FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2574672608> ?p ?o ?g. }

• W2574672608 endingPage "2026.e9" @default.
• W2574672608 startingPage "2023" @default.
• W2574672608 abstract "Group 1 allergens, exemplified by Der p 1, are the most significant triggers within the allergenic repertoire of house dust mite (HDM) proteins capable of eliciting the intracellular generation of reactive oxidant species (ROS) by airway epithelial cells.1Zhang J. Chen J. Allen-Philbey K. Perera Baruhupolage C. Tachie-Menson T. Mangat S.C. et al.Innate generation of thrombin and intracellular oxidants in airway epithelium by allergen Der p 1.J Allergy Clin Immunol. 2016; 138: 1224-1227Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar This is because Der p 1, a cysteine peptidase, behaves as a prothrombinase, thereby triggering canonical activation of protease-activated receptor (PAR) 1 and 4 by thrombin.1Zhang J. Chen J. Allen-Philbey K. Perera Baruhupolage C. Tachie-Menson T. Mangat S.C. et al.Innate generation of thrombin and intracellular oxidants in airway epithelium by allergen Der p 1.J Allergy Clin Immunol. 2016; 138: 1224-1227Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar These events are preventable by Allergen Delivery Inhibitors or antagonists of PAR1 and PAR4 G-protein–coupled receptors.1Zhang J. Chen J. Allen-Philbey K. Perera Baruhupolage C. Tachie-Menson T. Mangat S.C. et al.Innate generation of thrombin and intracellular oxidants in airway epithelium by allergen Der p 1.J Allergy Clin Immunol. 2016; 138: 1224-1227Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Intracellular ROS formation by any allergen is noteworthy because asthma is associated with deficits in antioxidant defences1Zhang J. Chen J. Allen-Philbey K. Perera Baruhupolage C. Tachie-Menson T. Mangat S.C. et al.Innate generation of thrombin and intracellular oxidants in airway epithelium by allergen Der p 1.J Allergy Clin Immunol. 2016; 138: 1224-1227Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar and ROS promote inflammation through transcription factor regulation, histone modifications, and the direct activation of signal transduction. The partially delineated pathway that leads to ROS production by HDM allergens converges with signaling from the ligation of Toll-like receptor 3 or melanoma differentiation–associated protein-5, which are key in host responses to respiratory viruses associated with asthma exacerbations.1Zhang J. Chen J. Allen-Philbey K. Perera Baruhupolage C. Tachie-Menson T. Mangat S.C. et al.Innate generation of thrombin and intracellular oxidants in airway epithelium by allergen Der p 1.J Allergy Clin Immunol. 2016; 138: 1224-1227Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar This convergence opens pannexons, releasing ATP, which is essential for allergen and viral RNA-dependent ROS production.1Zhang J. Chen J. Allen-Philbey K. Perera Baruhupolage C. Tachie-Menson T. Mangat S.C. et al.Innate generation of thrombin and intracellular oxidants in airway epithelium by allergen Der p 1.J Allergy Clin Immunol. 2016; 138: 1224-1227Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Other pertinent effects of ATP include stimulation of IL-33 release, TH2 bias in dendritic antigen presenting cells, mast cell activation, and dyspnea. “Sheddase”-dependent activation of epidermal growth factor receptor is implicated in G-protein–coupled receptor crosstalk, so we explored whether HDM allergen-dependent ROS generation requires the participation of sheddase metalloenzymes, especially those of the a disintegrin and metalloprotease (ADAM) family. To investigate the production of intracellular ROS, we loaded human airway epithelial cells with dihydrorhodamine 123 and exposed them to a natural mixture of Dermatophagoides pteronyssinus allergens or 2′(3′)-O-(4-benzoylbenzoyl)adenosine 5′-triphosphate (BzATP) and uridine 5′-triphosphate (UTP) (to mimic the activation of P2X7 and P2Y purinoceptors by endogenously-released ATP) (see the Methods section in this article's Online Repository at www.jacionline.org). Exploration of metalloenzymes capable of ectodomain cleavage or regulated intracellular proteolysis was prompted by the finding that epidermal growth factor receptor signaling is crucial for ROS generation in cells stimulated by HDM allergens, BzATP