Suppression of acute and chronic inflammation by orally administered prostaglandins

Oral administration of a stable analog of prostaglandin E, (PGE₁), 15-(S)-15-methyl-prostaglandin E₁, can suppress both chronic adjuvant-induced polyarthritis and acute immune complex-induced vasculitis in a dose dependent manner. Histopathologic studies of tibiotarsal joints from rats with adjuvant disease showed suppression of arthritis in animals treated with the PGE, analog from time of adjuvant challenge. This study represents the first demonstration of suppressed experimental polyarthritis by an orally administered prostaglandin. Suppression of the acute immune complex-induced vasculitis was demonstrated using 15-methyl-PGE, administered orally 12 hours prior to antigen-antibody challenge. Diminution of tissue injury resulting from immune complex-induced vasculitis is reflected by a decrease in vaso-permeability, indicating suppressed vascular damage in animals treated with prostaglandin. These studies demonstrate the potential use of orally active prostaglandins as an antiinflammatory agent.     

Suppression of acute and chronic inflammation by dietary gamma linolenic acid

We examined the effect of diets enriched in gamma linolenic acid (GLA) on acute inflammation induced by monosodium urate crystals, and on subacute and chronic inflammation induced by complete Freund's adjuvant in the rat subcutaneous air pouch and in rats with adjuvant induced arthritis. Diets were enriched (15% fat) with borage seed oil (23% GLA) or safflower oil (less than 1% GLA). Diets enriched with GLA suppressed inflammation markedly in all models, whereas the safflower oil diet did not influence the inflammatory response. The degree of inflammation was quantified by measuring pouch exudate cell concentration, lysosomal enzyme activity, volume, protein concentration and prostaglandin E2 and leukotriene B4 concentrations. In the chronic air pouch model, the pouch lining was thickened, invaded by mononuclear cells and exhibited proliferation of lining cells 14 days after adjuvant injection. The lesion was far less severe and usual pouch lining architecture was maintained in animals given dietary GLA. Livers of rats fed borage seed oil were enriched in GLA and dihomo gamma linolenic acid (DGLA), and the DGLA/arachidonate ratio was increased 5-fold compared with animals fed safflower oil. Enrichment of diet with plant seed oils rich in GLA may provide a way to alter generation of prostaglandins and leukotrienes and to influence acute and chronic inflammatory responses.     

Roles of prostaglandins and leukotrienes in acute inflammation caused by bacterial infection

Prostanoids, including prostaglandins and thromboxanes, are generated by the phospholipase A2/cyclooxygenase pathway, and leukotrienes are generated by the 5-lipoxygenase pathway from arachidonic acid. At physiological concentrations, vasodilator prostaglandins enhance the vascular permeability effects of histamine and bradykinin, and leukotrienes are important mediators of leukocyte accumulation during acute inflammation. On the other hand, prostaglandin metabolites such as cyclopentenone prostaglandins contribute to the resolution of acute inflammation through inhibition of nuclear factor-kappaB activation. Thus, arachidonic acid oxygenation products mediate diverse effects that induce and resolve acute inflammation caused by bacterial infection.     

Fibronectin in acute and chronic inflammation

Recent evidence suggests that fibronectin (Fn), a high molecular weight glycoprotein, may be used as an indicator protein in rats with adjuvant-induced arthritis. Rocket immunoelectrophoresis, using purified goat anti-rat Fn, provided a specific and sensitive means of measuring plasma Fn in rats during the development of various inflammatory disease states. It was shown that normal rat plasma Fn levels of approximately 400 micrograms/ml double within 24 hours after injection of adjuvant. Plasma Fn levels in this model of chronic systemic inflammatory joint disease were tracked for more than 4 months and remained significantly higher than normal. On the other hand, a carrageenan-induced inflammatory response in the pleural cavity of rats resulted in a large local accumulation of leukocytes, but no change in plasma Fn levels. A carrageenan-induced model of acute inflammation resulted in increased paw swelling within 6 hours and enhanced plasma Fn levels within 24 hours; plasma Fn levels returned to normal within 1 week. Quantitation of plasma Fn levels in the rat may provide a useful biochemical parameter for the study of chronic systemic inflammatory diseases.     

Influence of bradykinin in gastrointestinal disorders and visceral pain induced by acute or chronic inflammation in rats

This work investigated the role of bradykinin in viscerosensitivity before and during inflammation in two models of visceral pain induced by rectal distension (RD) or abdominal distension (AD) in rats. RD induced both inhibition of colonic motility and an increase of abdominal spike bursts. Bradykinin receptor antagonist, Hoe 140 did not affect any of the RD-induced responses. After TNB-induced rectal inflammation, colonic inhibition and the number of abdominal contractions were enhanced. Hoe 140 selectively reduced the abdominal response to the highest distension volume, without affecting the colonic response. In AD group, acetic acid inhibited gastric emptying and increased the number of abdominal ontractions, whereas the same volume of saline did not affect any of the responses. Before inflammation, Hoe 140 (1–5 mg/kg, intraperitoneally) did not affectper se abdominal and gastric emptying responses; in contrast, at 5 mg/kg, intraperitoneally, it reduced significantly (P<0.05) both acetic acid-induced responses. We conclude that bradykinin is involved in viscerosensitivity changes related to abdominal and rectal distension in inflammatory conditions.     

