PubMed Health⌕ Search

Biomedical subjects

M J Parnham

Publications and source records attributed to M J Parnham.

At least 73 records · Page 4Linked to original sources
PubMed1981

Macrophages as targets of inhibitory effects of E-type prostaglandins in immune-related inflammation.

The anti-inflammatory effects of E-prostaglandins (PGE) are attracting interest because they are mediated through actions on cells which are also targets for the putative immunomodulator functions of PGE. In the majority of experimental inflammatory conditions, in which inhibitory effects of PGE have been demonstrated, a variety of immunocytes are implicated, including diverse lymphocyte populations. The inhibitory effects of PGE, however, are also readily observable on the tissue component of the carrageenin-induced granuloma (an immune-related inflammatory model) in which activated macrophages, but not lymphocytes participate. Granuloma-derived macrophages are particularly interesting cells for the study of responsiveness to PGE, because the results obtained on such cells in vitro are directly related to the anti-inflammatory effects of PGE on the macrophage phase of the granuloma in vivo. Such combined studies have revealed differences between the responsiveness of granuloma macrophages to PGE2 and prostacyclin, while with elicited peritoneal macrophages such a difference could not be observed. The adenylate cyclase in granuloma macrophages appears to be unusually sensitive to activation by PGE2, but insensitive to prostacyclin.

Animals↗
PubMed1981

Macrophages from different sources, their production of chemiluminescence under various stimuli and the effects of PGE2 and drugs.

We are currently characterizing different macrophages sub-populations according to their release of oxygen free radicals (measured as chemiluminescence) under various stimuli and their responses to drugs and mediators. Mouse macrophages were obtained by peritoneal or lung lavage and stimulated in vitro with opsonized zymosan (OpZ) or the calcium ionophore A23187. Chemiluminescence was measured in a luminometer and responses obtained after 5 min expressed as percentages of standard responses to the stimuli. Almost identical dose-response curves to OpZ were obtained with peritoneal and alveolar macrophages, while the dose-response curve of peritoneal macrophages to A23187 was much shallower. The response to A23187 was generally much weaker than that to OpZ and in both types of macrophages PGE2 was a more effective inhibitor of OpZ-induced chemiluminescence than of that induced by A23187. The response to OpZ in peritoneal macrophages was inhibited in a dose-related manner by both PGE2 and superoxide dismutase, but not by indomethacin, d-penicillamine, piroxicam or phenylbutazone. OpZ but not A23187, is a suitable stimulus for pharmacological studies on macrophage chemiluminescence.

Animals↗
PubMed1981

Prostaglandin E2 elevation of cyclic-AMP in granuloma macrophages at various stages of inflammation: relevance to anti-inflammatory and immunomodulatory functions.

In the carrageenin-induced granuloma of rats the inflammatory tissue growth and macrophage invasion on the one hand and the cyclic-AMP content of the macrophages on the other, display opposite directional changes. Macrophages, isolated from this tissue at different stages of inflammation, were used to examine the effect of prostaglandin E2 on intracellular levels of c-AMP. It appears that during infiltration of the macrophages into the inflammatory tissue, the sensitivity of adenylate cyclase to activation by PGE2 increases. Arguments are presented that these observations made in vitro, are in direct relevance to the previous described anti-inflammatory effect of PGE on granuloma tissue in vivo.

Animals↗
PubMed1981

Distinction between responsiveness of macrophages to cyclic-AMP elevation by prostaglandin E2 and prostacyclin.

Macrophages, isolated from carrageenin-induced granuloma (an immune-related inflammatory model), were used to examine the effects of prostaglandin E2 and prostacyclin on intracellular levels of cyclic-AMP. It appears that during the development of the tissue-growth component of this granuloma in rats the infiltrating mononuclear phagocytes undergo a change, resulting in macrophages which are very sensitive to cyclic-AMP elevation by PGE2 but insensitive to a similar effect of prostacyclin. Arguments are presented that the difference between the responsiveness of these macrophages to PGE2 and prostacyclin observed in vitro is directly related to the previously reported distinction between these two metabolites of arachidonate as inhibitors of the carrageenin-induced granuloma in vivo.