or UTP (see Fig E1, A-C, in this article's Online Repository at www.jacionline.org). The metalloenzyme inhibitors marimastat and TAPI-1 (N-[(2R)-2-[2-(hydroxyamino)-2-oxoethyl]-4-methyl-1-oxopentyl]-3-(2-napthalenyl)-1-alanyl-N-(2-aminoethyl)-1-alaninamide acetate) blunted ROS production by either HDM allergens or BzATP (see Fig E2, A-D, in this article's Online Repository at www.jacionline.org). Surprisingly, TAPI-2 (N-(R)-(2-(hydroxyaminocarbonyl)methyl)-4-methylpentanoyl-L-t-butyl-glycine-L-alanine 2-aminoethyl amide acetate) (which has greater selectivity than TAPI-1 for the “classical” sheddase ADAM 17) did not affect responses to BzATP, although it was an effective inhibitor of mixed HDM allergens (see Fig E2, E and F). From these results, and consistent with additional data (see Fig E3, A-D, in this article's Online Repository at www.jacionline.org), we inferred that ROS production involved a metalloprotease component distinct from ADAM 17. Unexpectedly, the potent and selective ADAM 10 inhibitor, GI 254023X, attenuated intracellular generation of ROS by HDM, and was particularly efficacious in cells stimulated by BzATP or UTP (Fig 1, A-C), whereas it lacked effect in quiescent cells. Substantial involvement of ADAM 10 in responses to all 3 stimuli was confirmed by siRNA knockdown (Fig 1, D-F). As further proof, exogenously added recombinant human ADAM 10 elicited concentration-dependent ROS generation, which was inhibited by GI 254023X, thus authenticating its action (Fig 2, A-C). The effect of ADAM 10 was sensitive to AG 1478, confirming a receptor tyrosine-kinase–dependent component of the activation cycle (Fig 2, D).Fig 2Recombinant human (rh) ADAM 10 stimulates intracellular ROS formation in airway epithelial cells. A and B, Progress curves and concentration-response relationship for dihydrorhodamine oxidation following vehicle (veh) or rhADAM 10. All concentrations P < .001 with respect to the dashed line. C-E, Inhibition by GI 254023X, AG 1478, or argatroban, respectively, of responses to ADAM 10. BzATP is shown for reference (*P < .001 vs veh, **P < .001 vs ADAM 10, †P < .01 vs veh, ‡P < .001 vs veh). F, Gene-silencing prothrombin (PT) blunts the response to BzATP (*P < .001 vs veh, **P < .05 vs BzATP, †P < .05 vs BzATP stimulation in control transfection, ‡P < .001 vs BzATP stimulation). G, As in Fig 2, F, but stimulation by UTP (*P < .001 vs veh, **P < .001 vs UTP, †P < .05 vs UTP stimulation in control transfection, ‡P < .001 vs UTP). RFU, Relative fluorescence units; rhADAM 10, recombinant human ADAM 10.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Surprisingly, argatroban inhibited responses to rhADAM 10, implying the formation of thrombin (Fig 2, E). We have previously shown that Der p 1 is a prothrombinase,1Zhang J. Chen J. Allen-Philbey K. Perera Baruhupolage C. Tachie-Menson T. Mangat S.C. et al.Innate generation of thrombin and intracellular oxidants in airway epithelium by allergen Der p 1.J Allergy Clin Immunol. 2016; 138: 1224-1227Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar confirmed here by demonstrating that siRNA knockdown of prothrombin attenuated the response to mixed HDM allergens (see Fig E4, A, in this article's Online Repository at www.jacionline.org). Moreover, we have now found that prothrombin knockdown blunted the responses to BzATP or UTP (Fig 2, F and G). This is consistent with ADAM 10 activation, which we show to be downstream from purinoceptor stimulation, operating a pathway to enhance thrombin formation. The principle of metalloprotease-initiated thrombin formation and ROS production was further exemplified using the snake venom protease, ecarin, whose ability to activate prothrombin by proteolytic cleavage is well established from its use as a clinical diagnostic in the ecarin clotting test. Like ADAM 10, ecarin is a member of the M12B protease subfamily and comprises metalloprotease, disintegrin, and cysteine-rich domains. Like ADAM 10, ecarin is a potent generator of intracellular ROS (Fig E4, B). Detailed biochemical studies investigating the activation of prothrombin by ADAM 10 are underway and will be reported separately. Our data implicate purinoceptor-dependent activation of ADAM 10 as a downstream effector of ROS production in an innate response to HDM allergens. Significantly, ADAM 10 establishes a signaling cycle capable of sustaining prothrombin activation after its initiation by group 1 HDM allergens.1Zhang J. Chen J. Allen-Philbey K. Perera Baruhupolage C. Tachie-Menson T. Mangat S.C. et al.Innate generation of thrombin and intracellular oxidants in airway epithelium by allergen Der p 1.J Allergy Clin Immunol. 