急性和慢性呼吸道炎症疾病激肽形成机制探讨

目的探讨急性和慢性呼吸道炎症过程中激肽的生成途径和机制。方法测定支气管肺癌伴阻塞性肺炎,慢性支气管炎和健康对照组支气管肺泡灌洗液（ＢＡＬＦ）凝胶过滤前后激肽、激肽形成酶活性（ＴＡＭＥｅａ）,血浆血管舒缓素（ＰＫ）和α２巨球蛋白（α２Ｍ）,并进一步鉴定ＴＡＭＥｅａ性质。结果急、慢性组ＴＡＭＥｅａ和激肽水平与健康对照组比较差异有显著性（Ｐ＜０００１,Ｐ＜０．０１）,但两组间差异无显著性（Ｐ＞００５）;急性组ＰＫ和α２Ｍ与慢性组比较差异有显著性（Ｐ＜０００１）。凝胶过滤结果显示：急性组ＢＡＬＦ的ＴＡＭＥｅａ最高峰位于分子量约８０００００处,与第一个α２Ｍ峰重叠,而慢性组的最高峰位于４００００处。ＴＡＭＥｅａ抑制试验证实８０００００处的ＴＡＭＥｅａ来自于ＰＫ;而４００００处的ＴＡＭＥｅａ主要来源于组织血管舒缓素（ＴＫ）。结论急性呼吸道炎症的ＴＡＭＥｅａ主要来自血浆的ＰＫ;而慢性呼吸道炎症则以局部组织腺体分泌的ＴＫ为主。     

Suppression of endotoxin-induced inflammation by taxol.

The pathogenesis of acute lung injury includes transendothelial diapedesis of leukocytes into lung tissues and disruption of endothelial/epithelial barriers leading to protein-rich oedema. In vitro studies show that the microtubule network plays a role in the regulation of endothelial permeability as well as in neutrophil locomotion. It was hypothesised that the microtubule-stabilising agent, taxol, might attenuate inflammation and vascular leak associated with acute lung injury in vivo. The effect of intravenously delivered taxol was assessed using a model of murine lung injury induced by intratracheal lipopolysaccharide (LPS) administration. Parameters of lung injury and inflammation were assessed 18 h after treatment. Intravenously delivered taxol significantly reduced inflammatory histological changes in lung parenchyma and parameters of LPS-induced inflammation: infiltration of proteins and inflammatory cells into bronchoalveolar lavage fluid, lung myeloperoxidase activity, and extravasation of Evans blue-labelled albumin into lung tissue. Taxol alone (in the absence of LPS) had no appreciable effect on these parameters. In addition to lung proteins, intravenous taxol reduced accumulation of leukocytes in ascitic fluid in a model of LPS-induced peritonitis. Taken together, the present data demonstrate that microtubule stabilisation with taxol systemically attenuates lipopolysaccharide-induced inflammation and vascular leak.     

Potentiated cardiodepressant effect of serum by endotoxin in adrenalectomized rats

We have previously shown that in intact rats (IT) a sublethal and nonhypotensive dose (2 mg/kg IV) of Escherichia coli endotoxin was able to induce the early and sustained release of a lipid-soluble cardiodepressant factor, decreasing contractility of cultured rat heart cells by about 35%. As a humoral mediation may also be envisaged in cardiac dysfunction observed by other investigators in adrenal insufficiency, this study was designed to assess serum cardiodepressant effects of endotoxin in 6-10-day, saline-maintained, adrenalectomized rats (ADX). In ADX 2 mg/kg endotoxin caused severe hypotension and 100% lethality within the first 90 min. To obtain in ADX a depressant effect of serum on cultured heart cells fairly similar to that observed in IT, it was necessary to reduce the endotoxin dose by about 200 times (0.01 mg/kg). The latter proved sublethal and nonhypotensive in ADX and was without depressant effect of serum in IT. Serum from ADX (no endotoxin) induced a slight but significant decrease by about 9% in cultured heart cell contractility when compared to serum from IT or sham-operated controls. These data show that adrenalectomy confers a cardiodepressant effect on rat serum and potentiates the release of endotoxin-induced cardiodepressant substance(s) without relation to systemic hypotension.     