Animals↗
PubMed1980

The inflammatory response to lymph node cells from adjuvant-diseased rats: late changes in local and systemic leucocyte counts in the Wistar strain.

In contrast to previous studies on Lewis rats, lymph node cells from Freund's complete adjuvant (FCA)-treated Wistar rats did not stimulate granuloma formation when injected into into subcutaneous sponge implants in syngeneic recipient rats. No morphological differences were observed between the cell suspensions from FCA-treated and incomplete adjuvant (FIA)-treated control animals. Following transfer of both types of lymph node cells, granuloma exudate neutrophil counts were high after 3 days and rapidly declined thereafter, while exudate monocyte/macrophage counts slowly increased. In the control group of recipient rats, this latter increase was associated with increased peripheral blood monocyte counts by day 11, whereas in rats receiving FCA-treated cells the only significant changes in blood cells increased total leucocytes on day 3 and increased neutrophil counts on day 7. Another difference between FIA and FCA groups was that exudate small lymphocyte counts in the former group fell rapidly between days 3 and 7, while in the latter group this fall was significantly slower. It was concluded that these leucocyte changes, both local and systemic, reflect certain more sustained cell stimulating effects of FCA-treated lymph node cells when compared with FIA-treated cells, particularly on neutrophils and small lymphocytes. In addition, in rats which received FIA-treated lymph node cells, significant correlations existed between exudate and peripheral blood small lymphocyte counts on day 3 and between both exudate monocyte/macrophage and neutrophil counts and granuloma weight on day 7. No significant correlations were found following injection of FCA-treated cells. It was concluded that FCA treatment stimulates the appearance of suppressor functions of lymph node cells from Wistar rats, which together with their other more sustained inflammatory activities result in the net failure to observe significant changes in or correlations between leucocyte counts and granuloma formation. These findings may shed light on the relative sinsensitivityof Wistar rats to the induction of adjuvant arthritis.

Animals↗
PubMed1980

Redistribution of cardiac output during localized granulomatous inflammation and the effect of methysergide in anesthetized rats.

The distribution of cardiac output (CO) to different organs and tissues was determined by the radioactive microsphere technique in anesthetized rats 3, 5, 7, and 10 days after subcutaneous implantation of carrageenan-impregnated sponges to induce granulomatous inflammation. Distribution of CO to organs which usually respond to stress (heart, spleen, adrenals) was increased during the acute-subacute inflammatory response, at the expense of the distribution to the head, brain, abdominal muscle, and hind legs. Later decreases were seen in distribution of CO to the kidneys, tail, forelegs, and urogenitals. Vascular-related skin temperature (measured by thermography) and distribution of CO to the back skin generally showed a decrease, particularly to the skin covering the granuloma. This latter decrease was reversed by systemic treatment with methysergide (40 mg/kg) which also increased distribution of CO to the head and decreased that to the liver. Most of the effects observed can be attributed to the extra burden on the circulation presented by the highly vascularized granuloma tissue and/or to the release of 5-hydroxytryptamine, but may differ from changes in conscious rats.

Anesthesia↗
PubMed1980

Immune enhancement of granuloma formation as an experimental model for the pannus of rheumatoid arthritis.

The pannus of rheumatoid arthritis is a proliferating mass of various cells and tissues, including follicles of lymphoid cels, and is the major agent of destruction of the surrounding structural tissues. Infiltrating lymphocytes are thought to be the prime stimuli for the growth of the pannus, through the secretion of of lymphokines. In contrast to this high turnover, destructive rheumatoid granuloma, most commonly used experimental granuloma models are of the non-immune, low turnover variety and thus give a rather poor reflection of clinical conditions. A model has been developed in our laboratory in which lymph node cells are removed from Freund's complete adjuvant sensitized rats and injected into sponge implants in normal syngeneic recipient animals, leading to enhancement of granuloma formation. This response has been characterized and shown to be related to lymphocyte activation and to the sensitivity of rats to polyarthritis induction. The lymphocyte transfer model may be useful in studying the action of drugs on lymphocyte mediated chronic inflammatory responses and the principle of lymphocyte transfer may be applied to other hypersensitivity granuloma models.

