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Biomedical subjects

E F Morand

Publications and source records attributed to E F Morand.

At least 37 records · Page 2Linked to original sources
PubMed1998

Glucocorticoid inhibition of adjuvant arthritis synovial macrophage nitric oxide production: role of lipocortin 1.

Nitric oxide (NO) is a mediator of inflammatory injury which is inhibited by glucocorticoids and is implicated in rheumatoid (RA) and adjuvant arthritis (AA). The glucocorticoid-induced anti-inflammatory molecule lipocortin 1 is expressed in RA synovium, but the effects of lipocortin 1 on synovial inflammation have been little studied. We investigated the effects of glucocorticoids and lipocortin 1 on inducible NO synthase (iNOS) and glucocorticoids on the induction of lipocortin 1 in AA synovial macrophages. NO production was measured by Griess assay in supernatants of day 14 AA rat synovial explants and of synovial macrophages purified from enzyme-digested synovium and treated with lipopolysaccharide (LPS) 1 microg/ml, dexamethasone (DEX) 10(-7) M, and anti-lipocortin 1 MoAb. iNOS and lipocortin 1 expression were detected by flow cytometry using specific MoAb. Cell surface lipocortin was determined by Western blot. NO was produced by all AA synovial explants and NO was released by cultured synovial macrophages (14.5 +/- 2.1 micromol/24 h). iNOS was detected in synovial macrophages (ED-1+) by permeabilization flow cytometry. LPS increased synovial macrophage NO release (P < 0.0001) and iNOS expression (P = 0.04). DEX inhibited constitutive (P = 0.002) and LPS-induced (P < 0.001) NO release and iNOS expression (P = 0.03). DEX inhibition of synovial macrophage NO was associated with induction of cell surface and intracellular lipocortin 1. Anti-lipocortin 1 MoAb treatment reduced the inhibition of NO release by DEX (P = 0.002), but had no effect on iNOS expression. These findings demonstrate a role for lipocortin I in the inhibition by glucocorticoids of AA synovial macrophage iNOS activity.

Animals↗
PubMed1998

Endogenous glucocorticoids modulate neutrophil migration and synovial P-selectin but not neutrophil phagocytic or oxidative function in experimental arthritis.

Pharmacologic glucocorticoids are powerful inhibitors of the inflammatory response at many levels, including leucocyte trafficking and function. The adhesion molecule P-selectin is a key participant in polymorphonuclear neutrophil (PMN) migration to sites of inflammation. The extent to which endogenous glucocorticoids influence PMN migration and activation is not clear. We used the glucocorticoid receptor antagonist RU486 to examine the effect of endogenous glucocorticoid blockade on PMN migration and function in carrageenan monoarthritis in the rat. Arthritis was induced by intraarticular injection of carrageenan and disease severity measured by PMN count in synovial lavage fluid. Decalcified frozen sections of injected joints were analysed for expression of P-selectin by immunohistochemistry. Adrenal glucocorticoid action was blocked in vivo with RU486 20 mg/kg. PMN phagocytosis and reactive oxygen species synthesis were measured by flow cytometry. Carrageenan injection was associated with severe arthritis (synovial lavage PMN 5.9 +/- 0.7 x 10(6), P < 0.01 versus control) which was dose-dependent. P-selectin was not detected in normal joints but was abundant in joints injected with 500 microg carrageenan. RU486 resulted in exacerbation of carrageenan arthritis (9.7 +/- 0.8 x 10(6), P < 0.05). RU486 also altered the threshold for disease induction, in that most RU486-treated animals were susceptible to arthritis at a dose of carrageenan (2.5 microg) which did not induce arthritis in most control-treated animals (P < 0.05), denoting an altered threshold for arthritis induction. RU486 treatment was associated with increased synovial P-selectin expression. Activation status as measured by PMN phagocytic and oxidative function were not influenced by endogenous glucocorticoid blockade. These findings suggest that endogenous glucocorticoids selectively influence PMN migration to inflamed joints via P-selectin expression, but have no effect on PMN activation status.

