The lung is a major target of injury when systemic inflammatory responses are activated, and local inflammation contributes to lung injury in a wide variety of diseases. We have developed a new approach for identifying genes potentially important in inflammation-related diseases, using a screening procedure targeting the subset of genes characterized by both (1) induction of message expression in response to inflammatory stimulation and (2) attenuation by glucocorticoids of stimulus-induced message expression. We refer to this class of genes as Glucocorticoid-Attenuated Response Genes, or GARGs. An initial test of this approach using the Swiss 3T3 cell line demonstrated that the screening procedure successfully identified an important group of inflammation-related genes, and led to the identification of a new murine ELR+CXC chemokine, LIX. LIX is related to two human chemokines, ENA-78 and GCP-2, but has some distinctive structural features. In this project, we will characterize the biological functions and regulation of LIX in comparison with KC and MIP-2, the two other known murine neutrophil-chemoattractant chemokines (Aims 1-3). These studies in mice will provide a framework for developing an testing hypotheses about the roles of ENA-78 and GCP-2 in human lung disease. We will also apply a modification of the GARG screening approach to an in vivo model for discovering glucocorticoid-attenuated genes expressed in the lung (Aim 4).
The specific aims are: (1) to identify the biologically relevant forms of LIX and evaluate their ability to bind and activate leukocytes. These studies will indicate whether LIX acts via the same receptors and has the same activities on leukocytes in vitro as KC and MIP-2; (2) to determine which cells in the lung and other organs express LIX in response to inflammatory stimulation in vivo, and evaluate the modulation of LIX expression by glucocorticoids; (3) to characterize leukocyte recruitment and inflammatory changes induced in the lung and other sites by administration of exogenous LIX and by overexpression of LIX under the control of the surfactant protein C promoter in transgenic mice; and (4) to identify novel genes induced in the lung in response to acute endotoxemia whose message expression is attenuated by glucocorticoids. Genes identified in this search are likely to encode pro-inflammatory mediators that participate in a wide range of inflammatory lung diseases in addition to endotoxemia.
| Widney, Daniel P; Hu, Yan; Foreman-Wykert, Amy K et al. (2005) CXCR3 and its ligands participate in the host response to Bordetella bronchiseptica infection of the mouse respiratory tract but are not required for clearance of bacteria from the lung. Infect Immun 73:485-93 |
