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• W2007462046 abstract "contact hypersensitivity matrix metalloproteinase myeloperoxidase poly(ADP-ribose) polymerase reactive oxygen intermediate reactive nitrogen intermediate tissue inhibitor of metalloproteinases TO THE EDITOR Contact hypersensitivity (CHS) is a form of a delayed type of hypersensitivity, a classic T-cell-mediated, clinically important phenomenon elicited by small molecular weight molecules (haptens) that bind to host proteins to form a complete allergen (Grabbe and Schwarz, 1998Grabbe S. Schwarz T. Immunoregulatory mechanisms involved in elicitation of allergic contact hypersensitivity.Immunol Today. 1998; 19: 37-44Abstract Full Text PDF PubMed Scopus (460) Google Scholar). The CHS reaction can be divided in to two phases: sensitization and elicitation. The elicitation phase is dominated by the production of proinflammatory cytokines and cellular infiltration by lymphocytes and granulocytes. Infiltration is accompanied by strong oxidative stress due to the formation of superoxide, nitric oxide, peroxynitrite, and further reactive species (Rowe et al., 1997Rowe A. Farrell A.M. Bunker C.B. Constitutive endothelial and inducible nitric oxide synthase in inflammatory dermatoses.Br J Dermatol. 1997; 136: 18-23Crossref PubMed Scopus (93) Google Scholar; Ross et al., 1998Ross R. Gillitzer C. Kleinz R. Schwing J. Kleinert H. Forstermann U. et al.Involvement of NO in contact hypersensitivity.Int Immunol. 1998; 10: 61-69Crossref PubMed Scopus (60) Google Scholar). The poly(ADP-ribose) polymerase (PARP) superfamily consists of 17 members (Ame et al., 2004Ame J.C. Spenlehauer C. de Murcia G. The PARP superfamily.Bioessays. 2004; 26: 882-893Crossref PubMed Scopus (1110) Google Scholar). A subgroup of these enzymes can be activated by DNA single-strand breaks and aberrant DNA forms (Ame et al., 1999Ame J.C. Rolli V. Schreiber V. Niedergang C. Apiou F. Decker P. et al.PARP-2, A novel mammalian DNA damage-dependent poly(ADP-ribose) polymerase.J Biol Chem. 1999; 274: 17860-17868Crossref PubMed Scopus (563) Google Scholar; Schreiber et al., 2006Schreiber V. Dantzer F. Ame J.C. de Murcia G. Poly(ADP-ribose): novel functions for an old molecule.Nat Rev Mol Cell Biol. 2006; 7: 517-528Crossref PubMed Scopus (1461) Google Scholar). In tissues and cells, PARP-1 is responsible for most of the PARP activity due to its abundance and high catalytic activity. Activated PARP-1 uses NAD+ as a substrate and synthesizes the formation of poly(ADP-ribose) polymers covalently attached to different acceptor proteins. The presence of poly(ADP-ribose) polymers may regulate the functions of the acceptor proteins (Schreiber et al., 2006Schreiber V. Dantzer F. Ame J.C. de Murcia G. Poly(ADP-ribose): novel functions for an old molecule.Nat Rev Mol Cell Biol. 2006; 7: 517-528Crossref PubMed Scopus (1461) Google Scholar). Inhibition of PARP activity or knocking out the PARP-1 gene has been shown to suppress inflammatory reactions such as colitis, arthritis, and uveitis (Shall and De Murcia, 2000Shall S. De Murcia G. Poly(ADP-ribose) polymerase-1: what have we learned from the deficient mouse model?.Mutat Res. 2000; 460: 1-15Crossref PubMed Scopus (451) Google Scholar; Virag and Szabo, 2002Virag L. Szabo C. The therapeutic potential of poly(ADP-ribose) polymerase inhibitors.Pharmacol Rev. 2002; 54: 375-429Crossref PubMed Scopus (1182) Google Scholar; Cuzzocrea, 2005Cuzzocrea S. Shock, inflammation and PARP.Pharmacol Res. 2005; 52: 72-82Crossref PubMed Scopus (77) Google Scholar). Prevention of cellular dysfunction and inhibition of NF-κB activation have been proposed to be the mechanisms underlying the anti-inflammatory effects of PARP inhibition/knockout (Virag and Szabo, 2002Virag L. Szabo C. The therapeutic potential of poly(ADP-ribose) polymerase inhibitors.Pharmacol Rev. 2002; 54: 375-429Crossref PubMed Scopus (1182) Google