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H J Forman

Publications and source records attributed to H J Forman.

106 records · Page 6Linked to original sources
PubMed1974

Activation of carbamoyl phosphate synthase by N-acetyl-L-aspartate.

Carbamoyl phosphate synthase from liver of both rat and frog, normally dependent on N-acetyl-l-glutamate (on the basis of K(m) and physiological concentrations) as an activator, was shown to be activated by high concentrations of N-acetyl-l-aspartate. However, the high concentrations of N-acetyl-l-aspartate required for activation produce non-competitive inhibition. Similarly, high concentrations of N-acetyl-l-glutamate, in very large excess of the amount required to activate the enzyme, inhibit. The limit for N-acetyl-l-glutamate as an impurity in N-acetyl-l-aspartate was found to be less than 1 in 5000 parts, far below the 1 in 250 parts needed to produce the activation observed with N-acetyl-l-aspartate.

Animals↗
PubMedDate not supplied

Redox signaling in macrophages.

Macrophages are phagocytic cells that produce and release reactive oxygen species (ROS) in response to phagocytosis or stimulation with various agents. The enzyme responsible for the production of superoxide and hydrogen peroxide is a multi-component NADPH oxidase that requires assembly at the plasma membrane to function as an oxidase. In addition to participating in bacterial killing, ROS, which have recently been shown to be produced enzymatically by non-phagocytic cells, have been implicated in inflammation and tissue injury. These toxic effects have been largely explored over the years and these studies have overshadowed initial observations supporting a role for ROS in modulating cellular function. In recent years, it has become increasingly evident that ROS can function as second messengers and, at low levels, can activate signaling pathways resulting in a broad array of physiological responses from cell proliferation to gene expression and apoptosis. Macrophages can also produce large amounts of nitric oxide (nitrogen monoxide, *NO). *NO was first identified as the endothelial-derived relaxing factor, EDRF and its role in the signaling pathway leading to its physiological effect was rapidly established. The ability of *NO to react with O(2)(*-) to produce peroxynitrite (ONOO(-)) was later recognized. As it is diffusion-limited, this reaction is more likely to occur in cells like macrophages that produce both ROS and RNS. In this review, we will summarize the current knowledge in redox signaling, and describe more specifically studies that are particular to macrophages.

Animals↗
PubMedDate not supplied

The alveolar macrophage as a model of calcium signaling in oxidative stress.

Regulation of the free intracellular calcium concentration, [Ca2+]i, plays a major role in physiological signal transduction. Many of the essential enzymes in signaling cascades are Ca(2+)-dependent, as are numerous proteins that participate in the regulated function. Oxidative stress, which for many years was considered synonymous with cell and tissue injury, has more recently been demonstrated to alter signal transduction in both positive and negative directions. The realization that hydrogen peroxide and lipid hydroperoxides are produced as part of normal metabolism has led to the proposal that these oxidants function as second messengers. Exposure to environmental and other agents that produce hydroperoxides or the addition of exogenous hydroperoxides also causes elevation of [Ca2+]i in some cells. At sublethal exposure to hydroperoxides, the elevation in [Ca2+]i can either alter or mimic physiological stimulation. In addition to endoplasmic reticulum, mitochondria, and the extracellular space, the phospholipid- and Ca(2+)-binding proteins known as annexins constitute a Ca2+ pool from which this ion may be released under situations of oxidative stress. In this article, the source and consequences of Ca2+ elevation are reviewed with an emphasis on studies done with alveolar macrophages. These phagocytes, which modulate much of the physiological and immunological function of the lung, are susceptible targets for environmental oxidants.

Calcium↗
PubMedDate not supplied

Glutathione, stress responses, and redox signaling in lung inflammation.

Changes in the ratio of intracellular reduced and disulfide forms of glutathione (GSH/GSSG) can affect signaling pathways that participate in various physiological responses from cell proliferation to gene expression and apoptosis. It is also now known that many proteins have a highly conserved cysteine (sulfhydryl) sequence in their active/regulatory sites, which are primary targets of oxidative modifications and thus important components of redox signaling. However, the mechanism by which oxidants and GSH/protein-cysteine-thiols actually participate in redox signaling still remains to be elucidated. Initial studies involving the role of cysteine in various proteins have revealed that cysteine-SH may mediate redox signaling via reversible or irreversible oxidative modification to Cys-sulfenate or Cys-sulfinate and Cys-sulfonate species, respectively. Oxidative stress possibly via the modification of cysteine residues activates multiple stress kinase pathways and transcription factors nuclear factor-kappaB and activator protein-1, which differentially regulate the genes for proinflammatory cytokines as well as the protective antioxidant genes. Understanding the redox signaling mechanisms for differential gene regulation may allow for the development of novel pharmacological approaches that preferentially up-regulate key antioxidants genes, which, in turn, reduce or resolve inflammation and injury. This forum article features the current knowledge on the role of GSH in redox signaling, particularly the regulation of transcription factors and downstream signaling in lung inflammation.

