Inflammation. Mediators of inflammation.
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Animals↗
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Endotoxin-induced uveitis in the rat. A study of the role of inflammation mediators.
Intraocular inflammation was induced in the rat by footpad injection of salmonella endotoxin in order to study the influence of chemical inflammation mediators in this uveitis model. Ocular inflammation was assessed 1, 6, 18, 24 and 72 h after endotoxin administration as well as in control rats, by measuring aqueous protein concentration, aqueous inflammatory cell content, and pupillary diameter. Thromboxane B2 (TXB2), prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2-alpha), leukotriene B4 (LTB4), and substance P were simultaneously measured in the aqueous humor by radioimmunoassay. Inflammation parameters peaked at 18 h. TXB2 was already significantly elevated at 1 h. PGE2 peak values of 2.7 ng/ml were reached at 18 h. PGF2-alpha was never significantly raised over control values. LTB4 peaked at 18 h, together with a polymorphonuclear peak. Substance P was significantly elevated after 6 h. It is concluded that maximal uveitis in this model occurs at 18 h. TXB2 is an early mediator, and PGE2 is probably implicated in blood-ocular barrier disruption for which levels as high as 2.7 ng/ml in aqueous seem necessary. PGF2-alpha does not play a major role in this model, while LTB4 seems to be the main chemotactic factor for polymorphonuclears (PMNs) in the anterior chamber and substance P is clearly related to pupil miosis.
Animals↗
Evidence of a neurogenic component during IgE-mediated inflammation in mouse skin.
IgE-mediated inflammation was measured in mouse footpads that lacked sciatic innervation. Mice were passively sensitized with a monoclonal antibody, IgE anti-dinitrophenol, or were immunized for specific IgE production. Antigen-induced swelling in the denervated footpads was reduced 23-39% when compared to sham or untreated controls. Reduced IgE-mediated swelling responses were attributed to the loss of a mast cell-nerve interaction and not to blood vessel sensitivity to vasoamines. Furthermore, electrical stimulation of the distal segment of the sciatic nerve completely restored IgE-mediated inflammation. These data provide in vivo evidence that peripheral nerves participate in cutaneous IgE-mediated swelling reactions with the net effect of increasing inflammation.
Analysis of Variance↗
[Prooxidant effect of inflammation mediators].
The authors studied the effect of inflammation mediators--serotonin, histamine, bradykinin, as well as that of trypsin on lipid peroxidation (LPO). It was demonstrated by chemiluminescence of native hepatic mitochondria in vitro and blood serum in vivo and tests for diene conjugates and malonic dialdehyde that inflammation mediators (histamine, serotonin, bradykinin) and the proteolytic enzyme trypsin activate LPO processes, which correlates with the antiinflammatory effect of these biologically active substances.
Animals↗
Effects of endogenous and exogenous calcitonin on inflammation-mediated osteopenia in the rat.
Inflammation-mediated osteopenia (IMO) in the rat is characterized by loss of bone mass within 3 weeks after induction of nonspecific inflammation (s.c. talcum injections) in growing rats. Histologically, this shows as marked inhibition of osteoblasts 3 days after the initiation of IMO. The role of calcitonin (CT) was investigated in the present study. A reversible increase of serum CT levels was found after intraperitoneal calcium challenge in rats on day 4 after induction of IMO, which was thought to be a result from calcium efflux from bone. No difference in stimulated serum CT levels between the rats with and without IMO was seen on any other day during 4 weeks after initiation of IMO. Bone loss after IMO was more pronounced in normocalcemic and euthyroid rats with deficiency of endogenous CT (thyroidectomy with parathyroid gland reimplanted) (-12.9%) compared with sham operated controls with IMO (-3.25%). Daily subcutaneous injections of 100 mIU salmon CT in rats with and without IMO did not prevent the development of bone loss. This might have been due to the growing state of rats of this age group. Our results support the hypothesis that endogenous CT physiologically has a bone protective role. They furthermore are consistent with the view that endogenous CT itself is not pathogenetically involved in the development of osteoporosis.
Animals↗
Inflammation-mediated osteopenia (IMO) during acute inflammation in rats is due to a transient inhibition of bone formation.
