INFLAMMATORY CELLS AND MATRIX METALLOPROTEINASE EXPRESSION

J CUENCA MORENO, L BOSCA GOMAR, N GOREN

Paris, France.

Congreso; : 16th European Congress of Immunology. 1st Joint Meeting of European National Societies of Immunology.; 2006

Septic shock is caused by massive systemic microbial infection and is characterized by refractory hypotension and severe cardiac dysfunction. Although the pathogenesis of this cardiac dysfunction remains poorly understood, the contribution of pro-inflammatory mediators, such as nitric oxide (NO) and prostaglandins (PGs), has been recognized and the condition is characterized by the persistent presence of macrophages and other mononuclear cells, tissue destruction, fibroblast proliferation and the deposition of extracellular matrix (ECM). The relationship between NO, PGs and MMPs activation has been clearly demonstrated in vascular smooth muscle, where NO and cyclicGMP up-regulate the expression of MMP-9. However, confusion exists regarding the contribution of cardiomyocytes to the expression and activity of nitric oxide synthase-2 (NOS-2), cyclooxygenase-2 (COX-2) and MMPs since most of the studies have been performed using whole organ extracts or isolated neonatal cardiomyocytes. In the present study we have investigated the contribution of resident non-myocytic cells to heart alterations in wild type and NOS-2 KO mice under septic shock condition by LPS administration. These cells contribute to the rapid infiltration of additional inflammatory cells that enhance the onset of heart disease through the release of inflammatory mediators. Our data show that early expression of NOS-2 and COX-2 after LPS challenge is due to the activation of resident and infiltrating cells, mostly monocytes/macrophages, with a minor (COX-2) or negligible (NOS-2) contribution by cardiac cells. Moreover, using NOS-2 KO mice or NOS-2 and COX-2 pharmacological inhibitors we observed an impaired LPS-dependent infiltration in the heart. The release of NO and PGs by these cells plays an important role in MMP-9 accumulation and activation not only in infiltrating cells, but also in heart tissue and cardiomyocytes cells lines, as was studied by real time PCR, Western blot, immunohistochemical studies and enzyme activity assays. These results provide a direct link between the inflammatory response in the heart and ECM remodelling by the MMPs released by the cardiomyocytes. These data suggest that the activation and recruitment of inflammatory cells to the heart is a major early event in the cardiac dysfunction promoted by septicemia.