Scholar). Poly(ADP-ribose) polymerase plays a role in the regulation of the transcription of various inflammatory mediators such as cytokines, chemokines, inducible nitric oxide synthase, and matrix metalloproteinases (MMPs). In our previous report, we have demonstrated peroxynitrite production, DNA breakage, and poly(ADP-ribose) formation during the elicitation phase of the CHS (Szabo et al., 2001Szabo E. Virag L. Bakondi E. Gyure L. Hasko G. Bai P. et al.Peroxynitrite production, DNA breakage, and poly(ADP-ribose) polymerase activation in a mouse model of oxazolone-induced contact hypersensitivity.J Invest Dermatol. 2001; 117: 74-80Crossref PubMed Google Scholar). Moreover, we have shown that peroxynitrite, superoxide, and hydrogen peroxide impair proliferation and viability of HaCaT keratinocytes (Szabo et al., 2001Szabo E. Virag L. Bakondi E. Gyure L. Hasko G. Bai P. et al.Peroxynitrite production, DNA breakage, and poly(ADP-ribose) polymerase activation in a mouse model of oxazolone-induced contact hypersensitivity.J Invest Dermatol. 2001; 117: 74-80Crossref PubMed Google Scholar). PARP inhibitors prevented necrotic cell death with a slight increase in apoptotic DNA fragmentation and also reduced cytokine-induced expression of IL-8 and ICAM-1 in HaCaT cells. (Szabo et al., 2001Szabo E. Virag L. Bakondi E. Gyure L. Hasko G. Bai P. et al.Peroxynitrite production, DNA breakage, and poly(ADP-ribose) polymerase activation in a mouse model of oxazolone-induced contact hypersensitivity.J Invest Dermatol. 2001; 117: 74-80Crossref PubMed Google Scholar). Kehe et al., 2008Kehe K. Raithel K. Kreppel H. Jochum M. Worek F. Thiermann H. Inhibition of poly(ADP-ribose) polymerase (PARP) influences the mode of sulfur mustard (SM)-induced cell death in HaCaT cells.Arch Toxicol. 2008; 82: 461-470Crossref PubMed Scopus (66) Google Scholar reported similar findings in a model of sulfur mustard-induced cell death of HaCaT cells. They also found that the PARP inhibitor 3-aminobenzamide diverted the vesicant-induced necrotic cell death toward apoptosis. The aim of this study was to investigate (1) whether PARP activation contributes to CHS and (2) whether the role of PARP in CHS is related to regulation of chemokine expression and MMP activation. In our current experiment, we have investigated the effect of the PARP inhibitor PJ34 in the mouse model of oxazolone-induced CHS as described earlier (Szabo et al., 2001Szabo E. Virag L. Bakondi E. Gyure L. Hasko G. Bai P. et al.Peroxynitrite production, DNA breakage, and poly(ADP-ribose) polymerase activation in a mouse model of oxazolone-induced contact hypersensitivity.J Invest Dermatol. 2001; 117: 74-80Crossref PubMed Google Scholar). Similar to the majority of PARP inhibitors, PJ34 (see structural formula on Figure 1) inhibits the enzyme as an NAD+ analog (Jagtap et al., 2002Jagtap P. Soriano F.G. Virag L. Liaudet L. Mabley J. Szabo E. et al.Novel phenanthridinone inhibitors of poly(ADP-ribose) synthetase: potent cytoprotective and anti-shock agents.Crit Care Med. 2002; 30: 1071-1082Crossref PubMed Scopus (164) Google Scholar; Jagtap and Szabo, 2005Jagtap P. Szabo C. Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors.Nat Rev Drug Discov. 2005; 4: 421-440Crossref PubMed Scopus (726) Google Scholar). PJ34 has been shown to exert potent cytoprotective and anti-inflammatory effects in various cell-based and animal studies (Virag and Szabo, 2002Virag L. Szabo C. The therapeutic potential of poly(ADP-ribose) polymerase inhibitors.Pharmacol Rev. 2002; 54: 375-429Crossref PubMed Scopus (1182) Google Scholar; Jagtap and Szabo, 2005Jagtap P. Szabo C. Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors.Nat Rev Drug Discov. 