Immunopharmacology of Free Radical Species (Handbook of Immunopharmacology)
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Inhibition of Citral Deterioration-- Protective effect of phytic acid and its hydrolysis products on iron ion-induced oxidative damage in the large intestinal mucosa: In vitro and ex vivo study-- Generation of lipid peroxyl radicals from oxidized edible oils and heme-iron: Implication of a high-fat diet in colon carcinogenesis-- This book intends to illustrate the potential chemical links between food and health. The book is organized into three main sections: Food Chemistry, Antioxidants, and Nutritional Biochemistry and Health. Chapters in the Food Chemistry section cover free radical participation in Maillard reactions, emulsions and lysozymes, milk, meat, and extruded grains.
This section also addresses detection of radicals by ESR and spin trapping techniques. Chapters in the Antioxidant section cover phenolic and polyphenols from seeds and tea, tannins, and isoflavonoids. Chapters in the Nutritional Biochemistry and Health section cover the influence of food antioxidants and radical damaged ingredients on oxidases, colon carinogenesis, atherosclerosis, and liver epithelial RL34 cells. The ability of specific food components and supplements to intervene in free radical reactions is believed to play a significant role in their ability to promote health and ameliorate disease.
Free Radicals in Food presents specific chemical evidence to support these hypotheses. Bibliographic information.
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Browse related items Start at call number: RB Missense mutations in the extracellular domain of the gene encoding TNFR1 lead to inheritable autosomal dominant disorder known as tumor necrosis factor receptor-associated periodic syndrome TRAPS TRAPS is an auto-inflammatory disease that is associated with recurrent fevers, peritonitis, migratory rash, myalgia, and arthralgia.
Although the basis by which TNFR1 mutations leads to increased mitochondrial ROS is not clear, possible mechanisms include retention of the mutated protein in the endoplasmic reticulum, which can induce unfolded protein response, triggering calcium release from ER and depolarizing mitochondria by disruption of the mitochondrial ETC NLRP3 inflammasome, the most well-characterized form, is redox sensitive 99 , MtROS has also been implicated in increasing oxidative stress through cross-talk with nitric oxide synthases NOSs Arginase II, which activates NOS, was shown to promote the macrophage inflammatory response that contributes to insulin resistance and atherogenesis Inflammasome activation by ROS.
Block et al. In an independent study, Ago et al. However, no such localization of NOX4 or any other NADPH oxidase was observed in mitochondria in other reports , whereas Gorlach group localized NOX4 to endoplasmic reticulum in endothelial cells and was shown to be essential for endothelial ROS production and proliferation A dysregulation in this relationship may drive the vicious feed-forward cycle of ROS accumulation that can enhance inflammatory response in different diseases 96 , Of these isoforms, only eNOS is the membrane-associated protein and is the predominant source of NO in vascular endothelial cells The prosthetic heme group connects the two monomers.
NO is produced by eNOS in two successive mono-oxygenation reactions of arginine, leading to formation of L-citruline Fig. The superoxide generated by eNOS uncoupling has been implicated in a variety of inflammatory conditions, including acute lung injury , diabetes mellitus , and Ang II-induced hypertension NO possesses strong anti-inflammatory properties. Dal et al. Moreover, the mice that have been treated with NOS inhibitors such as NG-nitro-l-arginine, or with a soluble guanylate cyclase inhibitor, ODQ exhibited enhanced LPS-induced neutrophil migration that was accompanied by enhanced expression of ICAM-1 on endothelial cells The anti-inflammatory effects of NO are mediated by suppressing LPS-induced increase in ICAM-1 expression and decreasing the rolling and adhesion of the neutrophils on the endothelium The dimer interface of eNOS carries the binding sites for the cofactor tetrahydrobiopterin BH 4 and the substrate L-arginine.
The reduced bio-availability of BH4 has been reported to be due to oxidation by peroxynitrite, resulting in the formation of inactive BH2 Increased levels of ADMA have been reported in endothelial cultures treated with low-density lipoprotein, mouse lung exposed to endotoxin LPS, and septic shock patients 44 , , ADMA are generated by S -adenosylmethionine—dependent protein arginine methyltransferases that themselves are induced by enhanced oxidative stress The activity of XO is up-regulated in the airway inflammatory disorders, ischemia reperfusion injury, atherosclerosis, diabetes, and autoimmune disorders such as rheumatoid arthritis The serum samples from rheumatic patients may have approximately fold higher levels of XO compared with healthy donors XO-derived ROS has also been implicated in pulmonary vascular remodeling induced by chronic hypoxia in neonatal rats The serum activity of XO is up-regulated by hypoxia, and administration of allopurinol limited the hypoxia-induced oxidative stress in the lung and pulmonary vascular remodeling; highlighting the critical role of XO-derived ROS in the chronic hypoxia induced pulmonary hypertension Altogether, the XO-derived ROS seems to be important in a variety of inflammatory disorders; however, the therapeutic advantage of XO inhibitors such as allopurinol for other inflammatory diseases and other forms of organ injury remains to be investigated.