Animals↗
PubMed1998

Body composition in systemic lupus erythematosus.

The objectives were to determine the body composition, and the effects of disease and corticosteroid therapy on body composition, in a population of female patients with systemic lupus erythematosus (SLE). All female SLE patients managed through a single centre were invited to participate in a cross-sectional study of body composition. Data were collected by standardized interview and examination, and review of medical records. Body composition was assessed by dual-energy X-ray absorptiometry (DXA). Eighty-two subjects were evaluated, 30 of whom were post-menopausal. Univariate linear regression analysis revealed a significant association of reduced fat-free mass with SLE severity [as measured by the Systemic Lupus International Collaborative Clinics (SLICC)] (P = 0.020), a history of corticosteroid exposure (P = 0.043) and age (P = 0.048). Reduced total body bone mineral density (BMD) was also significantly associated with SLICC (P < 0.001) and corticosteroid exposure (P = 0.017), and with age (P < 0.001), post-menopausal status (P = 0.003) and the duration of menopause (P < 0.001). Stepwise multiple linear regression analysis revealed a significant association between fat-free mass and total body, lumbar spine and femoral neck BMD (P = 0.007, P = 0.025, P = 0.003, respectively). Fat mass was significantly associated only with lumbar spine BMD (P = 0.008). In this SLE population, disease severity and corticosteroid exposure were independently associated with a negative effect both on total body BMD and on fat-free mass. Fat-free mass was a significant predictor of lumbar spine, femoral neck and total body BMD.

Absorptiometry, Photon↗
PubMed1998

Corticosteroids in the treatment of rheumatologic diseases.

As understanding of the role of endogenous corticosteroid production by the adrenal glands in rheumatologic diseases has increased, attempts to refine their use in accordance with this knowledge have been reported. Similarly, as understanding of the induction of bone loss by corticosteroids increases, trials of agents designed to antagonize these actions are reported. The lack of large-scale comparative studies means that the optimal method of use of corticosteroids and the optimal antiresorptive protocols have yet to be defined.

Adrenal Cortex Hormones↗
PubMed1998

Pregnancy outcome in systemic lupus erythematosus (SLE): a review of 54 cases.

AIM: To compare the pregnancy outcome, in particular gestational age and birth weight in women with systemic lupus erythematosus (SLE) diagnosed before and after pregnancy, and to review data on presence or absence of the antiphospholipid (aPL) antibody and flares of disease activity. METHOD: Case histories were reviewed of women with a diagnosis of SLE and an obstetric event attending Monash Medical Centre (MMC) over an eight year period (1988-96). Fifty-four pregnancies in 28 women were studied, with 44 occurring after the diagnosis of SLE (Group 1) and ten prior to the diagnosis of SLE (Group 2). RESULTS: In Group 1 there were 25 live births (63%) with 16 full term and nine premature deliveries, 12 spontaneous abortions, three foetal deaths in utero and four elective terminations. In Group 2 there were seven live births (70%), two spontaneous abortions and one foetal death in utero. The mean gestational age of live births was 35.8 weeks and 39.2 weeks respectively (p < 0.001). The mean birth weight of live births was 2448 g and 3030 g respectively (p < 0.023). a PL antibodies were positive in eight of 26 women tested with three live births and were negative in 18 of 26 women with 12 live births. Flares of disease activity occurred in 17 of 28 pregnancies. CONCLUSION: Pregnancy in women with a predisposition to SLE have a high risk of an adverse outcome. Clinical disease confers an additional risk. The mean gestational age and birth weight were significantly less in women with established disease. Mild flares in disease activity resulted in a favourable outcome while renal flares had a worse outcome.

Adult↗
PubMed1997

Antiinflammatory effect of lipocortin 1 in experimental arthritis.

