Oxidant-mediated activation of phospholipase A2 in pulmonary endothelium

Chakraborti, Sajal; Gurtner, G. H.; Michael, J. R.

doi:10.1152/ajplung.1989.257.6.l430

Cited by 75 publications

(59 citation statements)

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“…However, the rate-limiting step for prostacyclin production is the liberation of substrate, arachidonic acid, from cell membranes by the actions of PLA 2 (30). Activation of PLA 2 in endothelial cells is dependent on the liberation of calcium from intracellular stores and can be blocked by TMB-8 (11). In the present study, we found that EDHF responses were significantly reduced when TMB-8 was included as a pretreatment together with L-NAME.…”

Section: Discussionsupporting

confidence: 51%

Elucidation of the temporal relationship between endothelial-derived NO and EDHF in mesenteric vessels

Harrington¹,

Carrier²,

Gallagher³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Although the endothelium co-generates both nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF), the relative contribution from each vasodilator is not clear. In studies where the endothelium is stimulated acutely, EDHF responses predominate in small arteries. However, the temporal relationship between endothelial-derived NO and EDHF over more prolonged periods is unclear but of major physiological importance. Here we have used a classical pharmacological approach to show that EDHF is released transiently compared with NO. Acetylcholine (3 ϫ 10 Ϫ6 mol/l) dilated second-and/or thirdorder mesenteric arteries for prolonged periods of up to 1 h, an effect that was reversed fully and immediately by the subsequent addition of L-NAME (10 Ϫ3 mol/l) but not TRAM-34 (10 Ϫ6 mol/l) plus apamin (5 ϫ 10 Ϫ7 mol/l). When vessels were pretreated with L-NAME, acetylcholine induced relatively transient dilator responses (declining over ϳ5 min), and vessels were sensitive to TRAM-34 plus apamin. When measured in parallel, the dilator effects of acetylcholine outlasted the smooth muscle hyperpolarization. However, in the presence of L-NAME, vasodilatation and hyperpolarization followed an identical time course. In vessels from NOSIII Ϫ/Ϫ mice, acetylcholine induced small but detectable dilator responses that were transient in duration and blocked by TRAM-34 plus apamin. EDHF responses in these mouse arteries were inhibited by an intracellular calcium blocker, TMB-8, and the phospholipase A 2 inhibitor AACOCF3, suggesting a role for lipid metabolites. These data show for the first time that EDHF is released transiently, whereas endothelial-derived NO is released in a sustained manner.arteries; vasodilation; mediators; hyperpolarization; nitric oxide; endothelium-derived hyperpolarizing factor THE ENDOTHELIUM-DERIVED relaxing factor, described in 1980 by Furchgott and Zawadozki (18), is now known to be nitric oxide (NO) (22, 23), formed from the amino acid L-arginine (32). In 1988, reports emerged of a distinct factor released by the endothelium that relaxed blood vessels via a process of hyperpolarization (endothelium-derived hyperpolarizing factor; EDHF) (2,3,15). Since this time, EDHF biology has developed at a rapid pace (9). However, there is still considerable debate about the identity of EDHF. Potential candidates include CYP450 metabolites (17), K ϩ (16), hydrogen peroxide (26), and K ϩ and/or electrical communications through gap junctions (39) and possibly C-type natriuretic peptide (CNP) (13).Much of the evidence supporting a role for EDHF in endothelium-dependent dilation has been derived pharmacologically, for example, by removing other dilatory pathways (NO and prostacyclin), removing the endothelium, removing the ability to hyperpolarize (with high [K ϩ ]), or blocking K ϩ channels with agents such as TRAM-34 plus apamin. Usually, experiments are conducted where the vessels are stimulated acutely and the responses monitored for short periods of time (seconds or minutes). The temporal nature of EDHF is...

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Section: Discussionsupporting

confidence: 51%

Elucidation of the temporal relationship between endothelial-derived NO and EDHF in mesenteric vessels

Harrington¹,

Carrier²,

Gallagher³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…The enzyme phospholipase A2 can be activated by ROS or calcium. [44][45][46][47][48][49] Once activated, phospholipase A2 cleaves arachidonic acid from cellular membrane phospholipids. The arachidonic acid is a substrate for the enzymes cyclooxygenase (COX, constitutively expressed) and COX-2 (induced by inflammatory cytokines; see above), leading to enhanced synthesis and release of prostaglandins and leukotrienes.…”