To prevent the damaging effects of oxidants, vertebrate cells have evolved an array of antioxidant defense systems that functions to remove ROS. Thus, cells experience an oxidative stress when the capacity of antioxidant enzymes is overcome by enhanced oxidant production. All SODs are highly expressed in lung tissue, vessels, and airways However, when their relative distribution is compared, the activities of CuZnSOD and MnSOD are lower in the lung compared with the other organs such as the liver, kidney, heart, and brain; whereas the EC-SOD activity has been reported to be much higher in the lung The knockout mice deficient in CuZn SOD and EC-SOD are viable and show no abnormality associated with oxidative damage, indicating that other antioxidant enzymes compensate for their deficiency under normal physiological conditions 51 , However, the knockout mice deficient in MnSOD die in the neonatal stage from dilated cardiomyopathy and impaired neural development , However, SOD1 knockout mice showed no enhancement of LPS-induced hepatotoxicity or hyperoxia-induced lung injury , In contrast, EC-SOD knockout mice exhibited enhanced sensitivity to LPS-induced neutrophilic lung inflammation and hyperoxia-induced lung injury 46 , All these observations suggest that tissue-specific distribution of the SOD isoforms and their relative amounts in different tissues is important in determining their role in inflammation.
The expression of catalase has been reported in alveolar type II cells and macrophages, and highest expression has been reported in the liver and erythrocytes Arita et al. Despite this important physiological link, no increase in the activity of catalase was reported after hyperoxia in endothelial cells and bronchial epithelial cells, which made them more susceptible to hyperoxia-induced injury The congenital deficiency of catalase known as acatalasia is benign; however, in certain conditions, increased susceptibility to diabetes has been reported Whether catalase is important in the pathogenesis of inflammation remains an open question.
The family of GPx enzymes serves the similar function of detoxifying H 2 O 2 as catalase. There are four selenium-dependent GPx enzymes GPx1—4 in mammalian tissue with a wide tissue distribution The expression and activity of GPx is induced by hyperoxia in endothelial cells However, GPx knockout mice showed no hypersensitivity to hyperoxia-induced lung injury, indicating the compensation from other antioxidant enzymes Reduced levels of GSH have been reported in a variety of inflammatory conditions , indicative of its important role in the inflammatory response through enhancing oxidative stress.
Peroxiredoxins are a group of related antioxidant enzymes that catalyze the degradation of H 2 O 2 to water. All subtypes of Peroxiredoxins are expressed in lung tissue The Prx6 knockout mice exhibit enhanced hypersensitivity to hyperoxia-induced lung injury , whereas Prx6 overexpressed mice were resistant to such damage Prx1 knockout mice were also reported to be prone to bleomycin-induced lung inflammation and allergic airway inflammation Further, administration by N-acetyl-cysteine in Prx1 knockout mice was found to protect them against bleomycin-induced acute lung injury, indicating a protective role of Prx1 against oxidative damage in inflammation Three Trx enzymes have been identified thus far Trx1, 2, and 3.
Oxidized Trx is recycled back to its reduced state by Trx reductase. The protective effects of Trxs as an antioxidant enzyme was reported in a variety of oxidative stress-related diseases such as ishchemia reperfusion injury, inflammation resulting from activation of neutrohils, blemomycin-induced lung injury, and inflammation induced by pro-inflammatory cytokines The Kelch-like ECH-associated protein 1 Keap1 retains Nrf2 in the cytoplasm and promotes its proteosomal degradation under basal condition , The deficiency of Nrf2 enhances the susceptibility to experimental acute lung injury and impairs the resolution of lung inflammation in mice.
Nrf2 activators such as triterpenoids CDDO-Im that target cysteine residues of Keap1 have been used to specifically disrupt Keap1:Nrf2 interactions, thereby promoting Nrf2 nuclear accumulation and leading to Nrf2-target gene induction in Nrf2-sufficient but not in Nrf2-deficient cells in vitro and in vivo , suggesting that specific targeting of Nrf2-ARE signaling may provide a novel therapeutic strategy for treating human diseases. We and others have shown reduced levels of acute lung injury and inflammation and emphysema in mice treated with CDDO-Im Recently, triterpenoid analogue, bardoxolone methyl, showed improved renal function in early-stage chronic kidney disease in type 2 diabetes; however, Phase III clinical trial with this compound for very severe-stage patients was halted due to undisclosed safety issues Reata Phamaceuticals ClinicalTrials.
Moreover, the recent study by Zoja et al. Since Nrf2 confers protection against oxidation-related pathologies and Nrf-2 activation may be a useful antioxidant strategy, it is likely that the unwarranted effects of chronic CDDO treatment may be related to nonspecific off-target effects. Alternatively, it is possible that prolonged activation of Nrf2 signaling may be more complicated because of the possibility of activation compensatory pro-oxidative stress pathways.