The glucocorticoid-induced antiinflammatory protein lipocortin 1 is present in arthritic synovium but its ability to regulate joint inflammation has not previously been studied. We investigated the role of lipocortin 1 in the antiinflammatory activity of glucocorticoids in an acute arthritis model induced by intraarticular injection of carrageenan. Compared to control joints (0.09 +/- 0.08 x 10(6) synovial fluid cell count), carrageenan injected joints exhibited marked infiltration of PMN (10.2 +/- 0.7 x 10(6), p < 0.001). Both intraperitoneal (1.0 mg/kg) and intraarticular administration (5 micrograms) of dexamethasone (DEX) significantly suppressed arthritis severity (p < 0.001 and 0.005, respectively), and the effects of DEX were significantly prevented by intra-articular injection of antilipocortin 1 mAb (p < 0.05). Carrageenan arthritis was also significantly inhibited by intraarticular administration of the N-terminal lipocortin 1 peptide Ac2-26 at doses of 1 or 2 mg/kg (p < 0.01). Intraarticular injection antilipocortin 1 mAb in the absence of DEX also significantly exacerbated arthritis severity (p < 0.005). In vitro treatment of PMN with DEX was associated with significant inhibition of phagocytosis (p < 0.005) and reactive oxygen species (ROS) generation (p < 0.001). Antilipocortin 1 mAb significantly reduced the inhibitory effects of DEX (p < 0.01 and 0.005, respectively). These results demonstrate that lipocortin 1 mediates the effects of exogenous glucocorticoids on neutrophil migration in carrageenan-induced acute arthritis, exerts an endogenous antiinflammatory influence, and mediates glucocorticoid inhibition of neutrophil activation.

Animals↗
PubMed1997

Suppression of adjuvant arthritis and synovial macrophage inducible nitric oxide by N-iminoethyl-L-ornithine, a nitric oxide synthase inhibitor.

Nitric oxide (NO.) is a pro-inflammatory effector molecule in certain inflammatory diseases, including arthritis. We investigated the production of NO. by adjuvant arthritis (AA) synovial macrophages, and studied the effects of a NO. synthase inhibitor. N-iminoethyl-L-ornithine (L-NIO). Compared to control rats, rats treated with L-NIO in vivo exhibited significantly lower articular index (p < 0.05), paw volume (p < 0.05), and synovial fluid cell count (p < 0.05). No effect on cutaneous delayed-type hypersensitivity to the disease-initiating antigen was observed. Inducible NO. synthase (iNOS) was detected in AA synovial macrophages, and cultured AA synovial macrophage iNOS levels were increased by a factor of 138 +/- 17% (p < 0.01) by 1 microgram/ml LPS in vitro. Constitutive NO. production by AA synovial macrophages (43 +/- 1 nmol/10(5) cells/24 h) was significantly inhibited by 10 nM L-NIO in vitro (32 +/- 0.5, p < 0.01). NO. production induced by 1 microgram/ml LPS (48 +/- 2) was also decreased by L-NIO (39 +/- 2, p < 0.05). In vivo L-NIO treatment also inhibited alveolar macrophage NO. production (p < 0.05). The ability of L-NIO to decrease iNOS-mediated synovial macrophage NO. production and inhibit the clinical parameters of AA implicate macrophage-derived NO. in the pathogenesis of this disease.

Animals↗
PubMed1997

Anti-neutrophil monoclonal antibody therapy inhibits the development of adjuvant arthritis.

The aim of this study was to determine the contribution of neutrophils to adjuvant arthritis (AA) by in vivo depletion of peripheral blood neutrophils. Specific anti-neutrophil MoAb, RP3 (10 mg), or a control antibody was given twice daily on days 8-11 after injection of Mycobacterium tuberculosis in inbred male Sprague-Dawley rats. RP3 treatment inhibited the neutrophil leukocytosis associated with AA (3.3 +/- 0.6 x 10(3)/mm3 versus 21.2 +/- 6.9 x 10(3)/mm3; P<0.001). On day 12, control animals exhibited severe arthritis as assessed by articular index (AI) (9.2 +/- 1.3), increase in paw volume (149.3 +/- 10.6%), and synovial fluid (SF) cell count (5.3 +/- 0.5 x 10(5)). RP3 treatment significantly reduced AI (1 +/- 0.1; P<0.001), paw volume (103.6 +/- 5.8%; P<0.001) and SF cells (0.6 +/- 0.1 x 10(5); P<0.001) without affecting cutaneous DTH (treated 0.6 +/- 0.1 mm change in thickness, control 0.8 +/- 0.2 mm; NS). Additional experiments demonstrated that CD4+ cell depletion but not decomplementation inhibited AA development and synovial neutrophil accumulation. Depletion of circulating neutrophils prevented joint inflammation and synovial leucocyte influx in AA, suggesting a pivotal role for neutrophils in the effector phase of AA. Inhibition of neutrophil accumulation by CD4+ cell depletion and not by decomplementation suggests that neutrophil accumulation in AA is T cell-dependent.

