g. CVDs, less manageable diabetes) associated with this and other local diseases. Chronic periodontitis (CP) is one of (if not) the most common chronic inflammatory diseases known to mankind. It is not only the most common cause of tooth loss in adults but has also been associated, in a number of studies, with an increased risk for various Olaparib concentration medical disorders including cardiovascular disease

(CVD) (Genco & Stamm, 1998; Kuula et al., 2009), reduced diabetic control (Mealey & Ocampo, 2007), preterm delivery (Radnai et al., 2009) and osteoporosis (Golub et al., 2008). Destructive CP is initiated by infection with specific bacterial species, particularly anaerobic gram-negative microorganisms such as Porphyromonas gingivalis, but the breakdown and loss of the periodontal connective tissues, including bone, are primarily the result of the host response, particularly the production of inflammatory mediators (prostanoids, cytokines, nitric oxide), and neutral proteinases, particularly the matrix metalloproteinases (MMPs; e.g. collagenases and gelatinases) and serine proteinases (e.g. elastases) (Ryan, 2002; Lamster et al., 2008; Persson & Persson, 2008).

Chronic inflammatory conditions including CP are characterized by a local accumulation of leukocytes, predominantly (70%) mononuclear cells. Endotoxin derived from P. gingivalis, a virulent periodontal pathogen, can induce the production of proinflammatory cytokines in monocytes. These mediators exert autocrine and/or paracrine Apitolisib clinical trial activities by upregulating the expression of various proteinases including MMPs, resulting in the destruction of connective tissue including periodontal tissues. Because recent studies have also linked this oral infection with an increased risk for developing for a number of systemic disorders including CVD (Genco & Stamm, 1998; Kuula et al., 2009), it is essential to optimally

control this oral disease and maintain periodontal health. In our lab, we have repeatedly shown that tetracycline derivatives, some with no antimicrobial activity, can reduce inflammatory tissue damage (Ryan et al., 1996). We have previously shown that the activities of the polymorphonuclear leukocyte MMPs, MMP-8 and MMP-9, can be inhibited by therapeutically relevant doses of chemically modified nonantibiotic tetracyclines (Golub et al., 1995). In the current study, we used a complete interstitial extracellular matrix (ECM) secreted by R22 smooth muscle cells as a model system (Gu et al., 2005) to determine whether doxycycline (a tetracycline antibiotic) can inhibit inflammatory cytokines and MMPs in mononuclear cells, thereby preventing connective tissue breakdown. All chemical reagents, lipopolysaccharide and doxycyline were purchased from Sigma-Aldrich Co. (St. Louis, MO).