NF-E2-related factor 2 Nrf2 -dependent antioxidant mechanism. The migration of inflammatory cells across the endothelium of postcapillary venules is mediated by the adhesive interactions between the cell adhesion molecules CAMs expressed on activated endothelial and leukocytes. The neutrophils are the first cells to arrive at the inflamed location. The extravasation of neutrophils across the endothelial barrier occurs through endothelial junctions paracellular pathway and more rarely through the endothelial cell body transcellular pathway The three families of adhesion molecules that are crucial for leukocyte transmigration are selectins, integrins, and ICAM members of immunoglobulin Ig superfamily Fig.
The process of neutrophil transmigration is mediated by four sequential steps: i rolling, ii activation directed migration by setting up a chemoattractant gradient, iii adhesion to the endothelial cells, and iv transendothelial migration Fig. Schematic representation of transendothelial migration of leukocytes.
There are three main classes of CAMs: selectin family, integrin family, and immunoglobulin superfamily. The secretion of chemokine CXCL8 from WPB binds to chemokine receptor on neutrophils and activates integrin by changing its conformation from bend to a fully extended form. The activated integrins then subsequently bind to intercellular adhesion molecule-1 ICAM-1 and vascular cell adhesion molecule-1 VCAM-1 expressed in endothelial cells and cause neutrophil arrest on the endothelial surface. The Mac-1 integrins enable slow crawling of neutrophils toward the endothelial junctions.
The binding of JAM molecules further enables the deep penetration of neutrophils between endothelial cells. They are membrane glycoproteins that are expressed in both endothelial cells and leukocytes and are of three different types: P- expressed in platelets and endothelial cells , L- expressed in all leukocytes , and E- selectins expressed in endothelial cells 27 , The initial rolling of neutrophils on endothelial cells in response to inflammatory stimuli is mediated by selectins Fig.
Selectins are characterized by the presence of a carbohydrate recognition domain known as lectin that allows a low-affinity binding to sialylated carbohydrate moieties of mucin-like CAMs on leukocytes. These residues, known as sialyl Lewis-x SLex antigen, play an important role in leukocyte tethering and rolling Inherited defects in intracellular fucose transport impairs the formation of Lewis-x, resulting in leukocyte adhesion deficiency type II LAD II that is characterized by recurrent bacterial infection and impaired ability of neutrophils to bind endothelial cells expressing E-selectin , , Neutrophil rolling on vascular endothelium is the result of sequential formation and the detachment of selectin-mediated bonds between neutrophils and endothelial cells E-selectin binds to ligand E-selectin ligand-1 ESL-1 that is expressed in neutrophils and plays a key role in neutrophil rolling , On leukocyte activation, L-selectin is rapidly shed from the cell surface via a protease-dependent mechanism, which is important in the mechanism of transmigration and has also been implicated in mediating inflammation They are heterodimeric proteins, consisting of alpha and beta chains, and are expressed in leukocytes and many other cell types They facilitate firm adherence to the vascular endothelium.
The binding of chemokines to chemokine receptors CXCR1 and CXCR2 changes the conformation of integrins from bent to fully extended high-affinity configuration, enabling neutrophil arrest by binding to ICAM-1 that is expressed in endothelial cells Fig. LFA-1 is the principal adhesion molecule in neutrophils that binds to ICAM-1 in endothelial cells and mediates transition from rolling to adhesion on the endothelial cell surface Mac-1 also binds to ICAM-1 and mediates crawling of neutrophils along endothelial cells to the entry of endothelial junctions for paracellular migration There is a fold decrease in crawling displacement in Mac-1 null neutrophils, which forces them to transmigrate close to the initial site of adhesion and leads to transmigration The activation of LFA-1 is induced by the activation of chemokine receptors on neutrophils by ligands that are secreted by endothelial cells such as CXCL1 Fully activated LFA-1 mediates the stop of rolling and makes firm adhesion along with Mac-1 These patients suffer from recurrent bacterial infections.
The coating of fibronectin in an in vitro migration assay can greatly enhance the migration of human PMNs Polarization of neutrophils, which is important for efficient transendothelial migration, is mediated by the organization of filamentous actin F-actin cytoskeleton at the leading edge , It consists of CAMs that have an Ig-like domain and are expressed in endothelial cells, platelets, and leukocytes.
At the time of neutrophil transmigration, ICAM-1 and VCAM-1 are recruited in specialized preformed tetraspanin-enriched microdomains TEMs and promote nano-clustering of adhesion receptors to increase leukocyte binding to endothelium These specialized TEM domains have been termed endothelial adhesive platforms and are formed independent of ligand binding and actin cytoskeleton anchorage The binding of LFA-1 integrin on neutrophils with ICAM-1 on endothelial cells generate signals that activate Rho A, leading to actin polymerization and formation of transmigratory cups Transmigratory cups are microvilli-like projections that surround leukocytes and help in efficient transendothelial migration of leukocytes 24 , In the resting endothelium, PECAM-1 is stored along the cell borders in the intracellular compartment known as lateral border recycling compartment LBRC and translocates to the site of diapedesis when leukocyte migration occurs Fig.
The mechanism behind stimulus-dependent specificity of these junctional proteins is not clear. CD99L2, also known as leukocyte antigen, is a small membrane protein of amino acids that is expressed in endothelial cells. It is essential for neutrophil transmigration but not for lymphocytes CD99 L2 is not relevant for the adhesion between leukocytes and endothelium but rather for the transmigration step. The expression of ESAM, another endothelial adhesion molecule, is restricted to endothelial tight junctions TJs and plays a role in Rho A activation and junctional opening.