Animals↗
PubMed1997

Methotrexate use in systemic lupus erythematosus.

Low dose pulse oral methotrexate (MTX) is a well established treatment for rheumatoid arthritis, and short term open studies have suggested beneficial effects of MTX in SLE. This study was designed to investigate MTX treatment maintenance rates in SLE using life table analysis, and to determine whether MTX use was associated with a dose reduction of concomitant steroid therapy. All SLE patients managed by physicians affiliated with a single centre were studied cross-sectionally. Information regarding disease variables and drug use were ascertained by interview and chart review. Drug therapy data including dates of treatment and indications for treatment were analysed using Kaplan-Keier life table methods. Among 101 subjects with SLE, 25 MTX treatment episodes were observed in 24 subjects. The period studied totalled 19766 patient-days, with a median (range) duration of observed MTX treatment of 14.4 (5.1-41.6) months. The median (range) initial and peak MTX doses with 7.5 (2.5-10)mg/wk and 10 (7.5-15) mg/week respectively. The principal indication for commencing methotrexate therapy was arthritis. Only two subjects terminated treatment for toxicity, with the most common reason for termination being remission. The cumulative probability of continuing treatment was 68% at 12 months and 61% at 24 months, or 75% and 71% respectively if cessations for remission were excluded. The median (interquartile range) monthly steroid intake during MTX therapy [279.4 (193.4-492.9)mg] was somewhat lower than during the 6 months prior to [298.1 (237.9-531.4)428.8)mg] MTX therapy, but this difference was not significant. A total of 36% of subjects reduced their steroid dose during MTX therapy, but this reduction was not significant. Treatment of SLE with MTX, predominantly for arthritis, was well tolerated over prolonged periods of observation. Toxicity of sufficient severity to lead to treatment termination was uncommon. A subset of subjects were able to reduce steroid intake during MTX therapy, but no overall reduction in steroid dose was observed.

Adult↗
PubMed1997

Exacerbation of adjuvant arthritis by adrenalectomy is associated with reduced leukocyte lipocortin 1.

OBJECTIVE: Lipocortin 1 is a mediator of the antiinflammatory actions of therapeutic glucocorticoids. ENdogenous glucocorticoids modulate inflammatory arthritides including rheumatoid and adjuvant arthritis (AA), but the role of lipocortin 1 in this phenomenon is not known. We studied the effects of endogenous glucocorticoids on adjuvant arthritis and leukocyte lipocortin 1 content. METHODS: Adrenalectomy of sham adrenalectomy was performed 2 days before adjuvant injection in 170 g inbred Sprague-Dawley rats. Peripheral blood was obtained and disease severity assessed by delta paw volume and clinical score 14 days later. Leukocyte subset lipocortin 1 content was determined by double labeling permeabilization flow cytometry using specific monoclonal antibodies. RESULTS: Lipocortin 1 fluorescence was readily detected in control rat peripheral blood cells labeled with OX-1 (pan-leukocyte), OX-19 (CD5), W3/25 (CD4), and OX-8 (CD8). Lipocortin 1 fluorescence was significantly greater in polymorphonuclear leukocytes (PMN) (RP3; p < 0.01). Induction of AA was accompanied by significant increases in lipocortin 1 (p < 0.001) in all subsets. Sham adrenalectomy induced no significant change in AA rat leukocyte lipocortin 1. Adrenalectomy induced significant exacerbation of AA disease severity compared to sham operation (delta paw volume 1.43 +/- 0.1 vs 1.13 +/- 0 ml; p < 0.05). Adrenalectomy was also associated with significant reduction in lipocortin 1 content in all leukocyte subsets except PMN. Leukocyte lipocortin 1 content exhibited significant negative correlation with clinical disease severity (R2 = -0.55; p < 0.05). CONCLUSION: Endogenous glucocorticoids modulate leukocyte expression of lipocortin 1 in inflammatory disease, and reduced lipocortin 1 may be involved in the exacerbation of AA by adrenalectomy.

