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M J Parnham

Publications and source records attributed to M J Parnham.

At least 91 records · Page 5Linked to original sources
PubMed1979

The use of essential fatty acid deficient rats to study pathophysiological roles of prostaglandins. Comparison of prostaglandin production with some parameters of deficiency.

In a retrospective study on essential fatty acid deficient (EFAD) rats used to study pathophysiological roles of prostaglandins (PGs), slight increases in the linoleic acid content of the diet were found to gradually restore the depressed growth rate and to increase the reduced endogenous PG production. These apparently poorly deficient animals had a serum triene tetraene (omega9:omega6) ratio much higher than the value of 0.4 used as a criterion for EFA deficiency by nutritionists. Changes in body weight, serum omega9:omega6 and platelet PG production were not correlated with each other. Feeding rats on a diet containing less than 0.1 mg/g/linoleic acid led to decreasing platelet PG production as the degree of EFA deficiency increased. At this high level of deficiency, a serum omega9:omega6 ratio of 6 or over was achieved. This high ratio may be taken as an indicator of the degree of EFA deficiency required for studies on PG deprivation, but PG production by the tissue investigated or by platelets should preferentially be measured.

Animals↗
PubMed1979

Time-dependent stimulatory and inhibitory effects of prostaglandin E1 on exudative and tissue components of granulomatous inflammation in rats.

1 The effects of prostaglandin (PGE(1)), following local administration during different phases of developing sponge-induced granulomata, were studied in normal and essential fatty acid deficient (EFAD) rats.2 In normal rats, a single dose of 1 mug PGE(1) on implantation (day 1) increased exudate production without altering total leucocyte counts after 6 h and stimulated granulomatous tissue formation after 8 days.3 Repeated daily administration of the same dose of PGE(1) on days 1 to 3 had no effect, while administration on days 4 to 7 (i.e. when tissue growth is already in progress) inhibited granuloma formation.4 In EFAD rats, which are known to produce only very small amounts of endogenous prostaglandins, acute (6 h) exudate formation was unaffected by 0.05 mug PGE(1). However, early stimulatory and later inhibitory effects of 0.05 mug PGE(1) per day were obtained on the granulomatous tissue, similar to those obtained with the 20 fold higher dose in normal rats.5 The early stimulatory action of PGE(1) on granulomatous tissue formation was enhanced, in normal rats, by concomitant administration of 10 mug theophylline. This latter compound did not influence the later inhibitory effect of PGE(1).6 These results indicate that PGE(1) exerts either pro- or anti-inflammatory actions on the proliferative (tissue) component of the inflammatory process, depending on the time of administration. While the stimulatory effect following early administration may have been secondary to an initial cyclic adenosine 3',5'-monophosphate-mediated, vascular response, such a mechanism is unlikely to have been responsible for the later anti-inflammatory action of PGE(1).7 The implications of these results are discussed in relation to the postulated negative-feedback role of endogenous PGE in chronic inflammation.

Animals↗
PubMed1979

Alterations in granulation tissue growth induced in vivo by lymphocytes from adjuvant-diseased rats.

Lymph node cells from Lewis and Wistar rats, treated 9 or 11 days previously with Freund's complete (FCA) or incomplete adjuvant (FIA), were transferred into polyether sponges implanted subcutaneously into syngeneic, recipient rats. FCA-treated lymphocytes enhanced or reduced granuloma formation (measured after 8 days), when compared with FIA-treated controls, depending on the strain of mycobacterium present in the FCA. The stimulatory effects of lymphocytes from FCA-treated, Lewis rats were abolished by pre-incubation with mitomycin C (25 microgram/ml). Whole serum and isolated serum immunoglobulin from adjuvant-diseased rats had no effect on the sponge granulomas. These data confirm that cell-mediated immunity is involved in the articular granuloma formation of adjuvant arthritis.

Animals↗
PubMed1979

Prostaglandins and granuloma formation in vivo.

The formation of granuloma tissue is one of the major characteristics of chronic inflammation. Infiltration of phagocytic cells (a major source of prostaglandins) and in many cases (including rheumatoid arthritis) lymphocytes, is one of the earliest events in granuloma formation. Prostaglandins (PGs) may modulate the infiltration of some or all of these cells, though much in-vivo data is lacking. Additionally, PGs may modulate the release of the products of these inflammatory cells, which contribute to granuloma formation. Once granulomatous tissue becomes established, PGs may also control the growth of the granuloma through actions on proliferating cells and connective tissue constituents. In-vivo data suggest that the anti-granuloma actions may be mediated by cyclic AMP. While prevention of endogenous PG production by anti-inflammatory drugs has little beneficial effect on preexisting granuloma, facilitation or mimickry of the anti-granuloma actions of PGs may be a possible line for future therapy of diseases such as rheumatoid arthritis.

