Wither the beauty's transient flower.
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Journal Article↗
Biomedical subjects
R J Flower
Publications and source records attributed to R J Flower.
Lipocortin: what is it and what does it mean?
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Annexins↗
Steroid inhibition of oedema formation in the rat skin.
1. A model has been developed to compare the inhibitory effects of the topical steroid, betamethasone-17-valerate, to those of systemically administered betamethasone upon oedema responses induced by 5-hydroxytryptamine (5-HT), platelet activating factor (PAF) and zymosan-activated serum (ZAS) +/- prostaglandin E1 (PGE1), measured in the rat skin by use of 125I-labelled human serum albumin. 2. Systemic betamethasone had a selective, time- and dose-dependent inhibitory effect upon oedema treatment, with 1 mg kg-1 and a 3 h pretreatment having the greatest effect of the doses and times employed. 3. Topical betamethasone inhibited the oedema responses to all of the stimuli showing no apparent selectivity. 4. Topical betamethasone inhibits inflammatory stimuli in a different manner from systemic betamethasone. The broad spectrum of inhibition suggests that topical betamethasone acts by affecting a fundamental feature of the inflammatory response common to all of the stimuli.
Administration, Cutaneous↗
Autoantibodies to lipocortin-1 are associated with impaired glucocorticoid responsiveness in rheumatoid arthritis.
Autoantibodies to the antiinflammatory protein lipocortin-1 have been found in patients with rheumatoid arthritis (RA) receiving oral glucocorticoids. The highest antibody titers correlated with a requirement for high maintenance doses of steroid (> 7.5 mg/day prednisolone). Forty-two patients with RA were grouped according to high or low autoantibody titer. In 18 patients, peripheral blood leukocyte counts and phenotypic analysis were performed before and 4 h after a single intravenous (iv) dose of 100 mg hydrocortisone. The group with low titer antibody exhibited a normal poststeroid peripheral blood lymphopenia, but the response in the group with high antibody titer was considerably blunted. In a 2nd study, 24 patients received 3 separate doses of 1000 mg iv methylprednisolone. After 8 weeks the group with the high titer antibody had shown no improvements in clinical or laboratory variables observed in the group with low titer antibody. Thus, the presence of high titer antilipocortin-1 antibody is associated with impaired responses to glucocorticoid therapy both in terms of clinical efficacy and effects on the immune system. This could explain the relative glucocorticoid resistance reported in a proportion of patients with RA.
Aged↗
Site of anti-inflammatory action of dexamethasone in rabbit skin.
Systemic pretreatment of rabbits with dexamethasone results in a time-dependent inhibition of oedema responses caused by intradermal injection of both 'direct-acting' and 'neutrophil-dependent' stimuli. Local injection of actinomycin D, an inhibitor of RNA synthesis, inhibits this effect. Our studies suggest that a major action of dexamethasone in this model may be a local inhibition of increased permeability of the vascular endothelium.
Animals↗
Circulating autoantibodies to recombinant lipocortin-1 in asthma.
One of the postulated mechanisms of corticosteroid action is through the de novo synthesis and release of lipocortins. We assayed circulating antibodies to lipocortin-1 in sera obtained from normal (n = 67) and asthmatic (n = 57) subjects using an ELISA technique. Asthmatic subjects with a wide range of severity, with the mildest needing only occasional inhaled beta-agonist therapy to the most severe needing maintenance oral corticosteroid treatment, were recruited from our Asthma Clinic and classified into five categories according to the need of therapy. Median values of IgM and IgG lipocortin-1 antibody for normal subjects were 19.3 (interquartile range (r) = 11.0-30.4) and 16.9 (r = 10.54-29.4) ELISA units (EU) ml-1 respectively. These levels were significantly elevated in asthmatic subjects: IgM = 43.9 EU ml-1 (r = 31.7-64.5) and IgG = 29.0 EU ml-1 (r = 21.2-44.7) (P less than 0.001). There was no significant relationship between the levels of lipocortin antibody and the clinical severity of asthma. Asthmatics with significantly raised levels of antibody were found within all five categories of severity. We conclude that the level of this antibody is not related to severity of asthma, to previous or current corticosteroid therapy or to the development of corticosteroid resistance.
Adolescent↗
Antipyretic actions of human recombinant lipocortin-1.
The effect of human recombinant lipocortin-1 (hrLC-1) on the pyrogenic actions of the synthetic polyribonucleotide polyinosinic:polycytidylic acid (poly I:C) has been studied in conscious rabbits. Poly I:C (2.5 micrograms kg-1) given i.v. produced a biphasic fever with a first peak after 90-105 min and a second peak between 225-240 min. hrLC-1 (50 micrograms kg-1) given i.v. simultaneously with the poly I:C produced a significant reduction in the febrile response but without complete suppression. The thermal response index over 5 h (TRI5) was 4.69 +/- 0.51 for poly I:C given with saline and the TRI5 for poly I:C given with hrLC-1 was 2.66 +/- 0.45 (values are for n = 5 +/- s.e. mean, P less than 0.05). hrLC-1 administered alone had no effect on body temperature and its antipyretic activity was lost on heating. In a separate series of experiments 1 h pretreatment with dexamethasone (1 mg kg-1) given i.v. reduced the pyrogenic response (TRI5) to poly I:C (2.5 micrograms kg-1) from 4.87 +/- 0.54 without dexamethasone to 2.00 +/- 0.25 (n = 5, P less than 0.05) and dexamethasone given alone had no effect on body temperature. These data demonstrate that LC-1 possesses antipyretic actions and raises the possibility that the antipyretic actions of dexamethasone are mediated through the induction of LC-1.