2016; 138: 1224-1227Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar In addition, as the principal sheddase of the adherens junction protein, E-cadherin,2Inoshima I. Inoshima N. Wilke G.A. Powers M.E. Frank K.M. Wang Y. et al.A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice.Nat Med. 2011; 17: 1310-1314Crossref PubMed Scopus (297) Google Scholar activation of ADAM 10 has the potential to augment any dysregulation of the epithelial barrier arising from targeted cleavage of tight junctions by group 1 HDM allergens.3Robinson C. Zhang J. Newton G.K. Perrior T.R. Nonhuman targets in allergic lung conditions.Future Med Chem. 2013; 5: 147-161Crossref PubMed Scopus (4) Google Scholar These findings expand the growing pleiotropic role of ADAM 10 in allergy. Illustratively, ADAM 10 drives TH2 bias4Mathews J.A. Ford J. Norton S. Kang D. Dellinger A. Gibb D.R. et al.A potential new target for asthma therapy: a disintegrin and metalloprotease 10 (ADAM10) involvement in murine experimental asthma.Allergy. 2011; 66: 1193-1200Crossref PubMed Scopus (38) Google Scholar and promotes IgE synthesis by being a CD23 sheddase,5Weskamp G. Ford J.W. Sturgill J. Martin S. Docherty A.J.P. Swendeman S. et al.ADAM10 is a principal ‘sheddase’ of the low-affinity immunoglobulin E receptor CD23.Nat Immunol. 2006; 7: 1293-1298Crossref PubMed Scopus (176) Google Scholar an effect incidentally ascribed to Der p 1 itself.3Robinson C. Zhang J. Newton G.K. Perrior T.R. Nonhuman targets in allergic lung conditions.Future Med Chem. 2013; 5: 147-161Crossref PubMed Scopus (4) Google Scholar In airway epithelial cells, ADAM 10 liberates CCL20 (which recruits dendritic cells and TH17 cells and promotes mucus hyperplasia), CCL2 (chemoattractant for dendritic cells), CCL5 (eosinophil chemokine), CXCL8 (neutrophil chemokine), and CXCL16 (T-cell chemoattractant).6Post S. Rozeveld D. Jonker M.R. Bischoff R. van Oosterhout A.J. Heijink I.H. ADAM10 mediates the house dust mite-induced release of chemokine ligand CCL20 by airway epithelium.Allergy. 2015; 70: 1545-1552Crossref PubMed Scopus (15) Google Scholar, 7Gough P.J. Garton K.J. Wille P.T. Rychlewski M. Dempsey P.J. Raines E.W. A disintegrin and metalloproteinase 10-mediated cleavage and shedding regulates the cell surface expression of CXC chemokine lLigand 16.J Immunol. 2004; 172: 3678-3685Crossref PubMed Scopus (216) Google Scholar It is also involved in stem cell factor-dependent mast cell migration. ADAM 10 expression is upregulated in a model of asthma and on B cells in patients with allergy and in TH2-prone mice.8Di Valentin E. Crahay C. Garbacki N. Hennuy B. Gueders M. Noel A. et al.New asthma biomarkers: lessons from murine models of acute and chronic asthma.Am J Physiol Lung Cell Mol Physiol. 2009; 296: L185-L197Crossref PubMed Scopus (96) Google Scholar, 9Cooley L.F. Martin R.K. Zellner H.B. Irani A.M. Uram-Tuculescu C. El Shikh M.E. et al.Increased B cell ADAM10 in allergic patients and Th2 prone mice.PLoS One. 2015; 10: e0124331Crossref PubMed Scopus (11) Google Scholar The combination of high ADAM 10 expression on B cells within a TH2 cytokine environment causes mimicry of disease pathophysiology, namely, mucus cell hyperplasia, airway constriction, inflammation, and IgE production, whereas development of these is attenuated in mice deficient in ADAM 10.9Cooley L.F. Martin R.K. Zellner H.B. Irani A.M. Uram-Tuculescu C. El Shikh M.E. et al.Increased B cell ADAM10 in allergic patients and Th2 prone mice.PLoS One. 2015; 10: e0124331Crossref PubMed Scopus (11) Google Scholar Intriguingly, ADAM 10 is also the cellular receptor for Staphylococcus aureus α-hemolysin toxin,2Inoshima I. Inoshima N. Wilke G.A. Powers M.E. Frank K.M. Wang Y. et al.A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice.Nat Med. 2011; 17: 1310-1314Crossref PubMed Scopus (297) Google Scholar suggesting that ADAM 10–dependent responses to allergens and infections, both viral and bacterial, may represent a signaling nexus in chronic severe disease exacerbations, which merits further examination in the clinic. Additional information is available (see this article's Methods, Results, and References section in the Online Repository at www.jacionline.org). Group 1 allergens from HDMs form a novel subfamily of C1 cysteine peptidases differentiated by structural and functional differences in their zymogen prodomains.E1Zhang J. Hamilton J.M. Garrod D.R. Robinson C. Interactions between mature Der p 1 and its free prodomain indicate membership of a new family of C1 peptidases.Allergy. 