St Bartholomew's Hospital

About: St Bartholomew's Hospital is a healthcare organization based out in London, United Kingdom. It is known for research contribution in the topics: Population & Cancer. The organization has 11054 authors who have published 13229 publications receiving 501102 citations. The organization is also known as: St. Bartholomew's Hospital & The Royal Hospital of St Bartholomew.

Lipocortin 1 mediates dexamethasone-induced growth arrest of the A549 lung adenocarcinoma cell line.

Abstract: The synthetic glucocorticoid dexamethasone (1 microM to 1 pM) strongly (maximum greater than 80%) inhibits proliferation of the A549 human lung adenocarcinoma line (EC50 greater than 1 nM) and leads to the appearance, or a further increase (approximately 3-fold) in the expression on the cell surface, of the calcium and phospholipid binding protein lipocortin (annexin) 1. Both these effects, which are shared by hydrocortisone (1 microM) but not by progesterone or aldosterone (1 microM), are inhibited by the antiglucocorticoids RU38486 and RU43044 (1 microM). The nonsteroidal antiinflammatory drugs indomethacin (1 microM) and naproxen (10 microM) and human recombinant lipocortin 1 (0.05-5.0 micrograms/ml) also produce growth arrest in this cell line. During proliferation A549 cells spontaneously release prostaglandin E2 [10-20 ng (28-57 pmol) per ml per 5-day period] into the growth medium. In concentrations that cause growth-arrest, dexamethasone, indomethacin, and lipocortin 1 abolish the generation of this eicosanoid by A549 cells. Prostaglandin E2 itself (0.01-1 pM) stimulates cell growth and partially reverses (approximately 50%) the inhibition of growth caused by dexamethasone and indomethacin. Addition of the neutralizing anti-lipocortin 1 monoclonal antibody 1A (5 micrograms/ml), but not the nonneutralizing anti-lipocortin monoclonal antibody 1B, substantially reversed (greater than 80%) the inhibitory activity of dexamethasone on both growth and prostaglandin E2 synthesis. The generation of prostaglandin E2 by A549 cells seems to be an important regulator of cell proliferation in vitro and the dexamethasone-induced suppression of proliferation in this model is attributable to eicosanoid inhibition caused by lipocortin 1.

Pro- γ -melanocyte-stimulating hormone cleavage in adrenal gland undergoing compensatory growth

Abstract: Regulation of the rapid compensatory growth seen in the remaining adrenal gland of rats following unilateral adrenalectomy is poorly understood. The role of adrenocorticotropic hormone (ACTH) is obscure as immunoneutralization of circulating ACTH does not affect the observed compensatory growth or hyperplasia. This finding, together with the fact that mechanical manipulation of one adrenal without extirpation is followed by growth only in the contralateral gland, has led to the concept of neural regulation of compensatory adrenal growth via a loop from one adrenal through the hypothalamus and back to the contralateral gland which is independent of ACTH secretion. We recently showed that peptides from the N terminal of ACTH precursor proopiocortin (POC), not containing the gamma-melanocyte-stimulating hormone (gamma-MSH) sequence, can stimulate adrenal mitogenesis and proposed that normal long-term adrenal growth and proliferation involves post-secretional proteolytic cleavage of pro-gamma-MSH [or N-POC(1-74)] to generate the mitogenic factor N-POC(1-48/49) and a C-terminal fragment N-POC(50-74), or rat gamma 3-MSH. We have now investigated this hypothesis further in rats by selectively quenching different regions of circulating POC peptides with specific antisera and observing the effect on the increases in weight, RNA and DNA normally seen in the remaining gland following unilateral adrenalectomy. Our results, reported here, suggest that neurally mediated proteolytic cleavage of the circulating inactive mitogenic precursor pro-gamma-MSH at the adrenal gland is the major mechanism of control of compensatory growth.

Expression of RANTES by human bronchial epithelial cells in vitro and in vivo and the effect of corticosteroids.

Abstract: Recent studies have demonstrated that RANTES, a member of the CC chemokine family affecting monocytes, T cells, basophils, and eosinophils, is expressed by several cell types. To investigate whether human bronchial epithelial cells can also express this chemokine, we investigated human bronchial epithelial cells for their ability to synthesize RANTES, both in vitro and in vivo. Additionally, we investigated the effect of treatment for 4 mo with inhaled corticosteroids on the expression of RANTES in these cells in vivo. Human bronchial epithelial cells cultured from surgical tissue expressed the mRNA for RANTES and synthesized RANTES, as demonstrated by polymerase chain reaction and immunocytochemical staining and enzyme-linked immunosorbent assay, respectively. Incubation of the cultures with 50 ng/ml of tumor necrosis factor-alpha (TNF-alpha) significantly increased the release of RANTES into culture medium after 18 to 48 h of incubation, an effect that was abolished by treatment of the cultures with anti-TNF-alpha antibody. RANTES was also expressed in the bronchial epithelium in vivo, as indicated by positive immunocytochemical staining of bronchial biopsy tissues obtained from mild asthmatic patients before and after treatment with 500 micrograms of inhaled beclomethasone dipropionate (BDP) twice daily or matched placebo for 4 mo. Quantitation, by color image analysis, of the percentage of epithelium staining for RANTES showed that treatment with BDP decreased the expression of RANTES in the bronchial epithelium from 17.12% to 4.22% (P < 0.05). The numbers of EG2-staining cells in the epithelium were also reduced, from 790.1/mm2 to 203.3/mm2 (geometric mean; P < 0.01), after BDP treatment. These results suggest that human bronchial epithelial cells are capable of synthesizing RANTES and may therefore play an important role in the development of inflammation in allergic airways disease. Furthermore, corticosteroids may prevent airway inflammation by downregulating the expression of proinflammatory cytokines in the bronchial epithelium.