Animals↗
Characterization of Gaddum's substance R.
1. When the isolated small intestine of the rat is perfused via the mesenteric artery, an oxytocic principle (Gaddum's substance R) is released which is detectable in the perfusate after 30 min and is present in samples collected 8 h later. 2. The oxytocic activity of substance R is lost after boiling but is unaffected by treatment with thioglycolate. Furthermore, atropine, methysergide and indomethacin failed to antagonize uterine contractions to substance R. 3. Neither substance R nor urinary kallikrein alone induce a contraction of the guinea-pig isolated ileum. However, in the presence of kininogen both substance R and urinary kallikrein produce a slow and prolonged contraction of the guinea-pig ileum. 4. The oxytocic and kininogenase properties of both substance R and urinary kallikrein are inhibited by Trasylol. 5. Soy bean trypsin inhibitor (SBTI) selectively inhibited both the oxytocic and the kininogenase activities of substance R but not those of urinary kallikrein. 6. Gel filtration of substance R resolved a single peak of oxytocic activity with an estimated molecular weight of 40 kDa. 7. We conclude that substance R is a kininogenase enzyme which may be distinguished from plasma kallikrein by its molecular weight and from urinary kallikrein by its susceptibility to SBTI. The exact nature of this enzyme remains to be elucidated.
Animals↗
Studies on the roles of phospholipase A2 and eicosanoids in the regulation of corticotrophin secretion by rat pituitary cells in vitro.
Dispersed anterior pituitary cells were used to investigate the possible roles of phospholipid metabolites released by phospholipase A2 (PLA2) in the control of immunoreactive ACTH (ir-ACTH) secretion in vitro. PLA2 (15,600-62,500 U/l), the PLA2 activator melittin (0.5-20 mg/l) and arachidonic acid (1 mmol/l) all produced increases in ir-ACTH release from the cells, whilst platelet-activating factor (PAF), prostaglandin F2 alpha (PGF2 alpha), the prostacyclin analogues iloprost and BW245C, the thromboxane A2 (TXA2) analogue U46619, and the leukotrienes LTB4 and LTC4 were ineffective in this respect. PGF2 alpha (100 nmol/l and 1 mumol/l), iloprost (1 mumol/l) and BW245C (100 nmol/l and 1 mumol/l) depressed corticotrophin-releasing factor-41-induced ir-ACTH secretion, while the PAF antagonist BN52021 (10 and 100 mumol/l) and LTC4 (100 nmol/l and 1 mumol/l) had no discernable effects. The secretory responses of the cells to hypothalamic extracts (0.2 hypothalami/ml) and arachidonic acid (1 mmol/l) were generally unaffected by the cyclooxygenase inhibitors ibuprofen (10 and 100 mumol/l) and indomethacin (10 mumol/l), the TXA2 synthetase inhibitor imidazole (10 mumol/l-1 mmol/l), the lipoxygenase inhibitor nordihydroguaiaretic acid (10 and 100 mumol/l) and the dual cyclo-oxygenase/lipoxygenase inhibitors phenidone (1-100 mumol/l) and BW755C (10 and 100 mumol/l). They were, however, inhibited by the dual cyclo-oxygenase/lipoxygenase inhibitor eicosatetraynoic acid (10 and 100 mumol/l), which also blocks epoxygenase and PLA2 activity and by the cytochrome P450 inhibitor SKF-525A (1 mmol/l). The results suggest that the stimulatory effects of PLA2 and arachidonic acid on ir-ACTH secretion are not effected by products generated by the cyclo-oxygenase or lipoxygenase pathways but may be mediated by metabolites generated by the cytochrome P450 pathway.
Adrenocorticotropic Hormone↗
An assay for the assessment of lipocortin 1 levels in human lung lavage fluid.