Suppression of monosodium urate crystal-induced acute inflammation by diets enriched with gamma-linolenic acid and eicosapentaenoic acid

A subcutaneous air pouch formed in Sprague-Dawley rats was used to study the effect of diets enriched in gamma-linolenic acid (GLA) (in plant seed oil) and eicosapentaenoic acid (EPA) (in fish oil) on acute inflammation induced by monosodium urate crystals. The GLA-enriched diet suppressed significantly the cellular phase of inflammation (polymorphonuclear leukocyte accumulation, crystal phagocytosis, and lysosomal enzyme activity), but it had little effect on the fluid phase (exudate volume and protein concentration). In contrast, the EPA-enriched diet suppressed the fluid phase but not the cellular phase of inflammation. The findings indicate that the fluid and cellular phases of acute inflammation can be controlled independently. A combined diet of fish oil and plant seed oil (EPA-enriched and GLA-enriched) reduced both the cellular and fluid phases of inflammation. Thus, dietary provision of alternative substrates for oxidative metabolism (other than arachidonic acid) modifies monosodium urate crystal-induced acute inflammation.     

Ascorbic acid metabolism in adrenalectomized rats

Male albino rats were adrenalectomized and their ascorbic acid, dehydroascorbic acid, and diketogulonic acid were determined in liver and urine, while only the total ascorbic acid was determined in blood, at the intervals of 4, 8, and 12 days after adrenalectomy. Activities of ascorbic acid synthesizing enzyme d-glucurono-δ-lactone hydrolase, l-gulono-γ-lactone hydrolase, and l-gulono-γ-lactone oxidase were estimated in liver. The activities of ascorbic acid degrading enzymes dehydroascorbatase and 2,3 diketoaldonate decarbozylase were studied in liver and kidney. In adrenalectomized rats there was a slight decrease in the ascorbic acid level and an appreciable decrease in dehydroascorbic acid content of the liver. On the other hand, there was about two-fold increase in the diketogulonic acid content of liver. The content of ascorbic acid and dehydroascorbic acid in the urine of adrenalectomized rats decreased significantly, while there was slight increase in the diketogulonic acid content. There was also a slight decrease in total ascorbic acid content of blood. Decreases of about 20% and 30% were observed in the activities of d-glucurono-δ-lactone hydrolase and l-gulono-γ-lactone oxidase respectively, while the activity of l-gulono-γ-lactone hydrolase remained practically unchanged. An appreciable increase in the activity of dehydroascorbatase and a moderate increase in the activity of diketoaldonate decarboxylase were observed in liver and kidney of adrenalectomized rats. All corresponding alterations were more conspicuous in rats 12 days after adrenalectomy.     

Suppression of chronic streptococcal cell wall-induced arthritis in Lewis rats by liposomal clodronate.

OBJECTIVES: To investigate the role of macrophages in the pathogenesis of chronic streptococcal cell wall (SCW)-induced arthritis using liposomal clodronate. METHODS: Female Lewis rats with SCW-induced arthritis received a single intravenous injection of 20 mg of clodronate encapsulated within small unilamellar vesicles (SUVc) 10 days post-arthritis induction. RESULTS: SUVc significantly suppressed the development of chronic SCW-induced arthritis for up to 26 days after treatment. At this time point, ED1(+) macrophages were significantly depleted in the liver and ankle joints, although splenic macrophage numbers were not significantly different from control groups. Macrophage elimination induced a significant reduction in local levels of interleukin (IL)-1beta, IL-6, tumour necrosis factor-alpha (TNFalpha) and matrix metalloproteinase-9 (MMP-9) from ankle joints. CONCLUSIONS: Macrophage elimination by SUVc inhibits local production of IL-1beta, IL-6, TNFalpha and MMP-9, and the pathogenesis of inflammatory arthritis.     

Vascular adhesion molecules in acute and chronic liver inflammation.

Adhesion to and penetration through the sinusoidal vascular endothelium is a mandatory step for leukocyte migration and accumulation at sites of liver inflammation. This leukocyte trafficking is controlled by interactions between adhesion molecules on leukocytes and corresponding ligands on endothelial cells. We have analyzed the in situ distribution of two recently described vascular adhesion molecules (i.e., endothelial leukocyte adhesion molecule-1 and vascular cell adhesion molecule-1) and of the lymphocyte "homing" receptor cluster of differentiation antigen-44 in normal and inflamed liver biopsy specimens. Endothelial leukocyte adhesion molecule-1 and vascular cell adhesion molecule-1 were absent from normal liver tissue, but they were strongly expressed on sinusoidal lining cells in inflammatory liver disease. Endothelial leukocyte adhesion molecule-1 expression predominated diffusely throughout the liver parenchyma in acute hepatitis; in contrast, vascular cell adhesion molecule-1 was mainly expressed in areas of periportal and intralobular inflammation in chronic active and persistent hepatitis. The "homing" receptor cluster of differentiation antigen-44 was weakly expressed on scattered mononuclear cells and on sinusoidal lining cells in normal liver tissue, but it was strongly up-regulated on mononuclear inflammatory cells and sinusoidal lining cells in acute and chronic hepatitis. In addition, reactivity for the cluster of differentiation antigen-44 was found on the membranes of variously sized clusters of hepatocytes in biopsy specimens with acute hepatitis. De novo or up-regulated expression of these adhesion molecules on sinusoidal lining cells in inflamed liver biopsy specimens indicates that these cells actively modulate their phenotype in response to environmental factors, thus playing a key role in the recruitment of leukocytes in acute and chronic liver inflammation.