2005; 4: 421-440Crossref PubMed Scopus (726) Google Scholar). Animal experiments conform with the “Guide for the Care and Use of Laboratory Animals” published by the US National Institute of Health, and the treatment protocol was approved by the institutional Ethical Committee. Thirty female CD1 mice were randomized into three groups (control, CHS, CHS+PJ34) and were sensitized by smearing 100μl of 2% (w/v) oxazolone onto the preshaved abdominal wall. Oxazolone was dissolved in acetone:olive oil 1:4 mixture. (The control group was mock-sensitized with the vehicle.) One week after sensitization, mice were treated with i.p. injection of phosphate-buffered saline (control group and CHS group) or with PJ34 (10mgkg-1) before the application of 4 × 10μl 0.5% (w/v) oxazolone onto the inner and outer surface of the ear on both sides. After 24hours, thickness of ears was measured and tissue samples are taken for laboratory investigations. Oxazolone challenge of presensitized animals resulted in the swelling of the ears (Figure 2a and b). PARP inhibition by PJ34 prevented edema (Figure 2a and b), indicating a lower level of inflammation. We have determined cellular infiltration by enzyme histochemistry detecting peroxidase activity (Figure 2a). For the peroxidase staining, see Supplementary Method 1. The increase in the myeloperoxidase (MPO) activity (determined as described by Virag et al., 2004Virag L. Bai P. Bak I. Pacher P. Mabley J.G. Liaudet L. et al.Effects of poly(ADP-ribose) polymerase inhibition on inflammatory cell migration in a murine model of asthma.Med Sci Monit. 2004; 10: BR77-BR83PubMed Google Scholar) upon inflammation suggested the presence of granulocytes in the infiltrate. PARP inhibition by PJ34 decreased the number of infiltrating cells as shown by peroxidase staining and by determining the MPO activity of ear lysates (Figure 2a and c). Epicutaneously applied haptens may also induce nonantigen-specific irritant dermatitis (Grabbe et al., 1996Grabbe S. Steinert M. Mahnke K. Schwartz A. Luger T.A. Schwarz T. Dissection of antigenic and irritative effects of epicutaneously applied haptens in mice. Evidence that not the antigenic component but nonspecific proinflammatory effects of haptens determine the concentration-dependent elicitation of allergic contact dermatitis.J Clin Invest. 1996; 98: 1158-1164Crossref PubMed Scopus (141) Google Scholar). To see whether PARP inhibition also suppresses irritant dermatitis, we have determined the effect of PJ34 on 12-O-tetradecanoyl-phorbol 13-acetate-induced ear swelling. 12-O-tetradecanoyl-phorbol 13-acetate (10μl, 0.05% w/v) was smeared onto both sides of the ears of female mice (n=8 animals per group) immediately followed by PJ34 or vehicle treatment as described above. 12-O-tetradecanoyl-phorbol 13-acetate induced a less severe inflammation as compared with oxazolone, and the PARP inhibitor significantly reduced ear swelling and inhibited cellular infiltration (MPO activity) (Figure S1), indicating that it targets general inflammatory pathways rather than specific immune response. Download .pdf (.01 MB) Help with pdf files Supplementary Figure S1PJ34 inhibits TPA-induced irritant dermatitis. A. Mice (n=8) were treated with TPA for six hours and irritant dermatitis was quantified by measurement of ear thickness. TPA induced a moderate ear swelling as compared to oxazolone. PJ34 pretreatment significantly reduced swelling (n=8; *** p<0.001). B. Myeloperoxidase (MPO) activity of ear lysates also indicated granulocyte infiltration in the TPA group. MPO activity was efficiently reduced by PJ34 pretreatment. (n=5; *** p<0.001). Poly(ADP-ribose) polymerase-1 has been shown earlier to regulate the expression of chemokines in various models of inflammation (Virag and Szabo, 2002Virag L. Szabo C. The therapeutic potential of poly(ADP-ribose) polymerase inhibitors.Pharmacol Rev. 2002; 54: 375-429Crossref PubMed Scopus (1182) Google Scholar). Macrophage inflammatory protein-1α, one of the main chemoattractant of neutrophil granulocytes, and other proinflammatory chemokines/cytokines such as macrophage inflammatory