The physiological function of the lipocortins, proteins which are thought to be glucocorticoid-regulated, is unclear. An improved assay for lipocortins might help to elucidate their role. A rapid and specific sandwich enzyme-linked immunosorbent assay (ELISA) for lipocortin 1 with a working range of 1-2000 ng/ml and an interrun coefficient of variation of less than 10% is described and used in this pilot study to quantify human lipocortin 1 for the first time in acellular bronchoalveolar lavage fluid (BALF), and in media conditioned by BAL cells, from control patients and those with pulmonary sarcoidosis. Using this assay a statistically significant relationship, not previously observed in man, has been demonstrated between concentrations of lipocortin 1/ml of BALF and serum cortisol levels (n = 10, rs = 0.6939, P less than 0.05). Although lipocortin 1 levels in acellular BALF were the same in control and sarcoid patients, significantly more lipocortin 1 was released from sarcoid BAL cells in culture (median 21.6, range 8.1-45.4 ng lipocortin/10(6) cells/h in culture) than from control cells (2.5, 1.5-7.6 ng lipocortin/10(6) cells/h in culture). The possible clinical significance of these data is discussed, but remains to be established.
Annexins↗
Anti-inflammatory lipocortin 1 production by peripheral blood leucocytes in response to hydrocortisone.
The presence and amount of the anti-inflammatory protein lipocortin 1 was determined in plasma and peripheral blood leucocytes by a highly specific, enzyme-linked immunosorbent assay. Within 120 min of a single intravenous dose of 100 mg hydrocortisone, the intracellular concentrations of lipocortin 1 in peripheral monocytes in 7 of 8 healthy men increased by a median of 225% (range 129-507%) compared with pretreatment levels, and mononuclear cell-surface lipocortin increased by a median of 224% (range 76-483%). Placebo injections had no effect. There was no increase at any time in free plasma or polymorph-associated lipocortin. In 3 of 4 subjects, induction of lipocortin was also observed when whole unseparated blood was incubated in vitro after steroid administration, but cells which had first been isolated and purified were refractory to such induction. Thus rapid changes in the concentration of an active anti-inflammatory protein can occur in man after normal therapeutic doses of hydrocortisone.
Adult↗
Hydrocortisone induces lipocortin 1 production by peripheral blood mononuclear cells in vivo in man.
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Adult↗
The presence of autoantibody to recombinant lipocortin-I in patients with psoriasis and psoriatic arthritis.
Corticosteroids may mediate some of their anti-inflammatory effects via induction of a specific 38 kDa protein, lipocortin-I. Anti-lipocortin-I antibodies (ALA) were measured by enzyme-linked immunosorbent assay (ELISA) in 23 patients with plaque-type psoriasis alone (NAP), in 21 patients with psoriasis and arthritis (PA), and in 67 healthy controls. Only two of 23 NAP patients had elevated ALA, whereas six of 21 PA patients had raised levels of ALA (P = 0.2). Sero-negative polyarthritis was the most common pattern of joint disease in those PA patients with elevated ALA (4/6). ALA levels did not correlate with the extent or severity of cutaneous involvement, and are unlikely to be involved in the pathogenesis of cutaneous psoriasis.
Adult↗
Detection of lipocortin 1 in human lung lavage fluid: lipocortin degradation as a possible proteolytic mechanism in the control of inflammatory mediators and inflammation.
Lipocortins are structurally related, glucocorticoid-inducible proteins that inhibit phospholipase A2 (PLA2), thereby reducing the liberation of arachidonic acid from phospholipids and so limiting the synthesis of eicosanoid inflammatory mediators. This study is the first demonstration of one lipocortin, lipocortin 1 (Lc 1; 37 kDa), in human lung lavage supernatants. In lavage fluid from healthy volunteers, a higher percentage (greater than 70%) of the detected Lc 1 was in its native form, compared to that from patients with abnormal lungs. In patients' lavage fluids, Lc 1 was more likely to be partially degraded (34 kDa). In abnormal bronchoalveolar lavage fluid (BALF), the more polymorphonuclear neutrophils (PMN)/lavage, the lower the proportion of Lc 1 in the native (37 kDa) form (n = 7 pairs, rs = -0.8214, p less than 0.05). Furthermore, when BALF cells were cultured and the harvested conditioned media incubated with pure human recombinant Lc 1, degradation of the 37 kDa form increased with the percentage of PMN (n = 10 pairs, s = -0.7200 after 1 hr; n = 6 pairs, rs = -0.9241 after 6 hr). These results suggest that factors released from the PMN are responsible for Lc 1 degradation in man. When recombinant human Lc 1 was incubated with human neutrophil elastase, the enzyme degraded Lc 1 in a dose-dependent way, suggesting that neutrophil elastase may be one such factor. Since PMNs are ubiquitous at sites of inflammation, it is possible that Lc 1 degradation is a permissive mechanism, which ensures that sufficient inflammation occurs to destroy the provocative stimulus. However, it is equally possible that, in some circumstances, the mechanism may be pathological and that the inactivation of Lc 1 leads to chronic, uncontrolled inflammation.
Adult↗
History of aspirin and its mechanism of action.
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Animals↗
The role of lipocortin in corticosteroid actions.
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Animals↗
Lipocortin.
In this short article the author has attempted to review some of the areas of lipocortin research which are currently of interest. The area has become an extraordinary complex one with many conflicting claims in the literature, on the other hand there are enough interesting leads in the work that has already been done to encourage further research into this fascinating family of membrane-based regulatory molecules.
Animals↗