Biomolecular study of Chlamydia pneumoniae and Mycoplasma pneumoniae products in the progress of human chronic valvopaties

Abstract

Etiological association between rheumatic disease and streptococcus does not explain different outcomes of rheumatic valve disease: with myxoid degenerative with valvular insufficiency or with fibrosis and calcification in valvular stenosis. The aortic valve stenosis has similarities with atherosclerosis and present the same infectious agents already described in atheroma plaques: Mycoplasma pneumoniae (MP) and Chamydia pneumoniae (CP), having the biggest concentration of CP in the foci of calcification. In initial human aortic atherosclerosis, high proportion of MP antigens in relation with of CP was associated with fibrosis. Negative remodeling was associated with C5B9 deposits and lower amount of CP antigens. Rheumatic cases also showed CP in the foci of calcification, and in the áreas of myxoid degeneration, structuras suggestive of mycoplasmas. Then we hypothetized that the co-participation of products other than from streptococcus may be inducing fibrosis, calcification of myxoid degeneration of the extrac cellular matrix. Endotelin 1 (EDN-1) induces inflammatory response and vascular remodelling in the atherosclerosis, through increase of oxidative stress and activation of pro-inflammatory cytokines such as IL-6, MCP-1 and NFkB. Other condition presenting increased levels of EDN-1 is sepsis. EDN-1 is a powerful vasoconstrictor, whose production by macrophages is increased in pulmonar hypertension associated with mitral valvopathy. Presence, distribution, density of endothelin receptors (EDNR-A e EDNR-B) in several organs, specifically in the heart is increased in patients with valvular rheumatic and myxoid cardiopathies or with calcification of mitral valve anullus. These receptors are activated by the EDN-1, and it leads to subendothelial growth, contributing for valvar deformity and dysfunction. Similarly, the involvement of END-1 has been largely studied in atherosclerosis. Macrophages produce EDN-1 in response to a variety of microbe challenges, mainly gram positive and gram negative bacterial. Specific interaction receptor-ligante (such as LPS versus TLR4) induces production of EDN-1 by the macrophage. Toll receptors are transmembrane proteins responsible for recognizing the bacteria and fungi .TLR2 mediates cell responses to several pathogens and their products as for example from the external wall of fungi, micobacteria, gram negative bacteria, peptidoglicans (PGN), glicophosphatidyl inositol from T.cruzi. Co-expression of TLR2 and TLR6 is indispensable for the response against lipoprotein of Mycoplasma fermentans MALP2.In the present project we intend to study if different types of human chronic valvopathy, associated with fibrosis and stenosis or extracellular matrix degeneration and valvular insufficiency, in rheumatic or non-rheumatic disease, are associated with different quantities of products from CP and MP, inflammatory cells, TLR4, TLR2, endotelin-1, cytokines (IL-6, TNFalfa, NFkB), complement C5b9 and growth factors (PDGF A and B,. TGFbeta). The study will be performed in three institutes: Instituto do Coração do Hospital das Clínicas da FMUSP where the valvar tissue will be collected during surgery for valvular correction and the immunohistochemistry, in situ hybridization and PCR real time will be performed and conventional histology and RT-PCR at the Departamento de Morfologia da Faculdade de Medicina da Universidade de Brasília. (AU)