Design of group IIA secreted/synovial phospholipase A(2) inhibitors: an oxadiazolone derivative suppresses chondrocyte prostaglandin E(2) secretion.

Group IIA secreted/synovial phospholipase A(2) (GIIAPLA(2)) is an enzyme involved in the synthesis of eicosanoids such as prostaglandin E(2) (PGE(2)), the main eicosanoid contributing to pain and inflammation in rheumatic diseases. We designed, by molecular modeling, 7 novel analogs of 3-{4-[5(indol-1-yl)pentoxy]benzyl}-4H-1,2,4-oxadiazol-5-one, denoted C1, an inhibitor of the GIIAPLA(2) enzyme. We report the results of molecular dynamics studies of the complexes between these derivatives and GIIAPLA(2), along with their chemical synthesis and results from PLA(2) inhibition tests. Modeling predicted some derivatives to display greater GIIAPLA(2) affinities than did C1, and such predictions were confirmed by in vitro PLA(2) enzymatic tests. Compound C8, endowed with the most favorable energy balance, was shown experimentally to be the strongest GIIAPLA(2) inhibitor. Moreover, it displayed an anti-inflammatory activity on rabbit articular chondrocytes, as shown by its capacity to inhibit IL-1beta-stimulated PGE(2) secretion in these cells. Interestingly, it did not modify the COX-1 to COX-2 ratio. C8 is therefore a potential candidate for anti-inflammatory therapy in joints.

Osteoarticular involvement in a series of 100 patients with sarcoidosis referred to rheumatology departments.

OBJECTIVE: To analyze the pattern of osteoarticular lesions in patients with sarcoidosis hospitalized in 4 rheumatology departments. METHODS: We carried out a systematic retrospective analysis of cases with sarcoidosis admitted in the last 10 years, using hospital databases. Two distinct groups were defined from the outset: patients with Löfgren's syndrome (LS) or sarcoid rheumatism (SR). We assessed the following items: distribution of arthritis, chronicity, systemic manifestations, biochemical and immunological measures. RESULTS: We included 100 patients (75% women); 43% had LS and 57% SR. Osteoarticular symptoms revealed the disease in 85% of patients. The patients in the LS group were younger than those in the SR group (41 +/- 9 vs 48 +/- 13 yrs; p < 0.006) and were more likely to have oligoarthritis involving ankles (58% vs 32%; p = 0.04) and high C-reactive protein concentrations (63% vs 33%; p < 0.005). Patients with SR presented osteoarticular symptoms in the form of oligoarthritis (32%), polyarthritis (32%), bony erosion in 8/57 (14%), and osteitis in 9/57 (16%). Lung interstitial involvement was more frequent in the SR group than in the LS group (38% vs 18%; p = 0.03). Chronic polyarthritis was associated with the detection of rheumatoid factor (p = 0.004). Osteitis occurred in older patients (p = 0.02). CONCLUSION: SR was the most frequent manifestation leading to hospitalization; it was characterized by oligoarthritis and polyarthritis and associated with interstitial lung involvement. Osseous involvement occurred in a quarter of SR patients with similar frequency of erosions targeting the distal small bones and osteitis. These latter occurred at a later age.

Heme oxygenase-1 is a critical regulator of nitric oxide production in enterohemorrhagic Escherichia coli-infected human enterocytes.

Enterohemorrhagic Escherichia coli (EHEC) are the causative agent of hemolytic-uremic syndrome. In the first stage of the infection, EHEC interact with human enterocytes to modulate the innate immune response. Inducible NO synthase (iNOS)-derived NO is a critical mediator of the inflammatory response of the infected intestinal mucosa. We therefore aimed to analyze the role of EHEC on iNOS induction in human epithelial cell lines. In this regard, we show that EHEC down-regulate IFN-gamma-induced iNOS mRNA expression and NO production in Hct-8, Caco-2, and T84 cells. This inhibitory effect occurs through the decrease of STAT-1 activation. In parallel, we demonstrate that EHEC stimulate the rapid inducible expression of the gene hmox-1 that encodes for the enzyme heme oxygenase-1 (HO-1). Knock-down of hmox-1 gene expression by small interfering RNA or the blockade of HO-1 activity by zinc protoporphyrin IX abrogated the EHEC-dependent inhibition of STAT-1 activation and iNOS mRNA expression in activated human enterocytes. These results highlight a new strategy elaborated by EHEC to control the host innate immune response.

Pharmacologic induction of heme oxygenase 1 reduces acute inflammatory arthritis in mice.

OBJECTIVE: To determine the consequences of pharmacologic up-regulation of heme oxygenase 1 (HO-1), and inhibition of HO-1 by injection of an anti-HO-1 small interfering RNA (siRNA), in vivo in the acute phase of a mouse model of nonautoimmune arthritis. METHODS: In the K/BxN mouse serum transfer model, which mimics human inflammatory arthritis without lymphocyte influence, HO-1 was up-regulated by intraperitoneal injection of cobalt protoporphyrin IX (CoPP), a potent pharmacologic inducer, and was inhibited using a specific siRNA. The clinical progress of arthritis was monitored by measurement of paw thickness. Interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor alpha (TNFalpha), serum antioxidant, and nitric oxide (NO) levels, prostaglandin E(2) (PGE(2)) production, and matrix metalloproteinase 9 (MMP-9) activity were measured in serum. At the end of the experiments, joints were examined for immunohistopathologic changes. RESULTS: Intraperitoneal injection of CoPP alleviated disease symptoms, such as joint swelling, cartilage degradation, and proliferation of inflammatory tissue in joints, in the acute phase of inflammatory arthritis. The CoPP-induced expression of HO-1 in the joints and liver was associated with marked decreases in IL-1beta, IL-6, and TNFalpha levels, PGE(2) secretion, and MMP-9 activity in serum, and with a marked increase in systemic antioxidant activity. In contrast, NO production in serum and inducible NO synthase expression in chondrocytes were not affected by HO-1 induction. Specific inhibition of HO-1 by in vivo delivery of anti-HO-1 siRNA repressed the protective effects. CONCLUSION: Our data provide the first evidence that pharmacologically induced up-regulation of HO-1 triggers a robust protective antiinflammatory response in a model of nonautoimmune arthritis in mice. This suggests that exogenously induced HO-1 may have potential as therapy in the acute phase of inflammatory arthritis in humans.