Pulmonary tuberculosis is characterized by the development of granulomatous inflammation of the lungs which may culminate in tissue fibrosis and loss of lung function. The resurgence of tuberculosis as a major threat to public health highlights our limited understanding of the mechanisms that regulate the initiation, progression or resolution of tuberculosis-induced granulomatous inflammation. Using a murine model of lung granulomatous inflammation caused by the administration of a component of mycobacterial cell walls termed mycobacterial cord factor (trehalose 6,6' dimycolate or TDM), we have observed increased expression of the matrix molecule fibronectin, it's receptor the integrin alpha5beta1, and the matrix-inducing cytokine transforming growth factor pi. We hypothesize that, similar to the murine model, tuberculosis-induced lung granulomatous inflammation is accompanied by increased expression and deposition of the extracellular matrix molecule fibronectin. In turn, fibronectin may help perpetuate the inflammatory response that leads to expansion of granulomas and fibrosis by stimulating the recruitment and activation of immune cells into the lung. We will use a murine model of TDM-induced lung granulomatous inflammation to study the distribution and potential function of fibronectin in tuberculosis. This proposal has been divided in several phases designed to l) determine the factors that stimulate fibronectin expression and deposition in the lung during tuberculosis infection, 2) study the distribution of fibronectin and it's receptor in human tuberculosis and experimental induced lung granulomatous inflammation using immunohistochemical techniques, 3) explore the mechanisms by which fibronectin may affect the production of proinflammatory cytokines such as interleukin-1beta by human mononuclear cells using immunoprecipitation techniques, enzyme-linked immunoassays, and Northern blot analysis, 4) test the role of fibronectin and it's receptor in a murine model of TDM-induced lung granulomatous inflammation, and 5) determine if mononuclear cell production of interleukin-1beta in response to fibronectin differs among cells obtained from animals susceptible and resistant to developing granulomatous inflammation in response to TDM. In addition, it is hypothesized that differences observed in humans of various ethnic backgrounds with regard to their response to tuberculosis may result from alterations in the cellular events that control the response of mononuclear cells to TDM or fibronectin. If fibronectin appears to be critical for granulomatous inflammation in the murine model and if differences in the response to fibronectin are observed in animals with different susceptibilities to TDM, the project will be extended to include another phase designed to study the response of mononuclear cells (obtained from white and black human subjects) to TDM and fibronectin.
| Perez, R L; Roman, J; Roser, S et al. (2000) Cytokine message and protein expression during lung granuloma formation and resolution induced by the mycobacterial cord factor trehalose-6,6'-dimycolate. J Interferon Cytokine Res 20:795-804 |
| Perez, R L; Ritzenthaler, J D; Roman, J (1999) Transcriptional regulation of the interleukin-1beta promoter via fibrinogen engagement of the CD18 integrin receptor. Am J Respir Cell Mol Biol 20:1059-66 |
| Graves, K L; Roman, J (1996) Fibronectin modulates expression of interleukin-1 beta and its receptor antagonist in human mononuclear cells. Am J Physiol 271:L61-9 |
