The air pouch has been shown to provide a convenient model for studying the behaviour of synovial lining tissue. Air pouches of different ages were used to study the reactivity of newly developing lining tissue towards irritants known to cause inflammation. Pouches of 1 day in age were relatively inert in their reactivity as judged by the number of cells and volume of the exudate accumulating in the pouch. In contrast, 3-day-old pouches responded to a much greater extent, and 6-day-old pouches were highly responsive with a further increase in cell numbers and fluid volume. The different responses of 1-, 3- and 6-day-old pouches could be explained by (a) developing vascularity of the pouch, (b) formation of an organised lining of phagocytic cells, or (c) an increasingly organised mechanical barrier that retains the irritant and products of the inflammatory response. These studies of air pouch lining development permit a dissection of those components necessary for inflammatory reactivity of a lining tissue and may help explain the sensitivity of synovium to chronic inflammation.
In 1958, Sutherland and Rail identified adenosine 3', 5'-monophosphate (cAMP) as an intracellular second messenger of hepatic glycogenolysis [1]. Subsequently, cAMP was shown to act as second messenger for a variety of hormones, inflammatory mediators and cytokines, and has been shown to modulate models of immune and non-immune inflammation in vivo and a variety of cellular processes in vitro. Indeed, the current paper by Ottonello et al. is typical of research in this area. The authors show that in a population of adherent neutrophils, the oxidative burst induced by exposure to granulocyte-monocyte colony-stimulating factor is reduced by agents that elevate cAMP [2]. They speculate that therapeutic elevation of cAMP will result in reduced oxidative damage to tissues in neutrophildominated inflammatory reactions.Production of cAMP in leucocytes is stimulated by /3-adrenergic catecholamines, histamine and the E series prostaglandins by a receptor-coupled activation of adenylate cyclase, an enzyme which catalyses the conversion of adenosine triphosphate to cAMP [3]. Rises in intracellular cAMP are usually transient, cAMP being rapidly broken down by phosphodiesterases (PDEs) to 5'AMP. A role for cAMP in a particular cell function can be inferred from the use of agents that activate adenylate cyclase (receptor-coupled activation or direct activation with agents such as cholera toxin [4] or forskolin [5]), duplication of the cell response with a" hydrophobic (i.e. membrane-permeable) analogue of cAMP (e.g. dibutyryl cAMP), inhibition of PDEs with methylxanthines (e.g. theophylline [6]) or isoenzyme-specific agents (see below) and by assessing the effects of these various treatments on intracellular cAMP levels.At an infiammatory site, mast cells are stimulated to degranulate, causing release of vasoactive and other infiammatory mediators. Circulating leucocytes adhere to vascular endothelium and accumulate at the infiamed site under the direction of chemotactic factors. Phagocytic stimuli cause release of lysosomal enzymes and reactive oxygen species (ROS) from neutrophils, eosinophils and macrophages. Antigen recognition causes proliferation and differentiation of lymphocyte subsets. In vitro work has suggested that following cell stimulation, agents that elevate cAMP reduce: immunological release of histamine and leukotrienes from mast cells [7], monocyte [8] and neutrophil [9,10] [24]) cAMP levels vary during the reactions, low levels being observed as the reactions proceed and normal or higher levels being observed as the reactions subside [25]. The experimental data therefore suggest that cAMP is part of an endogenous mechanism for down-regulating the infiammatory response and preventing the beneficial effects of acute infiammation from progressing to chronic inflammation and its associated tissue destruction. This view is supported by the clinical finding that leucocytes from atopic individuals appear to have higher than normal PDE activity [26].The targeting ofa single mediator or group of mediators for treat...
experiment, which was repeated four times. Air cavities were produced by injecting 5 ml of air into the subcutaneous tissue of the back of the animals. Three days later 2*5 ml of air was injected into the same cavity to maintain its patency. Six days after the initial air injection animals were anaesthetised with ether and 1 ml of carrageenan was injected into the cavity. Control animals were injected with physiological saline. Groups of animals were killed at 30 min, and one, four, and 24 hours after the initial injection of the irritant. Total leucocyte numbers and the volume of fluid in the cavities were measured by the method previously described.8 The entire wall of the cavities was then removed, fixed in Bouin's fluid, and finally, embedded in paraffin wax. Serial sections were cut and stained with a modified Dominici9 and Csabas mast cell stain. Each section was microprojected on transparent paper at a magnification of 20x. The margins of the cavity wall including hair follicles, muscles, and blood vessels were drawn. The
Nitric oxide produced from L-arginine by nitric oxide synthase (NOS) acts in a variety of biological processes via the stimulation of guanylyl cyclase and subsequent elevation of cGMP. Constitutive, calcium-dependent isoforms of NOS are found in endothelial cells (eNOS) and neurones (nNOS), while macrophages express an inducible, calcium-independent isoform (iNOS) in response to the action of certain cytokines or bacterial endotoxin. While the regulation of NOS by exogenous glucocorticoids and steroid hormones is well documented, the effects of endogenous steroid hormones on NOS activity, such as those released during the oestrous cycle, is unknown. Here we demonstrate, using specific antibodies for eNOS, nNOS and iNOS, the presence of NOS in the epithelium of rat fallopian tubes at pro-oestrus, late pro-oestrus, oestrus, metoestrus and dioestrus. Western blot analysis of rat fallopian tube homogenates revealed a protein band at approximately 125 kDa which was recognised by antibodies to different isoforms of NOS, but no bands at the expected molecular weights (eNOS, 140 kDa; nNOS, 160 kDa; iNOS, 135 kDa). NOS activity in fallopian tubes was measured by the conversion of L-[3H]arginine to L-[3H]citrulline. Both calcium-dependent and -independent NOS activities were present. However, in late pro-oestrus when circulating oestrogens are low, NOS activity was reduced in comparison to all other stages of the oestrous cycle. Thus we show that NOS is present in the epithelial lining of the fallopian tube and is recognised at a previously undescribed molecular weight.(ABSTRACT TRUNCATED AT 250 WORDS)
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