protein-2, tumor necrosis factor-α, and IL-1β were induced in the allergic reaction and was reduced by PJ34 (Figure 3a). Levels of these cytokines were determined with commercially available (R&D System, Minneapolis, MN) ELISA assay kits. We also set out to investigate whether PARP activity regulates MMP expression in CHS. MMPs are secreted by a variety of skin-resident and infiltrating cells, including fibroblasts, endothelial cells, macrophages, neutrophils, and lymphocytes. These enzymes are expressed as zymogens, which are subsequently processed either by other proteolytic enzymes or by free radicals triggering structural changes resulting in full-length active MMPs (Pacher et al., 2003Pacher P. Liaudet L. Bai P. Mabley J.G. Kaminski P.M. Virag L. et al.Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction.Circulation. 2003; 107: 896-904Crossref PubMed Scopus (248) Google Scholar; Le et al., 2007Le N.T. Xue M. Castelnoble L.A. Jackson C.J. The dual personalities of matrix metalloproteinases in inflammation.Front Biosci. 2007; 12: 1475-1487Crossref PubMed Scopus (78) Google Scholar). The MMP activity is counterbalanced by a family of tissue inhibitors, called tissue inhibitors of metalloproteinases (TIMPs). Metalloproteinase activity of ear extracts was determined by gelatin zymography as described by Pacher et al., 2002Pacher P. Liaudet L. Bai P. Virag L. Mabley J.G. Hasko G. et al.Activation of poly(ADP-ribose) polymerase contributes to development of doxorubicin-induced heart failure.J Pharmacol Exp Ther. 2002; 300: 862-867Crossref PubMed Scopus (153) Google Scholar. In CHS samples, a band with an apparent molecular weight of 89–92kDa was found to be upregulated. PJ34 treatment suppressed this activity (Figure 3b). The molecular weight (89–92kDa) suggested that MMP-9 expression can be responsible for the appearance of this band. By western blotting, we have detected an increase in the level of MMP-9 upon inflammation and PJ34 reversed MMP expression (Figure 3b). Moreover, we have detected a decreased expression of TIMP-2 in CHS samples, which was prevented by PJ34 pretreatment (Figure 3b). Hereby, we provide evidence for the involvement of PARP in the pathomechanism of inflammation in CHS. PARP inhibition reduced edema (ear swelling) and the migration of inflammatory cells to the site of inflammation. Reactive oxygen and nitrogen intermediates (ROI and RNI, respectively) are produced in large quantity in inflammatory conditions including CHS and constitute important pathogenetic factors triggering endothelial dysfunction (Virag et al., 2002Virag L. Szabo E. Bakondi E. Bai P. Gergely P. Hunyadi J. et al.Nitric oxide-peroxynitrite-poly(ADP-ribose) polymerase pathway in the skin.Exp Dermatol. 2002; 11: 189-202Crossref PubMed Scopus (67) Google Scholar). ROI and RNI can stimulate the DNA breakage–PARP-1 activation pathway that has been shown to mediate endothelial dysfunction in other experimental settings such as in diabetic blood vessels (Soriano et al., 2001Soriano F.G. Virag L. Szabo C. Diabetic endothelial dysfunction: role of reactive oxygen and nitrogen species production and poly(ADP-ribose) polymerase activation.J Mol Med. 2001; 79: 437-448Crossref PubMed Scopus (126) Google Scholar; Pacher and Szabo, 2005Pacher P. Szabo C. Role of poly(ADP-ribose) polymerase-1 activation in the pathogenesis of diabetic complications: endothelial dysfunction, as a common underlying theme.Antioxid Redox Signal. 2005; 7: 1568-1580Crossref PubMed Scopus (135) Google Scholar). We hypothesize that similar mechanisms may underlie the anti-inflammatory effects of PARP inhibition in CHS (see Figure S2). Various skin-resident cell types and immigrating inflammatory cells can produce ROI and RNI (Trouba et al., 2002Trouba K.J. Hamadeh H.K. Amin R.P. Germolec D.R. Oxidative stress and its role in skin disease.Antioxid Redox Signal. 