Thus, there appears to be a great deal of redundancy in the role of these endothelial adhesion molecules in mediating leukocyte transmigration.
One of the key questions is whether they are activated sequentially and whether they have distinct roles in the transmigration response. Only with dissection of the specific elements of the transmigration response into discrete steps will it become clear whether the function of these adhesion molecules is, in fact, distinct. The postcapillary vascular endothelium of all the secondary lymphoid organs except spleen is constitutively enriched in CAMs. These regions were classified as HEVs, enabling circulation of naive lymphocytes between the blood and lymph node.
Certain chronic inflammatory conditions such as rheumatoid arthritis, psoriasis, Hashimoto's thyroditis, Crohn's disease, ulcerative colitis, and multiple sclerosis are accompanied by development of HEVs in normal organs, facilitating a large influx of lymphocytes that contribute to chronic inflammation 8 , This de novo formation of organized lymphoid tissue in chronic inflammation diseases has been termed lymphoid neogenesis.
Psoriasis is a common cutaneous inflammatory disorder in which the dermal microvasculature undergoes distinctive changes, including HEV formation, which facilitates trafficking of lymphocytes to the skin There is an interesting correlation between Ang II-mediated activation of the immune system and hypertension , with the increased risk of hypertension and cardiovascular mortality in psoriasis patients that is associated with elevated levels of Ang II , There is considerable evidence indicating that extravasation of leukocytes in response to inflammatory stimuli is regulated by oxidative stress that is produced by leukocytes.
The adhesion of neutrophils to the surface of endothelial cells has been demonstrated to elicit a biphasic response that is related to endogenous ROS production in endothelial cells Oxidative stress can regulate the expression of endothelial CAMs by a direct activation of CAMs that presents on the surface and also by a transcription-dependent mechanism involving redox-sensitive transcription factors i. In this regard, Patel et al. Treatment of cells with an antibody against P-selectin or antioxidant treatment abolished neutrophil adhesion to endothelial cells. Similar to this study, Gaboury et al.
Unlike P-selectin, expression of ICAM-1, VCAM-1, and E-selectin is regulated at transcription level in endothelial cells by oxidative stress, although there is also considerable evidence that a significant component of ICAM-1 up-regulation on the endothelial cell surface is due to phosphorylation of cell-surface-bound ICAM-1 at tyrosine residues Interestingly, Matheny et al.
Increased expression of ICAM-1 and P-selectin was also observed in the mouse model of acute pancreatitis that was dependent on enhanced ROS production These monocytes showed increased adherence in culture to human endothelial cells and generated more intracellular ROS compared with control subjects Continuous positive airway pressure treatment of these patients decreased basal ROS production in monocytes and concomitantly decreased the expression of CD15 and CD11c on monocytes The circulating levels of ICAM-1, VCAM-1, and E-Selectin are elevated in hyperlipidemic and hyperglycemic and noninsulin-dependent diabetic-patients in direct correlation with increased oxidative stress 58 , 69 , 86 , , Reducing oxidative stress by GSH administration or NAC or low-fat diet improved the circulating levels of adhesion molecules 5 , 57 , 85 , All of these reports indicate that increased expression of CAMs induced by oxidative stress can contribute to the pathogenesis of the inflammatory disorders.
The vascular endothelium lining the blood vessels forms a continuous, semi-permeable restrictive barrier enabling the passage of macromolecules, inflammatory cells, and fluid between the blood and interstitial space. There are two different routes of transport across the endothelial barrier, transcellular across the cell and paracellular between the cells. The plasma protein albumin is actively transported by transcellular route by binding to a docking protein gp60 present in caveoli that transport it across the endothelium The paracellular route is tightly controlled by inter-endothelial junctions IEJs and TJs, which provides an unperturbed restrictive barrier to the endothelium Fig.
The paracellular permeability is the major route of vascular leakage observed in a variety of inflammatory states. The paracellular permeability was first described by Majno and Palade in rat cremaster muscle microvessels treated with a subcutaneous injection of histamine. They found that treatment with histamine leads to the formation of 0. Paracellular permeability enables the extravasation of protein-rich fluid from the luminal to abluminal side of the endothelium though gaps formed between endothelial cells.
The resulting protein-rich fluid leads to edema formation, which is a characteristic feature of most of the inflammatory conditions. Many of the permeability enhancing agents such as VEGF, thrombin, and PAF exert their actions by forming gaps between endothelial cells. The composition of TJs and IEJs and their regulation by oxidative stress and permeability-enhancing agents is described next:.
Structure of endothelial junctional proteins. Interaction between two adjacent endothelial cells is regulated by Adherens junction AJ and tight junction TJ proteins. TJs consist of integral transmembrane proteins, claudin, occludin, and JAM , form integral TJs between adjacent endothelial cells. TJs are composed of transmembrane proteins occludins, claudins, and JAMs.