Local inflammation was induced in rats through the subcutaneous injection of magnesium silicate. Trabecular bone volume of the tibia decreased progressively during a 3 week observation period following the inflammatory stimulus. The trabecular bone surface covered with osteoblasts was strikingly reduced during the first week but had normalized by the end of the third week. Calcification rate in the cortical bone of the tibia was reduced with a parallel reduction in endosteal osteoid seam width. Both calcification rate and tetracycline double-labeled surface of vertebral trabecular bone were reduced during the first 2 weeks. Neither total bone resorption surface nor active bone resorption surface were increased. There was a decrease in osteoclast numbers/mm2 bone tissue associated with decreasing bone volume. Our data demonstrate a transient inhibition of bone formation during acute inflammation in the rat and indicate that changes in osteoblast function are part of the acute phase response following local inflammation.
Acute-Phase Reaction↗
[Modification of the adjuvans arthritis by carrageenin, compound 48/80, histamine- and serotonin antagonists, non-steroid antiphlogistics as well as protease inhibitors and their possible relations to inflammation mediators].
1. Injections of carrageenin (1,25 mg/kg i.v.) from the 1st to the 3rd day and then each 2nd or 3rd day inhibited paw swelling in adjuvant arthritis of the rat during the time of treatment. Injections from the 11th to the 15th day were ineffective. The level of plasma kininogen was slightly decreased but the total complement serum level was significantly lowered. 2,5 and 3 mg carrageenin/kg respectively were toxic after repeated injections. After a single administration the levels of plasma kininogen and of total serum complement were decreased by 50% although paw swelling was not affected. 2. Pentosane polysulfoester (25 mg/kg i.v.) did not influence paw swelling despite daily administration from the 1st to the 17th day. Heparin (10 000 IE/kg i.v.) was likewise ineffective. 3. Single or repeated injections of compound 48/80 (0,125-0,5 mg/kg i.v.; 1-5 mg/kg i.p.; 3-6 mg/kg s.c.), reserpine (0,2 mg/kg i.p.), cyproheptadine (5 mg/kg i.v.), bromolysergic acid diethylamide (2 x 2 mg/kg i.v.) or metiamide (10 mg/kg i.v.) were without effect on paw swelling. Neither did compound 48/80 effect the complement serum level. 4. Daily administration of chloropromazine (4-10 mg/kg p.o.) or of promethazine (10-15 mg/kg s.c. or p.o.) inhibited paw swelling in the first phase of adjuvant arthritis but not in the second one. 5. The soybean trypsin inhibitor (15 mg/kg i.v.) inhibited paw swelling significantly up to the 4th day, the Kunitz inhibitor (25 000 E/kg i.v.) was ineffective. 6. The content of prostaglandin E of the inflamed paws was increased threefold in both phases of arthritis. The results are discussed with regard to the putative role of mediators of inflammation (histamine, serotonin, kinins, prostaglandins, lysosomal enzymes, lymphokines, complement).
Animals↗
Inhibition of experimental autoimmune tubulointerstitial nephritis in Brown-Norway rats by (15S)-15-methyl prostaglandin E1. Analysis of the effect of prostaglandin E1 on the induction of the humoral immune response and the elicitation of humorally mediated inflammation.
Brown-Norway (BN) rats develop tubulointerstitial nephritis (TIN) after immunization with bovine tubular basement membrane (TBM) and adjuvants. Daily subcutaneous injections (either on Days 0-7 or Days 0-14) of (15S)-15-methyl prostaglandin E1 (M-PGE1) at a dose of 1 mg/kg/day markedly inhibited or completely abrogated the development of both the acute polymorphonuclear (Day 10) and the subsequent mononuclear (Day 14) inflammatory phases of BN rat TIN. Circulating anti-TBM antibody in Days 0-7 M-PGE1-treated rats was moderately diminished on Day 8 after immunization but not on Day 14. Circulating anti-TBM antibody in Days 0-14 M-PGE1-treated rats was only slightly diminished on Day 14. In experiments to test the effect of M-PGE1 on the elicitation phase of humorally mediated inflammation, M-PGE1 inhibited the acute inflammatory response observed 6 hours after intradermal injection of particulate TBM into TBM-sensitized BN rats. The inflammation in these skin tests was demonstrated by passive transfer experiments to be humorally mediated. The inhibition of acute humorally mediated intradermal inflammation was not attributable to neutropenia, because M-PGE1 caused a significant neutrophilia as demonstrated by peripheral blood smears. Although the inhibition of TIN in Days 0-14 M-PGE1-treated rats may have been due, in part, to dysfunction of the elicitation phase of humorally mediated inflammation, the inhibition of TIN in Days 0-7 M-PGE1-treated rats was more likely secondary to the diminished induction of either humoral or cellular immunity.