2007; 62: 1302-1309Crossref PubMed Scopus (20) Google Scholar, E2Robinson C. Zhang J. Newton G.K. Perrior T.R. Nonhuman targets in allergic lung conditions.Future Med Chem. 2013; 5: 147-161Crossref PubMed Scopus (10) Google Scholar Persuasive evidence indicates that the proteolytic activity of these HDM allergens activates a mixture of physical events and innate immune responses that promote the development of persistent allergic sensitization to any allergen.E2Robinson C. Zhang J. Newton G.K. Perrior T.R. Nonhuman targets in allergic lung conditions.Future Med Chem. 2013; 5: 147-161Crossref PubMed Scopus (10) Google Scholar, E3Jacquet A. The role of innate immunity activation in house dust mite allergy.Trends Mol Med. 2011; 17: 604-611Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar This occurs because the proteolytic bioactivity nonselectively increases the probability of contact with dendritic antigen presenting cells and facilitates the polarization to allergic immunity through a combination of mechanisms: recapitulation of these processes maintains sensitization and promotes pathophysiological changes.E2Robinson C. Zhang J. Newton G.K. Perrior T.R. Nonhuman targets in allergic lung conditions.Future Med Chem. 2013; 5: 147-161Crossref PubMed Scopus (10) Google Scholar Group I allergens from all species of HDM have a highly conserved sequence identity such that they could be considered as a single drug target in the design of first-generation Allergen Delivery Inhibitor drugs directed against their cysteine protease activity.E4Newton G.K. Perrior T.R. Jenkins K. Major M.R. Key R.E. Stewart M.R. et al.The discovery of potent, selective, and reversible inhibitors of the house dust mite peptidase allergen Der p 1: an innovative approach to the treatment of allergic asthma.J Med Chem. 2014; 57: 9447-9462Crossref PubMed Scopus (21) Google Scholar Der p 1 from D pteronyssinus, commonly used as the general exemplar of these allergens, has recently been identified as the dominant component in the allergenic repertoire of HDM that stimulates the formation of superoxide anion (O2−) in mitochondria of human airway epithelial cells.E5Zhang J. Chen J. Allen-Philbey K. Perera Baruhupolage C. Tachie-Menson T. Mangat S.C. et al.Innate generation of thrombin and intracellular oxidants in airway epithelium by allergen Der p 1.J Allergy Clin Immunol. 2016; 138: 1224-1227Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar The production of this ROS is independent of IgE. Rather, it is part of a signaling cascade initiated by the conversion of prothrombin to thrombin by Der p 1, the consequent activation of PAR 1 and PAR 4 and the G-protein–coupled receptor signal transduction pathways coupled to them, the extracellular release of ATP, and the stimulation of purinergic signaling inter alia through P2X7 receptors.E5Zhang J. Chen J. Allen-Philbey K. Perera Baruhupolage C. Tachie-Menson T. Mangat S.C. et al.Innate generation of thrombin and intracellular oxidants in airway epithelium by allergen Der p 1.J Allergy Clin Immunol. 2016; 138: 1224-1227Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar In the airways, peptidase allergen to ROS signaling may be relevant to the pathogenesis of asthma because ROS exert a TH2 bias to immune responses. This risk may be exacerbated by deficits in enzymatic and/or nonenzymatic antioxidant defences.E10King M.R. Ismail A.S. Davis L.S. Karp D.R. Oxidative stress promotes polarization of human T cell differentiation toward a T helper 2 phenotype.J Immunol. 2006; 176: 2765-2772Crossref PubMed Scopus (92) Google Scholar, E6Comhair S.A. Erzurum S.C. Redox control of asthma: molecular mechanisms and therapeutic opportunities.Antioxid Redox Signal. 