The transmembrane proteins of TJs are connected to actin cytoskeleton by cytoplasmic adaptor proteins zonula occludens [ZO]-1, -2, and -3, AF6, and cingulin.
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The tightness of TJs depends on the protein composition and varies in different tissues ranging from almost complete tightening of the paracellular cleft for solutes e. Occludin consists of four transmembrane domains and two extracellular loops that enable a homotypic interaction with other occludin molecules and contributes to the TJ assembly. Arterial endothelial cells that are less permeable compared with vein endothelial cells have almost fold greater expression of occludin The C-terminal of occludin is linked to actin cytoskelton by cytoplasmic adaptor protein ZO The role of occludin in maintaining TJ stability is not clear.
A compensatory up-regulation of other junctional proteins may account for the observed normal phenotype in these mice. Claudins are transmembrane proteins of TJs that are similar to occludins and possess four transmembrane domains, two extracellular loops, and an N-terminal and C-terminal cytosolic domains.
At least 24 claudins are identified in humans. Similar to occludin, the PDZ domain in the c-terminus of claudin interacts with ZO-1 and connects claudins with actin cytoskeleton. The composition of claudins varies in different endothelial barriers and, hence, determines whether the barrier is selectively permeable e. The claudins involved in the sealing of TJs include claudin 1, 3, 5, 11, and 19 JAMs belong to Ig superfamily of proteins consisting of a single-pass membrane protein with a long extracellular domain. The expression pattern of the JAMs varies significantly in different cell types.
JAM-A is more widely distributed in epithelial cells, endothelial cells, monocytes, and neutrophils. Moreover, antibodies directed against JAM-A significantly delayed the recovery of transepithelial electrical resistance during TJ reformation in epithelial cell monolayers Orlova et al. Notably, disruption of JAM-C function decreased basal permeability and prevented the further increase in permeability induced by VEGF and histamine in human dermal microvascular endothelial cells in vitro and skin permeability in mice.
JAMs are also known to interact with different integrins on adjacent cells. This heterophilic interaction regulated leukocyte—endothelial cell and leukocyte—platelet interactions , , ZOs belong to a membrane-associated guanylate kinase GUK homologue protein family. ZO is an acronym for ZO. ZO-1 was the first TJ-specific protein identified There are two types of cadherins present in endothelial cells: VE-cadherin vascular endothelial cadherin and N-cadherin N for neuronal Although both are abundantly expressed in endothelial cells, VE-cadherin mainly promotes the homotypic interaction between endothelial cells, and when present, it excludes N-cadherin from those sites VE-cadherin is a homophilic binding protein that mediates the interaction of endothelial cells in a calcium-dependent manner.
It has five cadherin-like repeats in its extracellular domain that oligomerize in a cis- and trans-manner with other VE-cadherin molecules between the same and adjacent cells Fig. Both the N- and C-terminus of VE-cadherin are essential in the regulation of endothelial barrier function.
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Monoclonal antibodies targeted against N-terminus of VE-cadherin prevented the formation of IEJs and increased the microvascular permeability 70 , Interestingly, the C-terminal-truncated mutant of VE-cadherin in CHO cells did not impair the ability of cells to form aggregates; however, it greatly enhanced the intercellular junction permeability to high-molecular-weight molecules 56 , This finding suggests that the N-terminal region of VE-cadherin is required for cell—cell adhesion, whereas the C-terminal provides a tight restrictive barrier regulating paracellular permeability.
VE-cadherin is essential for the development of endothelial barrier in embryos, and VE-cadherin knockout mice die in the embryonic stage due to abnormal vascular development Moreover, expression of dominant negative VE-cadherin mutants also resulted in leaky junctions and an increase in microvascular permeability Homotypic binding of VE-cadherin molecule between endothelial cells is stabilized by calcium, and chelation of calcium using EDTA destabilized the junctions and increased transendothelial permeability Catenins are equally important in regulating the stability of AJs by connecting them with actin cytoskelton.
Oxidative stress produced by leukocytes at the site of inflammation plays a crucial role in initiating junctional disassembly. Most of these molecular mechanisms converge on mediating disruption of AJs and TJs, leading to gap formation between cells. These pathways in relation to oxidative stress are described next.
Among the TJ proteins, occludins have been well documented to be redox-sensitive proteins. Increased oxidative stress has been related to down-regulation of occludin expression, reduced membrane localization, and reduced tightness of the junctional barrier , The C-terminal of occludin contains a coiled-coil CC -domain which carries cysteine residues that are essential for oligomerization of occludin by forming disfulfide bonds , , Masking of free sulfhydryl groups or the presence of DTT prevented occludin dimerization, suggesting the formation of intermolecular disulfide bridges.
The dimerization of full-length human occludin can also be prevented by the replacement of its cysteine by alanine in the cytosolic C-terminal CC-domain Under physiological conditions, there is a to fold greater GSH than GSSG, thus maintaining a cytosolic reduced state , Almost equal number of occludin monomers and oligomers are detected under physiological conditions Mice and rat deficient in SOD1 also have decreased expression of occludin, claudin-5, and ZO-1 correlating with excessive ROS generation , , These mice exhibited symptoms of amyotrophic lateral sclerosis-linked neurodegeneration In addition, occludin is regulated by tyrosine phosphorylation in C-terminal region by enhanced oxidative stress.