2002; 4: 665-673Crossref PubMed Scopus (196) Google Scholar; Virag et al., 2002Virag L. Szabo E. Bakondi E. Bai P. Gergely P. Hunyadi J. et al.Nitric oxide-peroxynitrite-poly(ADP-ribose) polymerase pathway in the skin.Exp Dermatol. 2002; 11: 189-202Crossref PubMed Scopus (67) Google Scholar; Okayama, 2005Okayama Y. Oxidative stress in allergic and inflammatory skin diseases.Curr Drug Targets Inflamm Allergy. 2005; 4: 517-519Crossref PubMed Scopus (176) Google Scholar). Oxidative stress may cause DNA breakage and activate PARP-1 in endothelial cells, which may cause endothelial dysfunction through depletion of NAD+ and ATP. PARP inhibitors may interfere with this pathway at two points. They may directly prevent the depletion of energy metabolites and may reduce the amount of ROI/RNI produced during inflammation. As most ROI/RNI are likely produced by the infiltrating granulocytes, inhibition of granulocyte migration from the circulation to the site of inflammation may result in suppressed ROI/RNI production. Indeed, our results indicate that PARP inhibition markedly inhibits the extravasation of granulocytes as indicated by peroxidase staining and MPO activity measurements of ear lysates. Extravasation of leukocytes is mediated by the expression of different adhesion molecules on the surface of the leukocytes and the endothelium. PARPs have been shown to regulate the expression of adhesion molecules, such as ICAM-1 in various cell types including endothelial cells and cytokine-stimulated HaCaT keratinocytes (Zingarelli et al., 1998Zingarelli B. Salzman A.L. Szabo C. Genetic disruption of poly (ADP-ribose) synthetase inhibits the expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia/reperfusion injury.Circ Res. 1998; 83: 85-94Crossref PubMed Scopus (309) Google Scholar; Szabo et al., 2001Szabo E. Virag L. Bakondi E. Gyure L. Hasko G. Bai P. et al.Peroxynitrite production, DNA breakage, and poly(ADP-ribose) polymerase activation in a mouse model of oxazolone-induced contact hypersensitivity.J Invest Dermatol. 2001; 117: 74-80Crossref PubMed Google Scholar). Therefore, it is likely that in vivo inhibition of PARP activity may regulate the adhesion of the infiltrating cells to the vascular endothelium and thus influences the severity of inflammation in CHS. The other mechanism that may explain the inhibitory effect of PARP inhibition on the migration of inflammatory cells is the reduced expression of inflammatory cytokines (for example, tumor necrosis factor-α and IL-1β), with special regard to chemokines, the chemotactic cytokines. PARP-1 has been shown to act as a coactivator of NF-κB, a transcription factor involved in the expression of inflammatory mediators. This effect may explain the suppressing effect of the PARP inhibitor on the production of chemokines and cytokines in CHS. Download .pdf (.03 MB) Help with pdf files Supplementary Figure S2PARP regulates various steps of the inflammatory response in CHS. Activated leukocytes leave the bloodstream with the help of MMPs and secrete ROI/RNI as well as pro-inflammatory cytokines. The reactive species and the cytokines activate PARP in the nuclei of the resident and infiltrating cells, thus contributing to activation of NFκB, a master transcriptional regulator of inflammatory mediators. Of note, activation of NFκB can also be induced by oxidative stress. ROI/RNI also induce PARP activation in the endothelial cells and in skin resident cells leading to cell dysfunction. Endothelial cell dysfunction leads to increased vascular permeability resulting in the edema of the ears. Matrix metalloproteinases are now considered as inflammatory mediators as indicated by the anti-inflammatory effects of MMP inhibitors as demonstrated in various models of inflammation including CHS (Hu et al., 2007Hu J. Van den Steen P.E. Sang Q.X. Opdenakker G. Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases.Nat Rev Drug Discov. 