2010; 12: 93-124Crossref PubMed Scopus (179) Google Scholar, E7Kirkham P. Rahman I. Oxidative stress in asthma and COPD: antioxidants as a therapeutic strategy.Pharmacol Ther. 2006; 111: 476-494Crossref PubMed Scopus (354) Google Scholar, E8Sackesen C. Ercan H. Dizdar E. Soyer O. Gumus P. Tosun B.N. et al.A comprehensive evaluation of the enzymatic and nonenzymatic antioxidant systems in childhood asthma.J Allergy Clin Immunol. 2008; 122: 78-85Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, E9Patel B.D. Welch A.A. Bingham S.A. Luben R.N. Day N.E. Khaw K.T. et al.Dietary antioxidants and asthma in adults.Thorax. 2006; 61: 388-393Crossref PubMed Scopus (101) Google Scholar Furthermore, components of the signaling mechanism activated by Der p 1 (eg, ATP and thrombin) are themselves implicated as primary transducers of innate immunity, which predispose to the development of acquired TH2 responses,E11Idzko M. Hammad H. van Nimwegen M. Kool M. Willart M.A. Muskens F. et al.Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells.Nat Med. 2007; 13: 913-919Crossref PubMed Scopus (488) Google Scholar, E12Muller T. Vieira R.P. Grimm M. Durk T. Cicko S. Zeiser R. et al.A potential role for P2X7R in allergic airway inflammation in mice and humans.Am J Respir Cell Mol Biol. 2011; 44: 456-464Crossref PubMed Scopus (115) Google Scholar, E13Kouzaki H. Iijima K. Kobayashi T. O'Grady S.M. Kita H. The danger signal, extracellular ATP, is a sensor for an airborne allergen and triggers IL-33 release and innate Th2-type responses.J Immunol. 2011; 186: 4375-4387Crossref PubMed Scopus (367) Google Scholar, E5Zhang J. Chen J. Allen-Philbey K. Perera Baruhupolage C. Tachie-Menson T. Mangat S.C. et al.Innate generation of thrombin and intracellular oxidants in airway epithelium by allergen Der p 1.J Allergy Clin Immunol. 2016; 138: 1224-1227Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar and/or they underlie fundamental aspects of asthma pathophysiology.E14Miyake Y. D'Alessandro-Gabazza C.N. Takagi T. Naito M. Hataji O. Nakahara H. et al.Dose-dependent differential effects of thrombin in allergic bronchial asthma.J Thromb Haemost. 2013; 11: 1903-1915PubMed Scopus (19) Google Scholar, E15Gabazza E.C. Taguchi O. Tamaki S. Takeya H. Kobayashi H. Yasui H. et al.Thrombin in the airways of asthmatic patients.Lung. 1999; 177: 253-262Crossref PubMed Scopus (110) Google Scholar, E16de Boer J.D. Majoor C.J. van't Veer C. Bel E.H. van der Poll T. Asthma and coagulation.Blood. 2012; 119: 3236-3244Crossref PubMed Scopus (116) Google Scholar, E17Ando S. Otani H. Yagi Y. Kawai K. Araki H. Fukuhara S. et al.Proteinase-activated receptor 4 stimulation-induced epithelial-mesenchymal transition in alveolar epithelial cells.Respir Res. 2007; 8: 31Crossref PubMed Scopus (37) Google Scholar Illustratively, thrombin—which is present in asthmatic airways in elevated amountsE18Terada M. Kelly E.A. Jarjour N.N. Increased thrombin activity after allergen challenge: a potential link to airway remodeling?.Am J Respir Crit Care Med. 2004; 169: 373-377Crossref PubMed Google Scholar, E19Brims F.J. Chauhan A.J. Higgins B. Shute J.K. Coagulation factors in the airways in moderate and severe asthma and the effect of inhaled steroids.Thorax. 2009; 64: 1037-1043Crossref PubMed Scopus (66) Google Scholar—is mitogenic in airways smooth muscle, is profibrogenic, and fosters the TH2 polarization of responses in dendritic antigen presenting cells.E14Miyake Y. D'Alessandro-Gabazza C.N. Takagi T. Naito M. Hataji O. Nakahara H. et al.Dose-dependent differential effects of thrombin in allergic bronchial asthma.J Thromb Haemost. 2013; 11: 1903-1915PubMed Scopus (19) Google Scholar, E18Terada M. Kelly E.A. Jarjour N.N. Increased thrombin activity after allergen challenge: a potential link to airway remodeling?.Am J Respir Crit Care Med. 2004; 169: 373-377Crossref PubMed Google Scholar Also present in asthmatic airways at elevated concentration is ATP,E12Muller T. Vieira R.P. Grimm M. Durk T. Cicko S. Zeiser R. et al.A potential role for P2X7R in allergic airway inflammation in mice and humans.Am J Respir Cell Mol Biol. 2011; 44: 456-464Crossref PubMed Scopus (115) Google Scholar which has wide-ranging effects beyond the capacity to evoke neurogenic bronchoconstriction and dyspnea.E20Basoglu O.K. Pelleg A. Essilfe-Quaye S. Brindicci C. Barnes P.J. Kharitonov S.A. Effects of aerosolized adenosine 5′-triphosphate vs adenosine 5′-monophosphate on dyspnea and airway caliber in healthy nonsmokers and patients with asthma.Chest. 