Synovial fluid phospholipase A2s and inflammation.

The activation of phospholipase A2 is believed to have an important role in the inflammatory process owing to its induction of eicosanoids, platelet activating factor, and other mediators. Soluble phospholipase A2 has been associated with exudates in different inflammatory conditions. In this review the general physiology and control of this enzyme and, in particular, the most recent findings on human synovial fluid phospholipase A2s are discussed.     

Changes in sexual behavior during a safety and feasibility trial of a microbicide/diaphragm combination: an integrated qualitative and quantitative analysis.

If proven effective, vaginal microbicides and diaphragms will likely be part of a larger HIV prevention model that includes condoms and other prevention strategies. It is, therefore, important to understand how introducing new prevention methods may affect overall patterns of sexual risk behavior. Data presented were collected as part of a safety and feasibility study of ACIDFORM gel with a diaphragm among 120 women in South Africa. Interviews were administered at enrollment and months 1, 3, 5, and 6 of the trial. Focus groups were conducted at trial exit. Frequency of sex increased significantly after enrollment. This increase appears to be owing to perceived protection from HIV and greater sexual pleasure afforded by the gel. Male condom use was high overall but increased significantly from enrollment. Data suggest this is because of increased partner involvement, increased negotiating power afforded by study participation, and provision of free condoms perceived to be of high quality.     

Histamine and tryptase modulate asthmatic airway smooth muscle GM-CSF and RANTES release.

Degranulating mast cells are increased in the airway smooth muscle (ASM) of asthmatics, where they may influence ASM function. The aim of the present study was to determine whether histamine and tryptase modulate ASM cell granulocyte-macrophage colony-stimulating factor (GM-CSF) and RANTES (regulated on activation, normal T-cell expressed and secreted) release and also to examine which receptors are involved in this release. Confluent, quiescent ASM cells from asthmatic and nonasthmatic donors were treated with histamine (1 microM-100 microM) with and without histamine receptor antagonist pre-treatment, or the protease-activated receptor (PAR)-2 agonists tryptase (0.5-5 nM) and SLIGKV (100 and 400 microM). The cells were then stimulated with interleukin (IL)-1beta and/or tumour necrosis factor (TNF)-alpha (10 ng.mL(-1)) or left unstimulated for 24 h. Release of GM-CSF and RANTES was determined by ELISA and prostaglandin (PG)E(2) measured by enzyme immunoassay. Neither histamine nor tryptase induced ASM GM-CSF or RANTES secretion. However, histamine increased IL-1beta-induced GM-CSF release and markedly reduced TNF-alpha-induced RANTES release by both asthmatic and nonasthmatic cells to a similar extent, but did not modulate PGE(2) release. All changes involved activation of the histamine H1 receptor as they were partially or fully blocked by chlorpheniramine, but not ranitidine. Tryptase, via its proteolytic activity, also potentiated GM-CSF, but not RANTES, release from asthmatic and nonasthmatic ASM cells induced by both cytokines. PAR-2 involvement in the tryptase potentiation was unlikely because SLIGKV had no effect. In conclusion, mast cells, through histamine and tryptase, may locally modulate airway smooth muscle-induced inflammation in asthma.     

Liver Transplantation Across Rh Blood Group Barriers Increases the Risk of Biliary Complications

Background Cold ischemia time and the presence of postoperative hepatic arterial thrombosis have been associated with biliary complications (BC) after liver transplantation. An ABO-incompatible blood group has also been suggested as a factor for predisposal towards BC. However, the influence of Rh nonidentity has not been studied previously. Materials Three hundred fifty six liver transplants were performed from 1995 to 2000 at our hospital. BC incidence and risk factors were studied in 345 patients. Results Seventy patients (20%) presented BC after liver transplantation. Bile leakage (24/45%) and stenotic anastomosis (21/30%) were the most frequent complications. Presence of BC in Rh-nonidentical graft–host cases (23/76, 30%) was higher than in Rh-identical grafts (47/269, 17%) (P = 0.01). BC was also more frequent in grafts with arterial thrombosis (9/25, 36% vs 60/319, 19%; P = 0.03) and grafts with cold ischemia time longer than 430 min (26/174, 15% vs 44/171, 26%; P = 0.01). Multivariate logistic regression confirmed that Rh graft–host nonidentical blood groups [RR = 2(1.1–3.6); P = 0.02], arterial thrombosis [RR = 2.6(1.1–6.4); P = 0.02] and cold ischemia time longer than 430 min [RR = 1.8(1–3.2); P = 0.02] were risk factors for presenting BC. Conclusion Liver transplantation using Rh graft–host nonidentical blood groups leads to a greater incidence of BC.     