2007; 6: 480-498Crossref PubMed Scopus (606) Google Scholar). Active MMPs facilitate the movement of the infiltrating immune cells through the protein mesh of the extracellular matrix. MMP-9 expression is inducible in many cell types by proinflammatory cytokines such as tumor necrosis factor-α or IL-1β (Doller et al., 2007Doller A. Akool E. Muller R. Gutwein P. Kurowski C. Pfeilschifter J. et al.Molecular mechanisms of cyclosporin A inhibition of the cytokine-induced matrix metalloproteinase-9 in glomerular mesangial cells.J Am Soc Nephrol. 2007; 18: 581-592Crossref PubMed Scopus (25) Google Scholar; Li et al., 2007Li H. Liang J. Castrillon D.H. DePinho R.A. Olson E.N. Liu Z.P. FoxO4 regulates tumor necrosis factor alpha-directed smooth muscle cell migration by activating matrix metalloproteinase 9 gene transcription.Mol Cell Biol. 2007; 27: 2676-2686Crossref PubMed Scopus (89) Google Scholar), and MMP-9 can be also be synthesized by a number of cell types in the inflamed skin, such as keratinocytes (Lamar et al., 2008Lamar J.M. Iyer V. Dipersio C.M. Integrin alpha3beta1 potentiates TGFbeta-mediated induction of MMP-9 in immortalized keratinocytes.J Invest Dermatol. 2008; 128: 575-586PubMed Scopus (33) Google Scholar), granulocytes (Matsuzaki et al., 2006Matsuzaki T. Amakawa K. Yamaguchi K. Ishizaka A. Terashima T. Matsumaru A. et al.Effects of diesel exhaust particles on human neutrophil activation.Exp Lung Res. 2006; 32: 427-439Crossref PubMed Scopus (11) Google Scholar), or dendritic cells (Zozulya et al., 2007Zozulya A.L. Reinke E. Baiu D.C. Karman J. Sandor M. Fabry Z. Dendritic cell transmigration through brain microvessel endothelium is regulated by MIP-1alpha chemokine and matrix metalloproteinases.J Immunol. 2007; 178: 520-529Crossref PubMed Scopus (90) Google Scholar). As MMP expression is under the control of NF-κB (Bond et al., 1998Bond M. Fabunmi R.P. Baker A.H. Newby A.C. Synergistic upregulation of metalloproteinase-9 by growth factors and inflammatory cytokines: an absolute requirement for transcription factor NF-kappa B.FEBS Lett. 1998; 435: 29-34Abstract Full Text Full Text PDF PubMed Scopus (455) Google Scholar), inhibition of MMP-9 expression by PJ34 may be explained by the same mechanism as outlined above for inflammatory cytokines and chemokines. Moreover, the decrease of TIMP-2 may also lead to the activation of MMPs. In summary, our data demonstrate that PARP activity mediates inflammation in CHS. PARP acts as a pleiotropic modulator of the inflammatory reaction by enhancing leukocyte migration, production of inflammatory cytokines and chemokines, and the activation of MMPs. Whether or not local PARP inhibition is a viable therapeutic approach in human CHS-like conditions requires further investigation, with special regard to a potential sensitizing effect of PARP inhibitors to carcinogenic stimuli. C.S. is a founder, shareholder, and consultant to Inotek Pharmaceuticals, a company involved in the development of PARP inhibitors. This work was supported by: ETT 12/2006, OTKA K60780, K75864, DEOEC Mecenatura grants, Bolyai fellowships to P.B. and E.S., Ambassade de France en Hongrie and Ministére des Affaires Étrangeres and Hungarian Science and Technology Foundation (TeT FR-11/2007) to P.B. We greatly acknowledge the technical assistance of Mrs Erzsébet Herbály in histochemical techniques. Supplementary Materials and Methods. Cytochemical staining for peroxidase activity in tissue sections. Figure S1. PJ34 inhibits 12-O-tetradecanoyl-phorbol 13-acetate-induced irritant dermatitis. Figure S2. PARP regulates various steps of the inflammatory response in CHS. Download .pdf (.02 MB) Help with pdf files Supplementary Text" @default.
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• W2007462046 title "Poly(ADP-Ribose) Polymerase Mediates Inflammation in a Mouse Model of Contact Hypersensitivity" @default.
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