2005; 128: 1905-1909Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar For example, ATP stimulates the release of IL-33 from airway epithelial cells,E13Kouzaki H. Iijima K. Kobayashi T. O'Grady S.M. Kita H. The danger signal, extracellular ATP, is a sensor for an airborne allergen and triggers IL-33 release and innate Th2-type responses.J Immunol. 2011; 186: 4375-4387Crossref PubMed Scopus (367) Google Scholar augments IgE-dependent mediator release from mast cells,E21Schulman E.S. Glaum M.C. Post T. Wang Y.H. Raible D.G. Mohanty J. et al.ATP modulates anti-IgE-induced release of histamine from human lung mast cells.Am J Respir Cell Mol Biol. 1999; 20: 530-537Crossref PubMed Scopus (83) Google Scholar and is another factor known to activate dendritic antigen presenting cells with a TH2 bias.E12Muller T. Vieira R.P. Grimm M. Durk T. Cicko S. Zeiser R. et al.A potential role for P2X7R in allergic airway inflammation in mice and humans.Am J Respir Cell Mol Biol. 2011; 44: 456-464Crossref PubMed Scopus (115) Google Scholar Moreover, intracellular ROS themselves have established roles in upregulating the expression of proinflammatory genes through operation of redox-sensitive transcription factors such as nuclear factor κappa B, AP-1, and Sp1,E22Lavrovsky Y. Chatterjee B. Clark R.A. Roy A.K. Role of redox-regulated transcription factors in inflammation, aging and age-related diseases.Exp Gerontol. 2000; 35: 521-532Crossref PubMed Scopus (257) Google Scholar histone modification and activation of signaling via members of the mitogen-activated protein kinase, and signal transducers and activators of transcription families.E6Comhair S.A. Erzurum S.C. Redox control of asthma: molecular mechanisms and therapeutic opportunities.Antioxid Redox Signal. 2010; 12: 93-124Crossref PubMed Scopus (179) Google Scholar In the experiments described here, we investigated the role of endogenous epithelial proteases in the signal transduction pathway leading to ROS production by Der p 1. Our specific focus was the role of zinc metalloproteases, especially ADAM enzymes. This supplementary information provides background data supporting the disclosure made in the accompanying “Letter to the Editor.” ARP 100 (2-[((1,1′-biphenyl)-4-ylsulfonyl)-(1-methylethoxy)amino]-N-hydroxyacetamide), CL 82198 (N-[4-(4-morpholinyl)butyl]-2-benzofurancarboxamide hydrochloride), GI 254023X ((2R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-[(1S)-1-(N-hydroxyformamido)ethyl]-5-phenylpentanamide), WAY 170523 (N-[2-[4-[[[2-[(hydroxyamino)carbonyl]-4,6-dimethylphenyl](phenylmethyl)amino]sulfonyl]phenoxy]ethyl]-2-benzofurancarboxamide), and AG1478 (N-(3-chlorophenyl)-6,7-dimethoxy-4-quinazolinanine hydrochloride) were obtained from Tocris (Avonmouth, Bristol, United Kingdom [UK]). TAPI-1 acetate (N-[(2R)-2-[2-(hydroxyamino)-2-oxoethyl]-4-methyl-1-oxopentyl]-3-(2-naphthalenyl)-l-alanyl-N-(2-aminoethyl)-l-alaninamide acetate salt), TAPI-2 acetate (N-(R)-(2-(hydroxyaminocarbonyl)methyl)-4-methylpentanoyl-l-t-butyl-glycine-l-alanine 2-aminoethyl amide),argatroban monohydrate ((2R,4R)-1-[(2S)-5-[(aminoiminomethyl)amino]-1-oxo-2-[[(1,2,3,4-tetrahydro-3-methyl-8-quinolinyl)sulfonyl]amino]pentyl]-4-methyl-2-piperidinecarboxylic acid), marimastat ((2S,3R)-N4-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-N1,2-dihydroxy-3-(2-methylpropyl)butanediamide), BzATP (2′(3′)-O-(4-benzoylbenzoyl)adenosine 5′-triphosphate triethylammonium salt), UTP (uridine 5′-triphosphate trisodium salt dehydrate), LPSs from Escherichia coli 0111:B4, and human thrombin were from Sigma-Aldrich (Poole, Dorset, UK). Dihydrorhodamine-123 was obtained from Life Technologies (Paisley, Renfrewshire, UK). Cell culture media and reagents were obtained from Life Technologies, Sigma-Aldrich, and GE Healthcare (Little Chalfont, Buckinghamshire, UK). Transfection reagents and siRNA duplexes (typically mixtures of 3 target-specific 19-25 nt siRNAs or scrambled controls against no known targets) were obtained from Santa Cruz Biotechnology (Dallas, Tex). Baculovirus-derived, rhADAM 10 (Thr214 – Glu672) expressed in sf21 