Kevil et al. In addition, Rao et al.
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Mutations of these residues to alanine in human occludin also abolished c-Src-mediated phosphorylation and regulation of ZO-1 binding In addition to the role of tyrosine phosphorylation of occludin in junctional disassembly, it also appears to be essential in mediating recovery of the junctions.
Meyer et al. Inhibitors of tyrosine kinases genistein and PP-2 inhibited the recovery of transepithelial resistance and perturbed the re-localization of ZO-1 and occludin at the TJ. There are at least five known tyrosines Y, Y, Y, Y, and Y and one serine residue S in VE-cadherin that are targeted phosphorylation sites for permeability-enhancing agents.
Tyrosine phosphorylation of VE-cadherin induces junctional disassembly by preventing interaction with its cytoplasmic binding partners and actin cytoskelton. Phosphorylation of these residues differs according to the inflammatory mediator used. Allingham et al 7 demonstrated that co-incubation of leukocytes and human endothelial cells enhanced tyrosine phosphorylation of VE-cadherin, specifically on residues Y and Y, which was essential for trans-endothelial migration of leukocytes by inducing junctional opening Fig.
Similar to this study, Turowski et al. Point mutations of these residues with phenylalanine suppressed the lymphocyte trafficking across endothelial monolayers by preventing junctional opening 7 , Phosphorylation of Y prevented the binding of c-Src tyrosine kinase CSK , which is an inhibitor of c-Src activity In a similar study, van Wetering et al. In another study, Tai et al. Dynamic behavior of actin filament. Actin tread-milling is driven by ATP-hydrolysis. ADF and cofilin sever actin filaments at point end and thus promote the release of ADP-actin monomers.
Actin depolymerizing factor ADF. Signaling mechanisms of ROS-mediated increase in leukocyte migration and junctional permeability. The phosphorylation of these residues destabilizes the AJs by preventing interactions with the cytoplasmic proteins such as beta catenin and p catenin. The low level of tyrosine phosphorylation of VE-cadherin under physiological conditions is regulated by the association with VE-protein tyrosine phosphatases VE-PTP that localized at cell—cell adhesion sites The cysteine residue at the catalytic site of classical PTPs is sensitive to oxidation and is the target of specific inhibitors such as pervanadate 91 , All of these reports suggest that ROS-mediated activation of tyrosine kinases c-Src and PYK2 is involved in phosphorylation of junctional proteins, resulting in junctional disassembly.
Independent of tyrosine kinases, oxidative stress during inflammation can also lead to generation of secondary by-products that enhance intracellular ROS generation and affect AJ assembly. One of such a by-product is 4-hydroxynonenal 4-HNE , which is generated by peroxidation of membrane lipids during inflammation and modifies AJ proteins by forming Michael adducts The actin cytoskeleton of endothelial cells plays an indispensable role in maintaining endothelial cell morphology, junctional stability, and endothelial motility.
The morphology of the cell, therefore, depends on the force that dominates. Thus, a decrease in the resistive force due to the loss of endothelial junctions results in rounded morphology of endothelial cells. Oxidative stress and inflammatory agonists are well-known inducers of actin cytoskeleton reorganization in endothelial cells, leading to junctional opening and gap formation between endothelial cells.
Actin is a kDa protein that can be present either as a free monomeric form known as G-actin or as a part of a linear polymer microfilament called F-actin Fig. A direct effect of exogenous application of H 2 O 2 on remodeling of actin cytoskeleton of endothelial cells has been documented in several reports. Endothelial monolayer treated with inflammatory agonists such as thrombin, histamine, and VEGF or directly with H 2 O 2 correlated with decreased cortical actin and formation of polymerized F-actin 61 , Reorganization of actin ctyoskelton into F-actin increased centripetal tension and induced gap formation in endothelial cells , , Oxidative stress can affect actin cytoskeleton reorganization in two different ways: i a direct effect on actin cytoskeleton or actin regulatory proteins by oxidative modification and ii indirectly by influencing the signaling networks intrinsic to endothelial cells affecting polymerization of actin cytoskeleton.
Both pathways are influenced by inflammatory agonists and oxidative stress. H 2 O 2 is known to induce actin polymerization at doses ranging from 0. The cysteine and methionine residues in G-actin are particularly susceptible to oxidation. Of all the residues studied, Cys was the earliest target of H 2 O 2 -induced oxidation The oxidative modification of these residues alters conformations of subdomain 1 which regulates binding to actin-binding proteins and subdomain 2 regulates polymerization of actin filament of actin Interestingly, treatment with H 2 O 2 did not increase actin polymerization at the barbed ends; however, it enhanced polymerization at the pointed end Fig.