Animals↗
PubMed1979

Modulation of granulomatous inflammation by prostaglandin E. Involvement of mononuclear cells.

The effects of exogenous PGE, administered locally to carrageenan sponge-induced granulomata in rats, have been studied in relation to changes in PGE-like material (PGL) and cell counts in exudates. Levels of PGL achieved a peak within 24h, declining thereafter. Administration of PGE during the acute phase led to irregular slight enhancement of subsequent granuloma formation. In contrast, administration of exogenous PGE to pre-formed granuloma, inhibited its formation. The early administration of PGE1, on day 1, inhibited mononuclear cell counts in 24h exudates. This inhibition was still present in 8 day exudates, together with reduced PGL levels. A significant correlation was also observed between phagocytosing macrophages and PGL levels in 8 day exudates after exogenous PGE1 treatment of pre-formed granuloma, suggesting that the exogenous PGE was inhibiting macrophage function, including PGL production. Further studies are necessary to establish whether the observed pharmacological effects indicate that PGE, released during granulomatous inflammation, modulates the process through actions on infiltrating leucocytes.

Animals↗
PubMed1979

Mimickry of anti-granuloma effect of prostaglandin E by dibutyryl cyclic-AMP and some phosphodiesterase inhibitors.

Local administration of PGE1 to pre-formed inflammatory granulomata of rats results in a decrease of granulomatous tissue and reduction of prostaglandin concentrations in granulomatous exudates. Under the same experimental conditions, a similar correlation between these two effects is observed with dibutyryl cyclic-AMP. An anti-granuloma effect is also achieved with the phosphodiesterase inhibitors, IBMX and RA-233, but not with theophylline, a rather feeble inhibitor of this enzyme. The present findings provide further support for the concept that elevation of cyclic-AMP in cell population(s) within granuloma is a promising line for pharmacological suppression of inflammatory tissue proliferation.

1-Methyl-3-isobutylxanthine↗
PubMed1978

Combination of theophylline and prostaglandin E1 as inhibitors of the adjuvant-induced arthritis syndrome of rats.

The effects of daily subcutaneous administration of prostaglandin E1 (PGE1), theophylline, and of both drugs together were studied on the Freund's adjuvant-induced inflammatory and arthritic syndrome in rats. In the doses used, neither drug affected the acute inflammatory response in the adjuvant-treated paw, but together they caused marked inhibition. Chronic inflammation in the contralateral (nontreated) hind paws was slightly inhibited by each drug and combined treatment resulted in marked inhibition. The drugs also counteracted splenomegaly in adjuvant-diseased rats and their effects on spleen weight paralleled the inhibition of chronic inflammation. Arthritic lesions, as judged by x-rays of tibiotarsal joint destruction in the nontreated paws, were partially prevented by PGE1 alone, but not by theophylline. The combined treatment entirely prevented these joint lesions. PGE1 did not cause an increase in adrenal weight, but enhanced the effect of theophylline on adrenal weight. Only PGE1 improved gait in arthritic rats, simultaneous theophylline treatement having little additional effect. Other workers have found the PGE1 increases intracellular cAMP and that this effect is enhanced by the phosphodiesterase inhibitor, theophylline. We propose that the anti-inflammatory and anti-arthritic effects of combined drug treatment involve cAMP changes in phagocytic cells at the site of tissue injury and in systemic lymphocytes.

Animals↗
PubMed1978

Cyclic AMP and prostaglandin E in perfusates of rat hind paws during the development of adjuvant arthritis.

The contralateral uninjected hind paws of rats which had been injected with Freund's complete (FCA) or incomplete (FIA) adjuvant 10,14, 18, or 22 days previously were perfused under urethane anaesthesia using a stainless steel coaxial catheter. In one series of experiments cyclic AMP (cAMP) levels were determined after a 2-hour perfusion. cAMP levels were also determined in rats treated on days 16-22 with either prostaglandin E(1) (PGE(1)) (500 mug/kg per day subcutaneously) or saline. When compared with control rats injected with FIA, after 22 days, cAMP levels in FCA-injected rats fell between days 10 and 18 and then rose between days 18 and 22. After PGE(1) treatment, paw volume on day 22 increased in rats injected with FCA, but cAMP levels were not significantly altered when compared with day 22 FCA-injected controls treated with saline. In a second series of experiments, using a slightly modified perfusion method, PG levels in extracts of 30-minute perfusates were determined after chromatography and bioassay. Protein levels and paw volume were also measured. No PGF was detectable in any perfusate. Changes in PGE levels in FCA-injected animals paralleled changes in paw volume, increasing from day 14 and reaching a maximum on day 22. Both parameters remained unchanged in FIA-injected rats. Protein levels in perfusates from FCA-injected animals were significantly greater than FIA-injected controls only on day 22. We suggest that the early changes in cAMP reflect the infiltration of activated leucocytes into the inflamed joint and that the increase in PGE is attributable to lysosomal enzyme activity. Later increases in cAMP are attributable both to the increasing PGE levels and to other changes in cellular activation. We suggest that high levels of PGE contribute to tissue damage which is reflected in raised protein levels.