cells was obtained from R&D Systems (Abingdon, Oxfordshire, UK). Ecarin from Echis carinatus venom and thrombin from human plasma were supplied by Sigma-Aldrich. Mixed, native HDM allergens in their natural proportions were prepared from laboratory cultures of D pteronyssinus according to our standard procedures. Der p 1 content of the allergen extracts was determined by ELISA (Indoor Biotechnologies, Cardiff, UK), whereas functional catalytic activity of Der p 1 was determined fluorimetrically using a Der p 1–selective substrate as described elsewhere.E4Newton G.K. Perrior T.R. Jenkins K. Major M.R. Key R.E. Stewart M.R. et al.The discovery of potent, selective, and reversible inhibitors of the house dust mite peptidase allergen Der p 1: an innovative approach to the treatment of allergic asthma.J Med Chem. 2014; 57: 9447-9462Crossref PubMed Scopus (21) Google Scholar, E5Zhang J. Chen J. Allen-Philbey K. Perera Baruhupolage C. Tachie-Menson T. Mangat S.C. et al.Innate generation of thrombin and intracellular oxidants in airway epithelium by allergen Der p 1.J Allergy Clin Immunol. 2016; 138: 1224-1227Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar HDM mixtures were normalized by reference to Der p 1 content expressed as μg/mL. Thus, HDM 1 refers to mixed HDM whose Der p 1 concentration is 1 μg/mL. Normalization was necessary because the extracts contain multiple components and batch-to-batch variation in activity is seen. Der p 1 is the most important normalization denominator in these studies because it is the principal active component responsible for intracellular ROS generation.E4Newton G.K. Perrior T.R. Jenkins K. Major M.R. Key R.E. Stewart M.R. et al.The discovery of potent, selective, and reversible inhibitors of the house dust mite peptidase allergen Der p 1: an innovative approach to the treatment of allergic asthma.J Med Chem. 2014; 57: 9447-9462Crossref PubMed Scopus (21) Google Scholar For consistent batch-to-batch proteolytic activity of Der p 1 in allergen preparations, experiments were conducted in the presence of 5 mM l-cysteine. Endotoxin content in allergen preparations was determined by kinetic chromogenic limulus amebocyte assay (Endochrome-K, Charles River Laboratories International, Inc, Wilmington, Mass) according to manufacturer instructions. Calu-3 cells, which are both well validated and a relevant cellular model for these investigations, were cultured according to our standard procedures as described elsewhere.E23Winton H.L. Wan H. Cannell M.B. Gruenert D.C. Thompson P.J. Garrod D.R. et al.Cell lines of pulmonary and non-pulmonary origin as tools to study the effects of house dust mite proteinases on the regulation of epithelial permeability.Clin Exp Allergy. 1998; 28: 1273-1285Crossref PubMed Scopus (98) Google Scholar, E24Wan H. Winton H.L. Soeller C. Tovey E.R. Gruenert D.C. Thompson P.J. et al.Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions.J Clin Invest. 1999; 104: 123-133Crossref PubMed Scopus (601) Google Scholar, E25Wan H. Winton H.L. Soeller C. Stewart G.A. Thompson P.J. Gruenert D.C. et al.Tight junction properties of the immortalized human bronchial epithelial cell lines Calu-3 and 16HBE14o.Eur Respir J. 2000; 15: 1058-1068Crossref PubMed Scopus (133) Google Scholar Our previous work has demonstrated that ROS generation by HDM allergen treatment of calu-3 cells is mechanistically similar to responses seen in primary cultures of human airway epithelium.E5Zhang J. Chen J. Allen-Philbey K. Perera Baruhupolage C. Tachie-Menson T. Mangat S.C. et al.Innate generation of thrombin and intracellular oxidants in airway epithelium by allergen Der p 1." @default.
• W2574672608 created "2017-01-26" @default.
• W2574672608 creator A5002958387 @default.
• W2574672608 creator A5019250148 @default.
• W2574672608 creator A5026544861 @default.
• W2574672608 creator A5059475751 @default.
• W2574672608 creator A5072575185 @default.
• W2574672608 creator A5081261971 @default.
• W2574672608 date "2017-06-01" @default.
• W2574672608 modified "2023-10-18" @default.
• W2574672608 title "Allergen-dependent oxidant formation requires purinoceptor activation of ADAM 10 and prothrombin" @default.
• W2574672608 cites W1601542379 @default.
• W2574672608 cites W1861812628 @default.
• W2574672608 cites W1964948273 @default.