Hepatic stellate cell activation in liver transplant patients with hepatitis C recurrence and in non-transplanted patients with chronic hepatitis C.

The pathogenic mechanisms of accelerated graft fibrosis in hepatitis C recurrence after liver transplantation (LT) are not well established. The aim of the study was to assess whether a greater activation of hepatic stellate cells (HSC), the major collagen-producing cells in the liver, can occur in these patients as compared to non-LT patients with chronic hepatitis C. We determined the amount of activated HSC by computer-based morphometric analysis of alpha-smooth muscle actin (alphaSMA)-positive cells and the hepatic TGFbeta(1) expression by immunohistochemistry in 46 LT patients with hepatitis C recurrence, 35 non-LT patients with chronic hepatitis C, and 16 controls. Hepatic alphaSMA and TGFbeta(1) expression was higher in LT patients with hepatitis C recurrence than in controls and was correlated with fibrosis stage and progression rate. No significant difference in alphaSMA and TGFbeta(1) expression was observed between LT and non-LT patients with hepatitis C, with the exception of a higher transforming growth factor beta-1 (TGFbeta(1)) expression in non-LT patients in the early stages of fibrosis. LT patients receiving cyclosporine (CsA) or tacrolimus (FK) had a similar fibrosis progression rate and alphaSMA and TGFbeta(1) expression. In conclusion, the accelerated fibrosis observed in LT patients with hepatitis C recurrence does not seem to be related to a greater amount of activated HSC and TGFbeta(1) expression in the grafts of these patients as compared to non-LT patients with chronic hepatitis C. In LT patients, the amount of activated HSC and TGFbeta(1) expression correlated with fibrosis stage and progression, without any apparent influence of the type of calcineurin inhibitor administered.     

Relaxin down-regulates renal fibroblast function and promotes matrix remodelling in vitro.

BACKGROUND: Renal fibroblasts are important effector cells in tubulointerstitial fibrosis, with experimental antifibrotic strategies focusing on the functional down-regulation of these cells. Several experimental models of fibrosis have provided evidence for the effectiveness of the polypeptide hormone relaxin as a potential antifibrotic agent. This study was conducted to further elucidate the antifibrotic mechanisms of relaxin on renal fibroblasts in vitro. METHODS: Rat cortical fibroblasts were obtained from outgrowth culture of renal tissue isolated from kidneys 3 days post-unilateral ureteric obstruction and constituted 100% of cells studied. A relaxin radio-receptor assay was used to establish binding of relaxin to renal fibroblasts in vitro. Functional studies then examined the effects of H2 relaxin (0, 1, 10 and 100 ng/ml) on fibroblast kinetics, expression of alpha-smooth muscle actin (alpha-SMA), total collagen synthesis, collagenase production and collagen-I lattice contraction. CTGF mRNA expression was also measured by northern analysis. RESULTS: H2 relaxin bound with high affinity to rat renal fibroblasts, but receptor numbers were low. Consistent with its previously reported bimodal effect, transforming growth factor (TGF-beta 1) reduced fibroblast proliferation, an effect abrogated by H2 relaxin. Fibroblasts exposed to H2 relaxin (100 ng/ml) for 24 h demonstrated decreased immunostaining for alpha-SMA and reduced alpha-SMA protein expression compared with controls. There was a trend for a relaxin-mediated reduction in total collagen synthesis and alpha 1(I) mRNA expression with large dose-related increases in collagenase protein expression being observed. TGF-beta 1-stimulated collagen-I lattice contraction was significantly inhibited following co-incubation with 100 ng/ml relaxin. Incremental doses of H2 relaxin had no significant effect on CTGF mRNA expression. CONCLUSIONS: The findings of this study suggest that the antifibrotic effects of relaxin involve down-regulation of fibroblast activity, increase in collagenase synthesis and restructuring of collagen-I lattices, which are consistent with its known physiological role of matrix remodelling. Although there appears to be an interaction between TGF-beta 1 and H2 relaxin, this does not appear to involve a reduction in CTGF mRNA expression.