NADPH oxidase mediated oxidative stress in hepatic fibrogenesis

NADPH oxidase (NOX) is a multicomponent enzyme complex that generates reactive oxygen species (ROS) in response to a wide range of stimuli. ROS is involved as key secondary messengers in numerous signaling pathways, and NADPH oxidases complex has been increasingly recognized as key elements of intracellular signaling of hepatic fibrogenesis. In the liver, NADPH oxidase is functionally expressed both in the phagocytic form and in the non-phagocytic form. The non-phagocytic NADPH oxidase complex is structurally and functionally similar to the phagocytic NADPH, resulting in reduction of molecular oxygen to generate superoxide. There are six homologous NOX proteins in the non-phagocytic forms of NADPH oxidase. An emerging concept is that both phagocytic and nonphagocytic NADPH oxidase components in hepatic stellate cells (HSCs) mediate hepatic fibrosis, suggesting its potential role as a pharmacological target for anti-fibrotic therapy. The molecular components and signaling pathways of various NADPH oxidase homologues that are critical for the fibrotic activity in HSCs need to be more clearly identified

Phagocytic properties of lung alveolar wall cells

For the purpose to define the mechanism of heavy metal intoxication by inhalation, morphologic observations were made on rat lungs after nasal instillation of iron colloid particles of positive and negative electric charges. Histochemical observation was also made on the liver and spleen of these animals. The instilled iron colloid particles reach the alveolar cavity easily, as can be seen in the tissue sections stained by Prussian blue reaction. Alveolar macrophages do take up them avidly both of positive and negative charges, though much less the positive particles than negative ones. In contrast, the alveolar epithelial cells take up solely positive particles by phagocytosis but not negative ones. Electron microscope observation revealed that the positive particles are ingested by Type I epithelial cells by pinocytosis and by Type II cells by phagocytosis as well. Then the iron colloid particles are transferred into the basement membrane by exocytosis. Travelling through the basement membrane they are again taken up by capillary endothelial cells by phagocytosis. Some particles were found in the intercellular clefts of capillary endothelial cells but not any iron colloid particles in the intercellular spaces of epithelial cells and in the capillary lumen. However, the liver and spleen tissues of the animals given iron colloid showed a strong positive iron reaction. On the basis of these observations, the mechanism of acute intoxication by inhaling heavy metal dusts like lead fume is discussed from the view point of selective uptake of alveolar epithelial and capillary endothelial cells for the particles of the positive electric cha'rge.</p

Suppression of antibody formation by the res-blockade. &#8546;. Effects of the res-blockade with methyl palmitate

The rats which received the repeated intra peritoneal or intravenous&#12288;injections of methyl palmitate showed a marked depressed phagocytic activity&#12288;of the RES as shown by the clearance test with radioactive iron as&#12288;well as by histological observations and a significantly suppressed antibody&#12288;formation against the challenge by BSA.&#12288;Differing from the cases of the blockade of the RES made by PVP or&#12288;radiogold, the injection of methyl palmitate did not result in any injurious&#12288;effect on the lymph follicles of lymph nodes and spleen and the plasma&#12288;cells proliferation as revealed by the histological observation. Histochemical observations of iron phagocytosis of the RES done by&#12288;Perls stain revealed that methyl palmitate&#12288;suppressed the phagocytic activity&#12288;of the Kupffer cells of the liver dramatically and also suppressed the&#12288;phagocytic activity of the sinus-lining cells in spleen to a lesser degree.&#12288;The result indicates that the injection of methyl palmitate attacks the phagocytic&#12288;function of the RES selectively and induces the reduced immune&#12288;response of the organism without giving any damages to the proliferation of immunologically com petent cells.&#12288;The fact suggests that the RES lowered in their phagocytic activity&#12288;fails to produce the informational substance for immune&#12288;response, showing&#12288;a lower level in the antibody formation even in the presence of antigen&#12288;and proliferating immunologically competent cells.</p

Suppression of antibody formation by the reticuloendothelial (RES)-blockade. I. Effects of the RES-blockade with macromolecular polyvinyl pyrrolidone

For the purpose of revealing the role of the reticuloendothelial system (RES) for the antibody formation, the rats which received the repeated intraperitoneal and subcutaneous injections of a vast amount of PVP were challenged by bovine serum albumin (BSA) introducing through 2 routes of intramuscular and intravenous, and then antibody formation was observed. Blood cell count and clearance rate of radiogold were observed for the purpose of obtaining the information of blockade grade of the RES by PVP. Phagocytic activity of macrophages ingesting PVP against iron colloid were also observed in vitro. 1. A severe anemia was induced by the administration of a vast amount of PVP, 15 ml of 3% solution daily or every other day for 63 days. Histological picture indicated the suppressed erythropoiesis probably by iron deficiency or the lowered iron transporting activity of the RES, as the anemia recovered after intraperitoneal iron injections. 2. With the generalized and marked swelling of the RES, the cells in germinal center of spleen and lymph nodes were extremely swollen and lymphocytes disappeared completely, suggesting that the macrophages in germinal center play an important role in reproduction and differentiation of lymphocytes. 3. The phagocytic activity of the RES as understood from the clearance rate of radiogold was suppressed only slightly even by a heavy deposition of PVP after the repeated injections. The state of blockade or the suppressed phagocytic activity persisted for 48 hours or more after the several PVP injections. However, complete blockade of the RES or inactivation of the phagocytic activity by PVP injection was not attained. 4. A prolonged treatment of animals with PVP caused delay in the appearance of circulating antibody but the final titration reached the same level as that of control. The data suggest that the blockade of the RES by PVP induces the delay in the transmittance of the information for the antibody formation from the macrophages to the immunologically competent cells but no delay in the ingesting antigen by the macrophages.</p

