Faculty Bibliography

Because the mechanisms of Helicobacter pylori-induced gastric injury are incompletely understood, we examined the hypothesis that H. pylori induces matrix metalloproteinase-1 (MMP-1) secretion, with potential to disrupt gastric stroma. We further tested the role of CagA, an H. pylori virulence factor, in MMP-1 secretion. Co-incubation of AGS cells with Tx30a, an H. pylori strain lacking the cagA virulence gene, stimulated MMP-1 secretion, confirming cagA-independent secretion. Co-incubation with strain 147C (cagA(+)) resulted in CagA translocation into AGS cells and increased MMP-1 secretion relative to Tx30a. Transfection of cells with the recombinant 147C cagA gene also induced MMP-1 secretion, indicating that CagA can independently stimulate MMP-1 secretion. Co-incubation with strain 147A, containing a cagA gene that lacks an EPIYA tyrosine phosphorylation motif, as well as transfection with 147A cagA, yielded an MMP-1 secretion intermediate between no treatment and 147C, indicating that CagA tyrosine phosphorylation regulates cellular signaling in this model system. H. pylori induced activation of the MAP kinase ERK, with CagA-independent (early) and dependent (later) components. MEK inhibitors UO126 and PD98059 inhibited both CagA-independent and -dependent MMP-1 secretion, whereas p38 inhibition enhanced MMP-1 secretion and ERK activation, suggesting p38 negative regulation of MMP-1 and ERK. These data indicate H. pylori effects on host epithelial MMP-1 expression via ERK, with p38 playing a potential regulatory role

The production of nitric oxide (NO) by chondrocytes is increased in human osteoarthritis. The excessive production of NO inhibits matrix synthesis and promotes its degradation. Furthermore, by reacting with oxidants such as superoxide anion, NO promotes cellular injury and renders the chondrocyte susceptible to cytokine-induced apoptosis. Thus, NO produced by activated chondrocytes in diseased cartilage may modulate disease progression in osteoarthritis and should therefore be considered a potential target for therapeutic intervention.

Traditional NSAIDs and some cyclooxygenase (COX)-2 inhibitors used to treat persons with osteoarthritis (OA) have adverse effects. However, traditional NSAIDs remain first-line therapy for some patients. The toxicities (eg, renal and GI effects) mostly are the result of COX inhibition. The ideal NSAID would inhibit COX-2 while sparing COX-1. The mechanisms for increased COX-2 cardiovascular toxicity remain less than fully understood. Several conservative strategies may help physicians use these agents effectively and safely. OA therapies under investigation (eg, inhibition of prostaglandin E synthases and disease-modifying osteoarthritis drugs) may render NSAIDs and COX-2 inhibitors obsolete

Since matrix metalloproteinases (MMP) play roles in inflammatory tissue injury, we asked whether MMP secretion by gastric epithelial cells may contribute to gastric injury in response to signals involved in H. pylori-induced inflammation and/or cyclooxygenase inhibition. TNF-alpha, IL-1beta and epidermal growth factor (EGF) stimulated gastric cell MMP-1 secretion, indicating that MMP-1 secretion occurs in inflammatory as well as non-inflammatory situations. MMP-1 secretion required activation of the mitogen-activated protein kinase (MAPK) Erk, and subsequent protein synthesis, but was downregulated by the alternate MAPK, p38. In contrast, secretion of MMP-13 was stimulated by TNF-alpha/IL-1beta but not EGF, was Erk-independent and mediated by p38. MMP-13 secretion was more rapid (peak 6 h) than MMP-1 (peak = 30 h) and only partly depended on protein synthesis, suggesting initial release of a pre-existing MMP-13 pool. Therefore, MMP-1 and MMP-13 secretion are differentially regulated by MAPKs. MMP-1 secretion was regulated by E prostaglandins (PGEs) in an Erk-dependent manner. PGEs enhanced Erk activation and MMP-1 secretion in response to EGF, but inhibited Erk and MMP-1 when TNF-alpha/IL-1beta were the stimuli, indicating that the effects of PGEs on gastric cell responses are context-dependent. These data show that secretion of MMPs is differentially regulated by MAPKs, and suggest mechanisms through which H pylori infection and/or cyclooxygenase inhibition may induce epithelial cell signaling to contribute to gastric ulcerogenesis

15-Deoxy-Delta-12,14-prostaglandin J2 (15d-PGJ2) is the most recently discovered prostaglandin. This cyclopentanone, the dehydration end product of PGD2, differs from other prostaglandins in several respects. There is no specific prostaglandin synthase (PGS) leading to 15d-PGJ2 production and no specific 15d-PGJ2 receptor has been identified to date. Instead, 15d-PGJ2 has been shown to act via PGD2 receptors (DP1 and DP2) and through interaction with intracellular targets. In particular, 15d-PGJ2 is recognized as the endogenous ligand for the intranuclear receptor PPARgamma. This property is responsible for many of the 15d-PGJ2 anti-inflammatory functions. In this review, we summarize the current understanding of 15d-PGJ2 synthesis, biology and main effects both in molecular physiology and pathological states

Recurrent fetal wastage has been attributed to thrombosis in the antiphospholipid antibody syndrome (APAS); however, this has not been proven. Assays of coagulation activation fragments which may provide evidence for a role for thrombosis, have not been previously reported in this setting. We therefore investigated whether F1.2 levels are altered in APAS pregnancies. F1.2 levels were performed on plasmas obtained from fifty-four APA patients with a history of persistent elevation of antiphospholipid antibodies and recurrent abortion who were studied during eighty-three consecutive visits. Results from these patients were compared to a control group of thirty-two healthy pregnant females. F1.2 levels were significantly higher in APAS patients than controls in the second trimester (6.5 nM +/- 4.3 nM vs. 1.2 nM +/- 0.9 nM, p < 0.0001), and in the third trimester of pregnancy (8.6 nM +/- 2.5 nM vs. 3.7 nM +/- 2.0 nM, p < 0.0001). The F1.2 levels in the APA group returned to baseline soon after delivery. No correlation was observed between F1.2 and APA values. This study shows that pregnant patients with a history of recurrent abortions and APA have significantly increased activation of prothrombin compared to healthy pregnant females. These data indicate that the potential value of activations peptide assays such as F1.2 in this setting should be tested in prospective clinical trials.