In addition, oxidative stress can influence cytoskeletal dynamics by direct modification of actin and actin-associated regulatory proteins through phosphorylation, nitration, carbonylation, disulfide formation, and glutathionylation , Moreover, actin was found to be the most abundant s-glutathionylated protein in PMNs and platelets in response to exposure to oxidants 59 , Actin-associated regulatory proteins affected by oxidative stress include cofilins, gelsolin, and filamin Fig. Cofilins exist in cells as both monomers and oligomers.
The monomers exhibited the known severing activity, whereas the oligomers exhibited reduced severing activity but increased actin bundling activity The transition from monomers to oligomers was regulated by reversible intermolecular disulfide bond formation between Cys 39 and Cys of two adjacent cofilin units Gelsolin regulated actin turnover in the cells by severing the barbed ends and capping actin filaments. Gelsolin is an unusual actin-binding protein that functions in two different redox environments.
Under basal conditions, plasma gelsolin contains a disulfide bond between cysteines and This alters its sensitivity to calcium and the rate of severing F-actin, which includes binding to actin monomers and nucleation of actin polymerization 6 , Enhanced oxidative stress induced by Rac activation resulted in dissociation of gelsolin from actin filaments, exposing more barbed ends for actin polymerization 13 , In resting endothelial cells, filamin is constitutively phosphorylated by PKA, which protects it against calpain-mediated proteolysis.
The translocation of filamin was inhibited by antioxidants such as TEMPO nonspecific free radical scavenger and Deferoxamine iron chelator Altogether, enhanced intracellular oxidative stress is the major inducer of actin stress fiber formation, leading to junctional disassembly and gap formation between endothelial cells. The converse is also true.
In one study, Balzer et al. They showed that expression of a dominant negative fragment of TRPC3 suppressed oxidant-induced membrane currents in endothelial cells. The TRPM subfamily only exhibits limited homology to the other TRP family ion channels, and functional channels comprising members of this subfamily are believed to be homotetramers A further mode of TRPM2 activation is through oxidative stress , , Perradud et al. In contrast, Hara et al. Hecquet et al.
The short variant of TRPM2, which lacks the pore domain and acts as a dominant-negative form by inhibiting the formation of functional homotetrameric channels, also significantly reduced H 2 O 2 -mediated microvascular hyper-permeability In another article, Di et al. The abscissa indicates time in hours; the ordinate, normalized resistance relative to basal value. Modified from Hecquet et al. Endothelial cells contain contractile machinery, which includes actin and myosin.
Phosphorylation of regulatory myosin light chain MLC leads to activation of the endothelial contractile elements and disrupts endothelial barrier function. Permeability increasing mediators such as thrombin, histamine, and H 2 O 2 enhance MLC phosphorylation, which precedes the onset of endothelial contraction Fig. The myosin phosphorylation in the endothelial cells is regulated by two enzymes: nonmuscle MLCK and myosin-associated protein phosphatase.
Zhao et al. Therefore, MLC phosphorylation does not appear to regulate H 2 O 2 -induced actin and myosin assembly but may play a role in induced actin rearrangement. The role of MLCK was also studied in hyperoxia-induced lung injury model Inflammatory mediators are known to inactivate myosin-associated phosphatases, which further promoted MLC phosphorylation , The active form of these small molecules interacts with their downstream targets and mediates their biological functions.
The mammalian Rho GTPase family consists of more than 20 distinct members, while the Ras family has 36 members. RhoA activation downstream of several endothelial permeability-increasing mediators causes loss of endothelial junctions by enhancing actomyosin contractility and increasing isometric tension at the cell margins However, Rac1 and Cdc42 are required for the assembly and maturation of endothelial junctions, and their activity increases during junction formation , , , In contrast, other studies showed that activation of Rac1 downstream of VEGF and other growth factors increased endothelial permeability , This points to the notion that an optimal level of Rac activity is required to maintain the stability of endothelial junctions and either inhibition or hyper-activation can disrupt the AJs.
Sundaresan et al. This was further confirmed by multiple reports in response to different stimuli in endothelial cells 92 , Over-expression of active Rac1 induced tyrosine phosphorylation of VE-cadherin and increased endothelial permeability in an ROS-dependent manner Contrary to this, active RhoA induced pronounced stress fiber formation but did not induce loss of cell—cell adhesion, indicating that Rac-mediated ROS generation was specifically involved in loss of cell—cell adhesion The role of RhoA family GTPases has also been investigated in endothelial cells under hypoxic condition.
Rac1 and RhoA oppose each other during changes in oxygen tension. Interestingly, there are also other mechanisms through which ROS can directly affect RhoA activity and RhoA-mediated cytoskeletal rearrangement. Campbell et al. Furthermore, using cysteine to alanine mutants, Aghajanian et al. It has been known for several years that Cdc42 activation is required to maintain endothelial barrier function.
Evidence of oxidative stress and defense mechanisms in pregnancy
Barrier-stabilizing effect of oxidized phospholipids was blocked by siRNA targeting Cdc42 38 , and expression of constitutively active Cdc42 abolished LPS-induced lung vascular permeability in vivo These studies suggest an obligatory role of Cdc42 for barrier maintenance. Although there is little information regarding the direct effects of ROS on Cdc42 function, studies showed the involvement of Cdc42 in ethanol-induced NOX activation and ROS generation and subsequently, reorganization of actin filaments in endothelial cells Further studies are needed to fully understand the mechanisms by which this important modulator of the cell cytoskeleton regulates endothelial barrier function under oxidant stress conditions.