Section: Mechanisms Of Inflammation and Carcinogenesismentioning

confidence: 99%

Inflammation as Cause for Scar Cancers of the Lung

Ardies

2003

Integr Cancer Ther

108

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The molecular and cellular basis of inflammation has become a topic of great interest of late because of the association between mechanisms of inflammation and risk for cancer. Inflammatory-mediated events, such as the production of reactive oxygen species (ROS), the activation of growth factors (for wound repair), and the altering of signaltransduction processes to activate cell-proliferation (to replace necrotic/apoptotic tissue cells), events that also can occur independently of inflammation, are all considered to be components of risk for a variety of cancers. Using scar cancer of the lung as an example, mechanisms of inflammation associated with recurring infections with Mycobacterium tuberculosis are discussed in the context that they may, in fact, be the major or sole cause of a cancer. Production of ROS, prostaglandins, leukotrienes, and cytokines in pulmonary tissues is greatly enhanced due to a cell-mediated immune response against macrophages infected with M. tuberculosis. These responses lead to the extensive fibrosis associated with recurring infections, possibly leading to decreased clearance of lymph and lymph-associated particles from the infected region. They also will enhance rates of cell division by inhibiting synthesis of P21, leading to enhanced progression from G0 arrest to G1 phase, from G1 to S phase, and from G2 to M phase of the cell cycle. By increasing rates of oxidative DNA damage and inhibiting apoptosis by enhancing synthesis of BCL-2, mutagenesis of progeny cells is enhanced, and these effects coupled with enhanced angiogenesis stimulated by COX-2 products lead to an environment that is highly conducive to tumorigenesis. Based on the evidence, it appears that but for an inflammatory response to recurring infections, some cases of scar cancer would not exist. By making appropriate lifestyle and dietary changes, a variety of anti-inflammatory effects can be produced, which should attenuate inflammation-induced risk for cancer.

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“…Increased epithelial cell paracellular permeability (decreased barrier function) has been reported in a) pulmonary epithelium of dogs exposed to sulfur dioxide (59) and nitrogen dioxide (60); b) Madin Darby canine kidney (MDCK) epithelial cells exposed to H202, glucose/glucose oxidase, and xanthine/XO (66); c) ferret tracheal epithelium exposed to xanthine/XO (67); and d) rat alveolar epithelium exposed to H202 (15). P/XO also induces permeability edema in isolated perfused rabbit lungs (68 pulmonary endothelial cells (70). AA and eicosanoids are released by BEAS-2B cells after in vitro 03 exposure (71,72).…”

Section: Airway Inflammationmentioning

confidence: 99%

Interactions of oxygen radicals with airway epithelium.

Wright

Cohn

et al. 1994

Environ Health Perspect

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Reactive oxygen species (ROS) have been implicated in the pathogenesis of numerous disease processes. Epithelial cells lining the respiratory airways are uniquely vulnerable regarding potential for oxidative damage due to their potential for exposure to both endogenous (e.g., mitochondrial respiration, phagocytic respiratory burst, cellular oxidases) and exogenous (e.g., air pollutants, xenobiotics, catalase negative organisms) oxidants. Airway epithelial cells use several nonenzymatic and enzymatic antioxidant mechanisms to protect against oxidative insult. Nonenzymatic defenses include certain vitamins and low molecular weight compounds such as thiols. The enzymes superoxide dismutase, catalase, and glutatione peroxidase are major sources of antioxidant protection. Other materials associated with airway epithelium such as mucus, epithelial lining fluid, and even the basement membrane/extracellular matrix may have protective actions as well. When the normal balance between oxidants and antioxidants is upset, oxidant stress ensues and subsequent epithelial cell alterations or damage may be a critical component in the pathogenesis of several respiratory diseases. Oxidant stress may profoundly alter lung physiology including pulmonary function (e.g., forced expiratory volumes, flow rates, and maximal inspiratory capacity), mucociliary activity, and airway reactivity. ROS may induce airway inflammation; the inflammatory process may serve as an additional source of ROS in airways and provoke the pathophysiologic responses described. On a more fundamental level, cellular mechanisms in the pathogenesis of ROS may involve activation of intracellular signaling enzymes including phospholipases and protein kinases stimulating the release of inflammatory lipids and cytokines. Respiratory epithelium may be intimately involved in defense against, and pathophysiologic changes invoked by, ROS. -Environ Health Perspect 1 02(Suppl 1 0): 85-90 (1994)

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Oxidant-mediated activation of phospholipase A2 in pulmonary endothelium

Cited by 75 publications

References 0 publications

Elucidation of the temporal relationship between endothelial-derived NO and EDHF in mesenteric vessels

Elucidation of the temporal relationship between endothelial-derived NO and EDHF in mesenteric vessels

Inflammation as Cause for Scar Cancers of the Lung

Interactions of oxygen radicals with airway epithelium.

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