Animals↗
PubMedDate not supplied

Ontogeny of antioxidant enzymes in the fetal lamb lung.

Pulmonary antioxidant enzyme ontogeny has been reported in species with a relatively short gestation such as hamsters, rats, rabbits, and guinea pigs. We examined the ontogeny of the antioxidant enzyme system together with the surfactant phospholipid disaturated phosphatidylcholine (DSPC) in fetal lamb lung (term is 148 days). Lung tissue from 36 fetuses with gestational ages ranging from 121 to 145 days were assayed for DSPC content and for the activities of three antioxidant enzymes: superoxide dismutase, catalase, and glutathione peroxidase. Between 121 and 145 days gestation superoxide dismutase activity increased from 25 +/- 4 to 139 +/- 18 IU/mg DNA, catalase activity from 164 +/- 23 to 483 +/- 48 IU/mg DNA, glutathione peroxidase activity from 301 +/- 33 to 447 +/- 53 IU/mg DNA, and DSPC content from 0.48 +/- 0.04 to 1.61 +/- 0.11 mg/mg DNA. During the final 15-20% of gestation in the fetal lamb antioxidant enzyme activity rises sharply in parallel with the development of the surfactant system.

Animals↗
PubMedDate not supplied

Dual effect of nitrogen dioxide on rat alveolar macrophage arachidonate metabolism.

Significant deficits in alveolar macrophage (AM) function have been associated with acute exposure to nitrogen dioxide (NO2). The present investigation examined changes in enzymatic production of arachidonate metabolites from rat AM exposed to NO2. While in vitro exposure of AM to NO2 concentrations between 0.1 and 5 ppm alone had small effects on basal synthesis of cyclooxygenase or lipoxygenase products, exposure to either 1 ppm (2 or 4 h) or 5 ppm (1 h) markedly enhanced the response of AM to stimulation by the calcium ionophore, A23187. This pre-exposure led to significant increases in cyclooxygenase products (thromboxane B2 (thromboxane), the stable metabolite of thromboxane A2, and 12-hydroxyheptadecatrienoic acid (12-HHT)) and lipoxygenase products (leukotriene B (LTB4) and monohydroxyeicosatetraenoate isomers) in response to A23187. In contrast, a 1-h exposure to 20 ppm NO2 alone significantly increased AM synthesis of thromboxane and 12-HHT, but suppressed the effect of subsequently added A23187. Increased synthesis of cyclooxygenase products with 20 ppm NO2 alone were blocked with the phospholipase inhibitor mepacrine and the cyclooxygenase inhibitor indomethacin. The lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) significantly reduced release of arachidonate; however, levels of thromboxane and 12-HHT were significantly increased. The results suggest a dual effect of NO2 on AM arachidonate metabolism in which low concentrations of NO2 had small effects on basal metabolism but markedly amplified the response to stimuli, while a high concentration of NO2 did the reverse. Such a complex dose-response effect may have significant impact in explaining the pathologic effects of NO2.

Animals↗
PubMedDate not supplied

Ethanol inhibition of signal transduction in superoxide production by rat alveolar macrophages. A proposed mechanism for ethanol related pneumonia.

Alveolar macrophages and neutrophils produce superoxide and other free radicals which are important in killing bacteria. The focus of this paper is the inhibition by ethanol of superoxide production and anti-bacterial activity. The signal transduction pathways leading to superoxide production by phagocytic cells will be reviewed. Our hypothesis is that ethanol alters these signal transduction pathways. Stimulation of superoxide production can be initiated by concanavalin A and phorbol esters. Previously, there were reports by us that ethanol, in vitro, inhibits phorbol ester induced superoxide production in rat alveolar macrophages. Our present report states that concanavalin A induced superoxide production was more sensitive to ethanol inhibition than phorbol ester induced superoxide production. The ethanol induced inhibition of alveolar macrophage superoxide production provides a possible mechanism to explain the increased sensitivity of alcoholics to pneumonia.

Cell Communication↗