PPARbeta/delta ligands as modulators of the inflammatory response.

Peroxisome proliferator-activated receptors (PPARs) are steroid hormone nuclear receptors encoded by three genes: alpha, gamma and beta/delta. Small-molecule agonists of this family of receptors, mostly PPARalpha and PPARgamma agonists, possess pronounced anti-inflammatory effects; however, the use of selective PPARbeta/delta agonists in preclinical studies suggests that this subtype also possesses anti-inflammatory properties. In vivo data suggest that ligands to the beta/delta isoform have activity in a number of disease models that are partly driven by the inflammatory response.

Use of a portable thermal imaging unit as a rapid, quantitative method of evaluating inflammation and experimental arthritis.

Introduction: Thermal imaging has been utilized, both preclinically and clinically, as a tool for assessing inflammation and arthritis. However, previous studies have employed large, relatively immobile devises to obtain the thermal signature of the tissue of interest. The present study describes the characterization of a hand-held thermal imaging device in a preclinical model of general inflammation and a model of rheumatoid arthritis (RA).

Synthesis and SAR comparison of regioisomeric aryl naphthyridines as potent mGlu5 receptor antagonists.

We describe three novel regioisomeric series of aryl naphthyridine analogs, which are potent antagonists of the Class III GPCR mGlu5 receptor. The synthesis and in vitro and in vivo pharmacological activities of these analogs are discussed.

Synthesis and SAR of 2-aryl pyrido[2,3-d]pyrimidines as potent mGlu5 receptor antagonists.

A novel series of potent 2-aryl pyrido[2,3-d]pyrimidine mGlu5 receptor antagonists are described. The synthesis and pharmacological activities of these analogs are discussed.

Central role of complement membrane attack complex in monosodium urate crystal-induced neutrophilic rabbit knee synovitis.

Objective: Monosodium urate monohydrate (MSU) crystals promote gouty inflammation that is critically mediated by neutrophil recruitment and activation. Interleukin-8 (IL-8) and closely related chemokines are major neutrophil chemotaxins in experimental gout. But MSU crystals also activate the classical and alternative pathways of complement, and MSU crystals directly cleave C5 on the crystal surface.

In vivo micro computed tomography of subchondral bone in the rat after intra-articular administration of monosodium iodoacetate.

Osteoarthritis (OA) is a degenerative disease that is characterized by joint discomfort, loss of articular cartilage, and changes to the subchondral bone. Studies to elucidate the pathophysiology of OA have been hampered by the lack of a rapid, reproducible animal model that mimics the structural changes associated with the disease. A single intra-articular injection of mono-iodoacetate (MIA), an inhibitor of glycolysis, into the femorotibial joint of rodents promotes loss of articular cartilage similar to that noted in human OA.

Modulation of leukocyte recruitment and IL-8 expression by the membrane attack complex of complement (C5b-9) in a rabbit model of antigen-induced arthritis.

The complement system is thought to be a major physiological mediator of injury in a number of diseases including rheumatoid arthritis (RA). The membrane attack complex (MAC) of complement has been detected in RA tissue, suggesting that the MAC may be relevant to the pathogenesis of the disease. Deposition of sublytic concentrations of the MAC has been shown to promote the expression of proinflammatory mediators.

Role of inflammatory mediators in thrombogenesis.

The role of inflammation in cardiovascular disease and especially in thrombogenesis has become increasingly recognized as an important component of the overall disease process. Plaque rupture promotes activation of the inflammatory response and increased expression of tissue factor (TF), which in turn acts as one of the major initiators of extrinsic coagulation. It is becoming apparent that the expression of TF on endothelial cells, underlying smooth muscle cells and monocytes is regulated, in part, by proinflammatory cytokines including tumor necrosis factor and IL-1.