Alprostadil↗
Calcitonin secretion in rats with inflammation mediated osteopenia.
The authors followed up the occurrence of inflammation-mediated osteopenia (IMO) in young and adult rats weighing 50 g and 150 g, respectively. The calcemia, the amount of bone calcium and the calcitonin content of the thyroid gland were determined. Calcium loss from bones was similar in both groups, irrespective of age. However, in the young animals a significant rise of calcitonin content of the thyroid gland was found (11.08 ng/ml as compared with 3.81 ng/ml in the controls). In adult animals with IMO the level of calcitonin in the thyroid gland showed no change as compared with the controls. Calcitonin reactive hypersecretion in the young animals was not able to prevent the development of IMO, characterized by an important loss of bone calcium.
Aging↗
[Inflammation mediators and the skin].
Inflammation is a complex process that results from injured tissues. Several chemical mediators armoniously participate in this process to accomplish its goal: the repair of damaged tissue. The skin is the organ that is most accessible to investigators to study how mediators work. Arachidonic acid metabolites, the eicosanoids, are some of these mediators, that have particular interest in several inflammatory diseases of the skin. In this article, the metabolism of arachidonic acid and its effects on the skin are discussed, as well as some therapeutic applications that result from the understanding of them.
Anti-Inflammatory Agents↗
[Interaction of inflammation mediators (myeloperoxidase and defensin) with mixed monolayers from lens lipids and crystallins].
Accumulation of inflammation mediators (myeloperoxidase and defensin) on lens membranes was studied in a model system. For this purpose ability of these proteins to interact with mixed monolayers from the lens lipids and lens proteins (crystallins) was appreciated.
Blood Proteins↗
Measurement of cell-mediated inflammation in experimental murine autoimmune encephalomyelitis by radioisotopic labeling.
A radioisotopic index test was used to detect that time of onset and intensity of cell-mediated immune inflammation of experimental autoimmune encephalomyelitis (EAE) in mice. Mice were tested at various time intervals after an encephalitogenic immunization with mouse spinal cord to homogenate for delayed-type hypersensitivity (DTH) to myelin basic protein (MBP) by intradermal challenge with antigen in the ear pinna. After 25 hr, the intensity of DTH was measured by 125I-radiometry which depends upon the migration of 125I-UdR radiolabeled mononuclear cells into the antigen depot. Cells reactive to MBP were detected by the ear assay as early as 7 days after the initial encephalitogenic sensitization. The degree of cell-mediated immune inflammation in the brain and spinal cord during the evolution of EAE was also measured by a radioisotopic technique; increased 125I-UdR uptake could be detected in the brain 3 to 4 days before the onset of signs of EAE at days 11 to 12, whereas 125I-UdR in the spinal cord was detected only 1 day before, or concomitant with, the onset of signs of EAE. Both, or concomitant with, the onset of signs of EAE. Both the "ear" and "organ" radiometric index tests are useful in measuring the degree of cell-mediated inflammation in EAE, and supplement routine histopathological and observational assessments.
Animals↗
1,25-Dihydroxyvitamin D3 prevents the decrease of bone mineral appositional rate in rats with inflammation-mediated osteopenia (IMO).
We have studied the effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on bone mass and bone mineral appositional rate in intact rats and rats with inflammation-mediated osteopenia (IMO), where osteoblast number and mineral appositional rate are decreased. 1,25(OH)2D3 prevents IMO-specific bone loss when given in a daily dose of 25 ng per rat, but does not when given in higher doses. The hormone was effective, when given over the complete duration of the experiment (21 days), but not when given over shorter time periods (7 and 14 days, respectively). 1,25(OH)2D3 prevents IMO-dependent reduction in mineral appositional rate and leads to an only moderate increase in intact rats. We conclude, that 1,25(OH)2D3 is more effective in stimulating mineral appositional rate in rats with IMO where mineral apposition is impaired.