Adrenalectomy↗
PubMed1995

Detection of intracellular lipocortin 1 in human leukocyte subsets.

Lipocortin 1, a putative mediator of the anti-inflammatory actions of glucocorticoids, is present intracellularly in a variety of tissues including human peripheral blood leukocytes. We investigated the presence of lipocortin 1 in human leukocyte subsets using permeabilization flow cytometry. Constitutive lipocortin 1 was detected in U937 myelomonocytic leukemia cells, and lipocortin 1 was increased by treatment with PMA or PMA+IFN-gamma (P < 0.05) but not by dexamethasone. Lipocortin 1 was present in all leukocyte subsets except B lymphocytes (CD19/20+, P < 0.001). Lipocortin 1 content was maximal in monocytes and polymorphonuclear neutrophils and least in lymphocytes (P < 0.001). Monocyte lipocortin 1 was strongly associated with surface expression of CD14 and HLA-DR. Among non-B lymphocytes, a range of lipocortin 1 fluorescence was observed. Lipocortin 1 fluorescence was greatest in natural killer cells (CD56+, P < 0.001) and CD57+ cells, but T cell subset markers did not otherwise discriminate variations in lipocortin 1. Induction of lymphocyte proliferation by PHA, anti-CD3, Con A, superantigen, and SAC was not associated with significant shifts in lipocortin 1 content. Dexamethasone (10(-10)-10(-6) M) did not induce increases in PB leukocyte lipocortin 1. We conclude that lipocortin 1 content in human leukocytes varies significantly among phenotypic subsets. This has significance for the investigation of inflammatory disease where certain cell types predominate.

Annexin A1↗
PubMed1995

Differential distribution of annexins-I, -II, -IV, and -VI in synovium.

OBJECTIVES: To examine the distribution of four annexins in non-inflamed rheumatoid arthritic and osteoarthritic synovial tissue. METHODS: Frozen sections were stained with monoclonal antibodies (MAb) specific for annexins-I, -II, -IV, and -VI, and for cell lineage related markers including CD68 and CD14 (macrophages), prolyl hydroxylase (fibroblasts), and CD3 (T cells). RESULTS: Each of the annexins was present in synovial tissues in significant amounts in the three groups studied. Annexin-I was predominantly found within the synovial lining layer and double labelling showed it to be present predominantly in cells of the macrophage lineage. In rheumatoid specimens there was increased staining within the lining layer, perivascularly and on macrophages within the tissue stroma. Annexin-II was present in a distribution similar to that of annexin-I, but with more prominent perivascular staining. Annexins-IV and -VI were seen chiefly in association with areas of lymphocyte infiltration in rheumatoid tissue, whereas annexins-I and -II were absent from these areas. Endothelial cells stained weakly positive for annexins-I and -II, and more strongly for -IV and -VI. CONCLUSIONS: This study demonstrates that annexins (particularly annexin-I, a putative mediator of the anti-inflammatory activities of glucocorticoids) are abundant in rheumatoid and non-rheumatoid synovial tissue, annexins-IV and -VI having a distribution distinct from that of -I and -II.

Annexin A1↗
PubMed1994

Impaired glucocorticoid induction of mononuclear leukocyte lipocortin-1 in rheumatoid arthritis.

