD44 wild-type (WT) mice with antibodies against CD44 can effectively block SEB-mediated pulmonary injury. SEB treatment led to induction of IL-2, IFN-gamma and TNF-alpha production and increased NK and NKT cell infiltration in the lungs. Based on this, we will test the central hypothesis that SEB-mediated CD44 expression on cytolytic lymphocytes plays a critical role in lung injury.
The specific aims of the current study are as follows: 1) To examine the role of SEB-reactive T cells, cytotoxic T cells, NK cells and NKT cells in CD44WT and CD44KO mice in induction of vascular leak and ALI. 2) CD44 bone marrow chimeras will be used to address the role of CD44 expression on cytotoxic lymphocytes, pulmonary EndoC and EpiC in SEB-induced ALI. 3) To determine the CD44 isoforms involved in lung injury by using siRNA technology 4) The role of CD44v6 and v7 isoforms in lung injury will be determined by using specific exon knockout mice 5) To develop strategies to prevent or treat lung injury using mimetics of CD44 or its ligand. Understanding the mechanism by which cytolytic lymphocytes cause alveolar EndoC and EpiC injury would help in developing novel strategies which could serve as potential biodefense against acute lung injury caused by bacterial toxins. ? ?
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