• W2574672608 cites W1974956135 @default.
• W2574672608 cites W1975112172 @default.
• W2574672608 cites W1976292850 @default.
• W2574672608 cites W1982023814 @default.
• W2574672608 cites W1995511753 @default.
• W2574672608 cites W1996955331 @default.
• W2574672608 cites W2000906360 @default.
• W2574672608 cites W2017429246 @default.
• W2574672608 cites W2022727685 @default.
• W2574672608 cites W2024413110 @default.
• W2574672608 cites W2026026508 @default.
• W2574672608 cites W2035448219 @default.
• W2574672608 cites W2048356493 @default.
• W2574672608 cites W2050161704 @default.
• W2574672608 cites W2070841999 @default.
• W2574672608 cites W2078401315 @default.
• W2574672608 cites W2095693670 @default.
• W2574672608 cites W2096349085 @default.
• W2574672608 cites W2096539359 @default.
• W2574672608 cites W2098126044 @default.
• W2574672608 cites W2099468529 @default.
• W2574672608 cites W2099716328 @default.
• W2574672608 cites W2112545191 @default.
• W2574672608 cites W2112549281 @default.
• W2574672608 cites W2112874194 @default.
• W2574672608 cites W2129250941 @default.
• W2574672608 cites W2140157501 @default.
• W2574672608 cites W2143788236 @default.
• W2574672608 cites W2147110025 @default.
• W2574672608 cites W2149952102 @default.
• W2574672608 cites W2153266189 @default.
• W2574672608 cites W2163499692 @default.
• W2574672608 cites W2165746205 @default.
• W2574672608 cites W2166083817 @default.
• W2574672608 cites W2396066516 @default.
• W2574672608 doi "https://doi.org/10.1016/j.jaci.2016.12.954" @default.
• W2574672608 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5457034" @default.
• W2574672608 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/28111309" @default.
• W2574672608 hasPublicationYear "2017" @default.
• W2574672608 type Work @default.
• W2574672608 sameAs 2574672608 @default.
• W2574672608 citedByCount "14" @default.
• W2574672608 countsByYear W25746726082018 @default.
• W2574672608 countsByYear W25746726082019 @default.
• W2574672608 countsByYear W25746726082020 @default.
• W2574672608 countsByYear W25746726082021 @default.
• W2574672608 countsByYear W25746726082022 @default.
• W2574672608 countsByYear W25746726082023 @default.
• W2574672608 crossrefType "journal-article" @default.
• W2574672608 hasAuthorship W2574672608A5002958387 @default.
• W2574672608 hasAuthorship W2574672608A5019250148 @default.
• W2574672608 hasAuthorship W2574672608A5026544861 @default.
• W2574672608 hasAuthorship W2574672608A5059475751 @default.
• W2574672608 hasAuthorship W2574672608A5072575185 @default.
• W2574672608 hasAuthorship W2574672608A5081261971 @default.
• W2574672608 hasBestOaLocation W25746726081 @default.
• W2574672608 hasConcept C185592680 @default.
• W2574672608 hasConcept C203014093 @default.
• W2574672608 hasConcept C207480886 @default.
• W2574672608 hasConcept C2780510475 @default.
• W2574672608 hasConcept C71924100 @default.
• W2574672608 hasConceptScore W2574672608C185592680 @default.
• W2574672608 hasConceptScore W2574672608C203014093 @default.
• W2574672608 hasConceptScore W2574672608C207480886 @default.
• W2574672608 hasConceptScore W2574672608C2780510475 @default.
• W2574672608 hasConceptScore W2574672608C71924100 @default.
• W2574672608 hasIssue "6" @default.
• W2574672608 hasLocation W25746726081 @default.
• W2574672608 hasLocation W25746726082 @default.
• W2574672608 hasLocation W25746726083 @default.
• W2574672608 hasLocation W25746726084 @default.
• W2574672608 hasLocation W25746726085 @default.
• W2574672608 hasLocation W25746726086 @default.
• W2574672608 hasOpenAccess W2574672608 @default.
• W2574672608 hasPrimaryLocation W25746726081 @default.
• W2574672608 hasRelatedWork W1982343230 @default.
• W2574672608 hasRelatedWork W2014471812 @default.
• W2574672608 hasRelatedWork W2018503391 @default.
• W2574672608 hasRelatedWork W2037019085 @default.
• W2574672608 hasRelatedWork W2145013427 @default.
• W2574672608 hasRelatedWork W2266295269 @default.
• W2574672608 hasRelatedWork W2611818413 @default.
• W2574672608 hasRelatedWork W30803436 @default.
• W2574672608 hasRelatedWork W4232270923 @default.

• next