OBJECTIVE: To investigate leukocyte lipocortin-1 production in rheumatoid arthritis (RA). METHODS: Eight control and 8 RA subjects received 100 mg hydrocortisone intravenously. Leukocyte lipocortin-1 was measured by enzyme-linked immunosorbent assay. RESULTS: Hydrocortisone induced significant increases in lipocortin-1 production by control mononuclear cells (MNC) (P = 0.006 versus baseline) but not by RA MNC (P = 0.44 versus baseline). Peak lipocortin-1 levels in control MNC were significantly higher than those in RA MNC (P = 0.014). CONCLUSION: These results indicate that glucocorticoid-induced MNC lipocortin-1 production is impaired in RA.

Annexins↗
PubMed1994

Abnormal hypothalamic-pituitary-adrenal axis function in rheumatoid arthritis. Effects of nonsteroidal antiinflammatory drugs and water immersion.

OBJECTIVE: To investigate the effects of nonsteroidal antiinflammatory drug (NSAID) therapy and water immersion on hypothalamic-pituitary-adrenal (HPA) axis function in rheumatoid arthritis (RA). METHODS: Plasma levels of adrenocorticotropic hormone (ACTH) and serum and urine levels of cortisol were compared in untreated RA patients, NSAID-treated RA patients, and healthy control subjects. RESULTS: ACTH levels were significantly higher in untreated RA patients (mean +/- SEM integrated area 11,377 +/- 5,246 hours ng/liter) than in NSAID-treated RA patients (2,285 +/- 388 hours ng/liter) or healthy controls (1,845 +/- 35.5 hours ng/liter) (P < 0.001). Serum and urine cortisol levels were not significantly different between groups. Two-hour head-out water immersion had no effect. CONCLUSION: Elevated ACTH levels without hypercortisolemia occur in untreated RA. NSAID therapy alters HPA axis response, but immersion has no effect.

Adrenocorticotropic Hormone↗
PubMed1994

Fibromyalgia syndrome and disease activity in systemic lupus erythematosus.

To study the effect of fibromyalgia syndrome (FS) on the expression of systemic lupus erythematosus (SLE) and on the measurement of disease activity, we performed a cross-sectional study of subjects with SLE. Eighty-seven subjects were studied and 22 (25.3%), all female, had FS (Yunus' criteria). Disease activity and organ system involvement were assessed using the systemic lupus activity measure (SLAM) and using 10 cm visual analogue scales (VAS) completed by both physician and patient. No significant difference between FS and non-FS groups in the objective measurement of disease activity was present, median (range) SLAM scores being 5 (0-18) and 6 (0-24), respectively (NS). Similarly, expression of SLE, as measured by the prevalence of specific organ system involvement, was similar in the two groups. In contrast the prevalence of glucocorticoid use, antibodies to DSDNA and fulfilling four ACR criteria was higher in the non-FS group. The rating of SLE disease activity was affected by concomitant FS. Physician and patient disease activity VAS correlated significantly with SLAM scores in non-FS subjects (P < 0.001, Spearman analysis), whereas in FS subjects, neither physician nor patient VAS correlated with SLAM scores. We conclude that FS is prevalent in individuals with SLE and does not affect disease expression but may interfere with the rating of disease activity.

Adult↗
PubMed1994

Single anticardiolipin measurement in the routine management of patients with systemic lupus erythematosus.

OBJECTIVE: To examine the usefulness of a single measurement of anticardiolipin antibodies (aCL) in systemic lupus erythematosus (SLE) in routine clinical practice. METHODS: All 127 patients with SLE currently followed by our rheumatology unit had an aCL measurement on routine clinic review. Their charts were then reviewed for specific disease manifestations. Basic statistical correlations of the aCL result and the specific disease manifestations were performed, and the clinical utility of the aCL test assessed using Bayesian analysis. RESULTS: aCL was positive (> 2 SD) in 24% and was associated with recurrent fetal loss, thrombosis, cerebrovascular disease, livedo reticularis and digital infarcts. Bayesian analysis showed that a single positive aCL test increased the relative and absolute risk of all the above complications. The criterion of aCL positivity as > 15 units (2 SD) was associated with the highest relative risk. CONCLUSION: A single positive aCL test in routine management of SLE is a useful predictor of important clinical events.

Adult↗