The PKC isoforms are divided into three subclasses according to their structure, activation, and substrate requirements. The PKC activity is regulated by its translocation to the membrane and phosphorylation and generally denotes enzyme activation PKC is the target for multiple tyrosine phosphorylations by various tyrosine kinases, including Src family kinases , These modifications further increase kinase activity of PKC Several PKC inhibitors such as staurosporine, H7, calphostin C, bisindolylmaleimide, and chelerytherine inhibited endothelial hyper-permeability in response to different pro-inflammatory agents , , , , Moreover, Titchenell et al.
These studies support a prominent role of different PKC isoforms in microvascular leakage associated with different pro-inflammatory mediators. Increased PKC activity has also been associated with various vascular disorders such as atherosclerosis, hypoxia, and ischemia reperfusion , , , All PKC isoforms contain redox-sensitive cysteine residues in both regulatory and catalytic domains, which are required for autoinhibition and catalytic activity, respectively. Direct oxidative modification of the regulatory domain results in increased PKC activity Oxidant-mediated activation of PKC also occurred through phosphorylation of distinct residues of different PKC isoforms Several lines of evidence suggest that PKC is likely to play a permissive role in H 2 O 2 -mediated endothelial permeability and lung edema , , Johnson et al.
Another study demonstrated that the selective inhibition of PKC by calphostin C abolished H 2 O 2 -mediated myosin light-chain phosphorylation in ECs Taher et al.
Thus, PKCs act as a key mediator of inflammation and microvascular hyper-permeability under stimulated conditions. A total of 10 and 14 TLRs have been identified in human and mouse, respectively 63 , TLRs are expressed in a wide range of immune cells, including DCs, macrophages, PMNs, and certain nonimmune cells such as endothelial and epithelial cells 28 , Liu et al. In another study, Wang et al. Increasing evidence suggests that enhanced ROS generation is central in the activation of TLR-mediated signaling pathways. Ryan et al.
Park et al. Accumulation of activated macrophages at the site of injury is the characteristic feature of chronic inflammatory diseases However, the current literature has shown that macrophages after undergoing a phenotypic shift also help in tissue repair. The classically activated macrophages induce tissue injury by releasing chemokines and reactive oxidants that induce cell death by activation of cell death receptors, culminating in caspase activation via either an extrinsic pathway i. In addition, oxidative stress produced by macrophages can induce cell death through creating an imbalance in antioxidant GSH equilibrium Activation of caspases appears to be central to most of the pathways of cell death.
The extrinsic pathway of cell death is mediated by cell death receptors, which after binding with their ligands initiate protein—protein interactions, resulting in activation of the initiator caspases. It was first defined by William Coley in his findings that cancer patients have necrotic tumors when they developed bacterial infections and was formally referred to as Coley's toxins The active component inducing cell death in tumors was later identified as a cytokine secreted by macrophages and hence, termed tumor necrosis factor Release of endosomal DISC to the cytosol further recruits initiator procaspase-8, resulting in its activation The extent of caspase-8 activation is an essential determinant of cells undergoing mitochondrial independent or dependent apoptosis Extensive caspase-8 activation directly activated effector caspases such as caspase-3 and induced cell death, whereas low caspase-8 activation activated an amplification loop that was dependent on the mitochondria described in the next section.
Schematic representation of ROS-mediated cell death and cell survival signaling pathways. The intricate balance between cell death and cell survival is largely modulated by intracellular ROS generation. In general, high intracellular ROS generation causes cell death by activation of cell death pathways mitochondrial dependent and independent , whereas low levels of ROS acts as a signaling molecules that help in cell survival. The extent of caspase-8 activation determines whether a cell will follow a mitochondrial-dependent pathway or an independent pathway.
The released cytochrome c then subsequently binds apoptosis activation factor-1 Apaf-1 and caspase-9 and activates effector caspases such as caspase-3, which causes cell death.
In the event of significant caspase-8 activation, it directly activates casapse-3 independent of mitochondria. High intracellular ROS induces sustained JNK activation and causes mitochondrial cytochrome c release-dependent cell death. High intracellular ROS also causes cardiolipin CL oxidation, which is translocated to the outer membrane and provides the docking site for t-bid, facilitating the cytochrome c-release. In contrast, low levels of intracellular ROS mediate a transient JNK activation that helps in cell survival by activating AP-1 transcription factor and anti-apoptotic genes.
Although caspase activation and enhanced ROS generation are central to the mechanism of apoptosis, there are reports suggesting no significant role of ROS in the progression of apoptosis and showing that reduced ROS generation is, in fact, the cause of apoptosis 15 , This is surprising, as the efficacy of pharmacological antioxidants such as GSH, NAC, deferoxamine , , , and antioxidant enzymes such as catalase or GPx , in preventing apoptosis have been shown by several groups.
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