Animals↗
PubMed1977

Metyrapone: a possible tool in investigating the role of endogenous corticosteroids in inflammation.

Despite much early work on corticosteroid levels in the blood and urine of patients with rheumatic diseases, little strong evidence is available concerning the role of endogenous corticosteroids in inflammation. Nevertheless, the modulating role of adrenal corticosteroids in inflammation seems to be taken for granted even though the small amount of evidence in laboratory animals is, in some cases, contradictory. In the light of the immunological aetiology of some chronic inflammatory diseases and the immunosuppressive properties of corticosteroids, investigations into the role of endogenous corticosteroids in these conditions seem particularly worthwhile. Adrenalectomy has been used widely in studies on the physiological roles of adrenal corticosteroids but the operation requires care to avoid mortality. The adrenal corticosteroid synthesis inhibitor, metyrapone, could be used quite profitably in such investigations. However, it has been shown to exert differential effects on prostaglandin (PG) production in uterine tissue and may produce non-selective antagonism of the actions of PGs. Because PGs are probably involved in inflammation, care should be exercised in the doses of metyrapone used in any studies on inflammatory models to avoid interactions with the PG system.

Adrenal Cortex Hormones↗
PubMed1977

A polyether sponge constituent which is antioxidant, anti-inflammatory and increases prostaglandin concentrations at the inflamed site.

Granuloma formation was studied in rats following s.c. implantation of polyether sponges soaked in carrageenin. Sponges, which had been boiled in ethanol, produced larger granulomata and more exudate than unboiled sponges, but prostaglandin (PG) concentrations were lower in exudates from boiled sponges. Sub-cutaneous injection of the ethanolic sponge extract inhibited the delayed phase of carrageenin-induced rat hind paw oedema. A counter irritant action was ruled out by the demonstration that local administration of the extract also inhibited hind paw oedema. Ultra-violet spectrophotometry of the anti-inflammatory extract indicated that the main constituent was probably a phenolic material, commonly used as an antioxidant in the manufacture of polymers. The antioxidant nature of the extract was confirmed by its inhibition of the autoxidation of adrenaline. The results are discussed in the light of recent reports on the anti-inflammatory properties of phenolic antioxidants and their effects on the PG biosynthetic pathway.

Animals↗
PubMed1977

Reduced exudation and increased tissue proliferation during chronic inflammation in rats deprived of endogenous prostaglandin precursors.

Two models of chronic inflammation were studied in rats deprived of endogenous precursors of prostaglandins by feeding the animals on essential fatty acid deficient (EFAD) food. During kaolin-induced pouch-granuloma, exudate production was markedly reduced in EFAD rats, when compared with normal animals. The exudates from normal rats contained large amounts of PGE, but in the exudates from EFAD rats the amount of PGE was very markedly reduced. Similarly, with carrageenan-impregnated polyether sponges, the exudative component of inflammation was reduced in EFAD rats. However, the proliferative component was significantly increased, particularly in relation to the stunted growth of EFAD rats. Sponge exudates from EFAD rats contained fewer leucocytes than those from normal animals but the fall in leucocyte count was much smaller than the very marked reduction in PGE activity. EFAD rats also exhibited a significant increase in adrenal weights. The results are discussed in the light of the ambivalent (pro- or anti-inflammatory) role of endogenous PGS. It appears that, in the proliferative phase of inflammation, the anti-inflammatory role of PGs is more dominant.

Animals↗
PubMed1977

Increased collagen metabolism in granulomata induced in rats deficient in endogenous prostaglandin precursors.

Collagen metabolism was measured (in terms of various hydroxyproline (HP), DNA and protein ratios) in granulomata obtained after s.c. implantation of carrageenan-impregnated and untreated polyether sponges into normal and essential fatty acid deficient (EFAD) rats for 8 and 15 days. Collagen synthesis (HP/protein) in day 8 and 15 untreated granulomata was the same for both normal and EFAD rats, though collagen breakdown (total HP) appeared to be greater in EFAD granulomata on day 15. With carrageenan-impregnated sponges, collagen synthesis in EFAD granulomata was much greater than in normal granulomata on both day 8 and day 15. Ratios of protein and/or HP to DNA (probably indicative of cellular infiltration) were increased in EFAD rats with both sponge types, though this increase was less pronounced with carrageenan-impregnated sponges. It is suggested that endogenous prostaglandin (PG) production (marledly reduced during EFA deficiency) may exert a negative feedback effect on collagen metabolism during proliferative inflammation.

Animals↗