Adjuvants, Immunologic↗
PubMed1980

Cyclic AMP in macrophages from experimental granulomas and the effect of prostaglandin E2.

Leucocytes were isolated by pronase digestion from granuloma tissue at different stages in inflammation induced by carrageenin-soaked sponge implants in rats and cyclic AMP was measured in these cells. In a mixed cell suspension, containing granulocytes and macrophages, the cyclic AMP levels increased during the early stages of inflammation but decreased when the granuloma became established. However, after correction for the proportion of infiltrating macrophages, as the inflammation progressed only a fall in cyclic AMP content was observable. Exposure of granuloma-derived cells to PGE2 resulted in a rise in cyclic AMP content, which was more pronounced in cells isolated during a later rather than an earlier stage of granuloma development. The results provide support for the earlier proposal that the anti-inflammatory effect of E-type prostaglandins on granulomas is partially explicable on the basis of cyclic AMP changes in infiltrating macrophages.

Animals↗
PubMed1979

Distribution and further studies on the activity of prostaglandin E in chronic granulomatous inflammation.

Pre-formed granulomata, induced by cannulated, carrageenin-soaked, subdermal sponge implants, were used to further analyse the effects of exogenous PGE and the involvement of endogenous PGE in this model of chronic inflammatory tissue changes in rats. Experiments with 14C-PGE2 indicated that administration of PGE into the sponge creates a kinetic situation likely to imitate, but superimposed upon, the continuous discharge of endogenous PGE in the granuloma. The granuloma-reducing, anti-flammatory effect of PGE can be mimicked by dibutyryl cyclic-AMP, phosphodiesterase inhibitors and indomethacin. Most probably these compounds, in common with PGE, exert their anti-granuloma action through elevation of intracellular cyclic-AMP (in macrophages and/or fibroblasts). The anti-granuloma action is not necessarily associated with a reduction in the endogenous PGE-level and vice versa. The involvement of endogenous PGE in the tissue events of granulomatous inflammation is conjectural as yet.

Animals↗
PubMed1979

Effects of 2-aminomethyl-4-t-butyl-6-iodophenol (MK-447) on granulomatous inflammation: lack of correlation with changes in levels of prostaglandin-like material.

MK-447, administered locally to carrageenan-soaked sponges implanted in the backs of rats, either on the day of implantation (day 1) or on days 4-7, exhibited a weak, dose-related inhibition of subsequent granuloma formation. With the later treatment period, prostaglandin (PG)-like material in day 8 exudates was increased at all doses, but with MK-447 treatment on day 1, levels of PG-like material after 24 h were unaffected. Thus, inhibition of granuloma formation was unrelated to local levels of PG-like material. Following treatment with low doses of MK-447 on implantation, mononuclear cell counts in 24 h exudates were reduced. Similar results were obtained with PGE1. Higher doses of MK-447 did not alter monuclear cell counts, but both high and low doses of MK-447 markedly increased polymorphonuclear cell counts in 24-h exudates. The results do not permit the conclusion that the anti-granuloma action of MK-447 is necessarily related to alteration of stable PG level at the inflamed site. Therefore, MK-447 cannot be used unequivocably as a tool to investigate the role of endogenous stable PGs during granulomatous inflammation.

Animals↗
PubMed1979

Development of enhanced blood flow responses to prostaglandin E1 in carrageenan-induced granulation tissue.

The distribution of cardiac output (c.o.) was measured by the radioactive microsphere method in rats at different time intervals after the implantation of carrageenan-impregnated sponges. The amount of blood distributed to the developing granulomata increased from day 5 after sponge implantation to day 7, but showed no further increase at day 10. A similar pattern in blood flow was observed in the skin covering the granulomata. Injection of PGE1 (100 Ng) into the sponges led to an increase in blood flow, the magnitude of which became gradually larger between days 5 and 10. A similar, though less marked increase in sensitivity to PGE1 was observed in the skin covering the granulomata, PGE1 causing a significant increase in blood flow to the skin on day 10. These changes in sensitivity to exogenous PGE1 may be due to decreasing levels of endogenous PGE and/or maturation of the newly formed blood vessels in the granulation tissue.

Animals↗