Animals↗
Inflammation-mediated osteopenia in the rat: the effects of artificial granuloma and sham operation on cortical and trabecular bone.
Recent studies have established that generalized loss of trabecular bone occurs in the growing rat following day-to-day inflammatory irritation for a period of 3 wk. We can now demonstrate that there are similar effects on bone in milder but more prolonged chronic inflammation (14 wk). Thus, there were significant decreases in trabecular bone mass as well as in cortical bone after weekly subcutaneous injections or implantations of nonspecific irritants. Osteopenia, induced by a single but extensive inflammatory lesion, remained apparent even 14 wk after induction. This indicates that inflammation-mediated osteopenia is at least incompletely reversible. A less pronounced but similar reduction of cortical and trabecular bone was observed in rats following sham operation. This might be of importance in all animal studies on bone metabolism that include surgical procedures.
Animals↗
Comparative bone analysis via inflammation-mediated osteopenia (IMO) in the rat.
Various methods exist for determination of trabecular or total bone mass in animal experiments. There is one group of simple techniques not requiring sophisticated equipment focusing on bone-calcium determination. By contrast, another group of newer methods requires complex equipment for procedures such as computerized analysis of bone X-rays or of nondecalcified bone sections. The methods of the first group require considerable time to perform, whereas those of the second group allow a great number of analyses in a short time. We have adapted the computerized techniques to the determination of rat-bone mass and then compared both types of methodology using the new animal model for pathological loss of bone mass: the syndrome of inflammation-mediated osteopenia (IMO) in rats [1, 2]. Reliable results were obtained with both approaches, but we recommend the use of one of the new techniques in cases where a large number of analyses is required.
Absorptiometry, Photon↗
Inflammation--mediators and mechanisms.
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Humans↗
Activation of HLA-DR and interleukin-6 gene transcription in resting T cells via the CD2 molecule: relevance to chronic immune-mediated inflammation.
Only a minority of T cells at cell-mediated immune lesions are antigen specific. In the lesions of human autoimmune disease, such as the synovial membrane in rheumatoid arthritis, the T cells are activated as shown by a variety of phenotypic and functional changes including the expression of HLA-DR and the production of interleukin-6 (IL-6). The stimulatory pathway involved is unknown but does not seem to involve the T-cell receptor. Alternative pathways of activation which may be involved include the CD2 molecule. It is shown that the formation of sheep red blood cell (SRBC) rosettes with resting T cells from human peripheral blood, which is equivalent to CD2/LFA-3 binding, leads to the de novo transcription of the HLA-DR and IL-6 genes and the expression of HLA-DR on the surface of the T cells. There was no transcription of the interleukin-2 (IL-2) or the interleukin-2 receptor (IL-2R) genes and Tac expression was not seen. The rosetted T cells did not proliferate. These are all characteristics of T cells at chronic inflammatory sites. It is concluded that receptor-ligand interactions between CD2/LFA-3, which are expressed in increased amounts in the rheumatoid joint, may be one pathway by which antigen non-specific T cells are recruited as effector cells in lesions of human autoimmune disease.
Antigens, Differentiation, T-Lymphocyte↗
IL-1 dependent model of inflammation mediated by neutrophils.
Interleukin-1 (IL-1) mediates a number of immunologic and physiologic responses associated with inflammation. A new model to monitor the primary effects of IL-1 and potential inhibitors on inflammation has been developed, which involves unilateral injection of 300 U of highly purified recombinant human IL-1 in mouse ears. Ear thickness of IL-1 injected ears increased 7-10-fold 24 hr posttreatment, concomitant with a corresponding increase in myeloperoxidase activity, suggesting that neutrophil influx contributes to this response. Administration of nonsteroidal antiinflammatory drugs did not influence the IL-1 effect in vivo. Inhibition of phospholipase A2 activity ameliorated the IL-1 stimulated inflammation; treatment with 10 mg/kg dexamethaxone eliminated approximately 80% of increased myeloperoxidase activity compared to control values. This model provides a well-defined in vivo assay with which to quantify the systemic effects of compounds capable of altering the activity of IL-1, and the data suggest that this mechanism may explain the unique efficacy of steroids as antiinflammatories.
Animals↗