In vivo immunomodulatory effect and histopathological features of mouse liver and kidney treated with neolignans isolated from red betel (Piper crocatum Ruiz & Pav) leaf

Purpose: To investigate in vivo immunomodulatory effect and histopathological feature of mouse liver and kidney following treatment with 2 neolignans (Pc-1 and Pc-2) isolated from red betel (Piper rocatum Ruiz &amp; Pav) leaf.Methods: Balb/c mice immune response was induced with Listeria monocytogenes. Immunomodulatory effect was tested by using macrophage phagocytic, nitric oxide, and lymphocyte proliferation assays. The morphological features of liver and kidney were observed with light microscope and then compared with the liver and kidney of control group.Results: At the dose of 5 and 10 mg/kg body weight, both Pc-1 and Pc-2 significantly increased the activity and the capacity of macrophages (p &lt; 0.05). Both Pc-1 and Pc-2 significantly increased phagocytic activity of macrophage by 25% and 23%, respectively, and phagocytic index to 38 and 52, respectively at a dose of 5 mg/kg body weight. Increases in nitric oxide production due to Pc-1 and Pc- 2 (at doses of 2.5, 5, and, 10 mg/kg body weight) were also observed although no lymphocyte proliferation effect was observed. Histopathological examination of liver and kidney of mice given Pc-1 demonstrated normal features. On the other hand, hydropic degeneration and liver necrosis were seen in mice given Pc-2 treatment. Based on this result and the structure similarity of the two compounds (Pc-1 and Pc-2), an interesting presumption was made that the –OH functional group (Pc-2) was responsible for the toxicity that caused liver damage.Conclusion: The two neolignans (Pc-1 and Pc-2) isolated from the leaves of P. crocatum Ruiz &amp; Pav. are capable of increasing macrophage phagocytosis as well as nitric oxide production but not lymphocyte proliferation. Histophatological features of liver given Pc-2 demonstrate hydropic degeneration and necrosis, possibly due to the –OH group on Pc-2.Keywords: Piper crocatum Ruiz &amp; Pav, Immunomodulatory, Liver necrosis, Kidney, Hydropic degeneration, Macrophage phagocytosi

MRI Tracking of Macrophages Labeled with Glucan Particles Entrapping a Water Insoluble Paramagnetic Gd-Based Agent.

PURPOSE: This study is aimed at demonstrating the in vivo potential of Gd(III)-loaded glucan particles (Gd-GPs) as magnetic resonance imaging (MRI)-positive agents for labeling and tracking phagocytic cells. PROCEDURE: GPs were obtained from Saccharomyces cerevisae and loaded with the water-insoluble complex Gd-DOTAMA(C18)2. The uptake kinetics of Gd-GPs by murine macrophages was studied in vitro and the internalization mechanism was assessed by competition assays. The in vivo performance of Gd-GPs was tested at 7.05 T on a mouse model of acute liver inflammation. RESULTS: The minimum number of Gd-GPs-labeled J774.A1 macrophages detected in vitro by MRI was ca. 300 cells/μl of agar, which is the lowest number ever reported for cells labeled with a positive T1 agent. Intravenous injection of macrophages labeled with Gd-GPs in a mouse model of liver inflammation enabled the MRI visualization of the cellular infiltration in the diseased area. CONCLUSIONS: Gd-GPs represent a promising platform for tracking macrophages by MRI as a T1 alternative to the golden standard T2-based iron oxide particles

Effects of stress on the immune system of fish

The effects of stress on the immune system of various fish species including dab Limanda limanda, flounder Platichthys flesus, sea bass Dicentrarchus labrax and gobies Zosterisessor ophiocephalus, were investigated from laboratory and field experiments, using various assays to measure immunocompetence, correlated with histological and ultrastructural observations. Modulation of the immune system was demonstrated at tissue, cellular and biochemical levels following exposure to various stressors. The spleen somatic index was depressed in dab stressed in the laboratory and gobies collected from polluted sites in the Venice Lagoon. Differential blood cell counts consistently showed an increase in phagocytes and decrease in thrombocytes in fish exposed to various stressors. Phagocytic activity from spleen and kidney adherent cells was stimulated in dab stressed by transportation but depressed in fish exposed to chemical pollutants. Respiratory burst activity in phagocytic cells was also stimulated in stressed dab but depressed in sea bass exposed to cadmium. The results are discussed in relation to current concepts on stress in fish and the regulation of the immune system

Possible role of the phagocytic proteinases, cathepsin B and elastas, in orthotopic liver transplantation

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