{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T05:39:34Z","timestamp":1761975574823},"reference-count":60,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,9,13]],"date-time":"2016-09-13T00:00:00Z","timestamp":1473724800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,9,13]],"date-time":"2016-09-13T00:00:00Z","timestamp":1473724800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The mechanism of penicillin immediate hypersensitivity reactions has not been completely elucidated. These reactions are generally considered to be mediated by IgE, but penicillin-specific IgE could not be detected in most cases. This study demonstrated that penicillin was able to cause vascular hyperpermeability in a mouse model mimicking clinical symptoms of penicillin immediate hypersensitivity reactions. The first exposure to penicillin also induced immediate edema and exudative reactions in ears and lungs of mice in a dose-dependent manner. Vasodilation was noted in microvessels in ears. These reactions were unlikely to be immune-mediated reactions, because no penicillin-specific IgE was produced. Furthermore, penicillin treatment directly elicited rapid histamine release. Penicillin also led to F-actin reorganization in human umbilical vein endothelial cells and increased the permeability of the endothelial monolayer. Activation of the RhoA\/ROCK signaling pathway was observed in ears and lungs of mice and in endothelial cells after treatment with penicillin. Both an anti-histamine agent and a ROCK inhibitor attenuated penicillin immediate hypersensitivity reactions in mice. This study presents a novel mechanism of penicillin immediate hypersensitivity reactions and suggests a potential preventive approach against these reactions.<\/jats:p>","DOI":"10.1038\/srep33192","type":"journal-article","created":{"date-parts":[[2016,9,13]],"date-time":"2016-09-13T10:18:04Z","timestamp":1473761884000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Involvement of Histamine and RhoA\/ROCK in Penicillin Immediate Hypersensitivity Reactions"],"prefix":"10.1038","volume":"6","author":[{"given":"Jiayin","family":"Han","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Yi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunying","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yushi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lianmei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Pan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aihua","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,9,13]]},"reference":[{"key":"BFsrep33192_CR1","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.jaci.2013.10.032","volume":"133","author":"R Solensky","year":"2014","unstructured":"Solensky, R. Penicillin allergy as a public health measure. J Allergy Clin Immunol 133, 797\u2013798 (2014).","journal-title":"J Allergy Clin Immunol"},{"key":"BFsrep33192_CR2","unstructured":"NICE clinical guideline 183. Drug allergy: diagnosis and management of drug allergy in adults, children and young people (2014)."},{"key":"BFsrep33192_CR3","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1016\/j.jaci.2012.08.021","volume":"130","author":"R Solensky","year":"2012","unstructured":"Solensky, R. Allergy to beta-lactam antibiotics. J Allergy Clin Immunol 130, 1442\u20131442, e1445 (2012).","journal-title":"J Allergy Clin Immunol"},{"key":"BFsrep33192_CR4","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1111\/all.12195","volume":"68","author":"J Hjortlund","year":"2013","unstructured":"Hjortlund, J., Mortz, C. G., Skov, P. S. & Bindslev-Jensen, C. Diagnosis of penicillin allergy revisited: the value of case history, skin testing, specific IgE and prolonged challenge. Allergy 68, 1057\u20131064 (2013).","journal-title":"Allergy"},{"key":"BFsrep33192_CR5","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1097\/ACI.0000000000000173","volume":"15","author":"E Macy","year":"2015","unstructured":"Macy, E. Penicillin allergy: optimizing diagnostic protocols, public health implications, and future research needs. Curr Opin Allergy Clin Immunol 15, 308\u2013313 (2015).","journal-title":"Curr Opin Allergy Clin Immunol"},{"key":"BFsrep33192_CR6","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1378\/chest.118.4.1106","volume":"118","author":"ME Arroliga","year":"2000","unstructured":"Arroliga, M. E. et al. A pilot study of penicillin skin testing in patients with a history of penicillin allergy admitted to a medical ICU. Chest 118, 1106\u20131108 (2000).","journal-title":"Chest"},{"key":"BFsrep33192_CR7","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.jaip.2013.02.002","volume":"1","author":"E Macy","year":"2013","unstructured":"Macy, E. & Ngor, E. W. Safely diagnosing clinically significant penicillin allergy using only penicilloyl-poly-lysine, penicillin, and oral amoxicillin. J Allergy Clin Immunol Pract 1, 258\u2013263 (2013).","journal-title":"J Allergy Clin Immunol Pract"},{"key":"BFsrep33192_CR8","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1007\/s12016-011-8279-6","volume":"43","author":"C Chang","year":"2012","unstructured":"Chang, C., Mahmood, M. M., Teuber, S. S. & Gershwin, M. E. Overview of penicillin allergy. Clin Rev Allergy Immunol 43, 84\u201397 (2012).","journal-title":"Clin Rev Allergy Immunol"},{"key":"BFsrep33192_CR9","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1517\/14740338.2012.643866","volume":"11","author":"P Lagace-Wiens","year":"2012","unstructured":"Lagace-Wiens, P. & Rubinstein, E. Adverse reactions to beta-lactam antimicrobials. Expert Opin Drug Saf 11, 381\u2013399 (2012).","journal-title":"Expert Opin Drug Saf"},{"key":"BFsrep33192_CR10","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1186\/1710-1492-7-S1-S10","volume":"7","author":"R Warrington","year":"2011","unstructured":"Warrington, R. & Silviu-Dan, F. Drug allergy. Allergy Asthma Clin Immunol 7 Suppl 1, S10 (2011).","journal-title":"Allergy Asthma Clin Immunol"},{"key":"BFsrep33192_CR11","doi-asserted-by":"crossref","first-page":"S67","DOI":"10.1016\/j.jaci.2010.11.047","volume":"127","author":"A Romano","year":"2011","unstructured":"Romano, A., Torres, M. J., Castells, M., Sanz, M. L. & Blanca, M. Diagnosis and management of drug hypersensitivity reactions. J Allergy Clin Immunol 127, S67\u201373 (2011).","journal-title":"J Allergy Clin Immunol"},{"key":"BFsrep33192_CR12","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1034\/j.1398-9995.1999.00020.x","volume":"54","author":"P Demoly","year":"1999","unstructured":"Demoly, P. et al. Predictive capacity of histamine release for the diagnosis of drug allergy. Allergy 54, 500\u2013506 (1999).","journal-title":"Allergy"},{"key":"BFsrep33192_CR13","doi-asserted-by":"crossref","first-page":"S126","DOI":"10.1016\/j.jaci.2009.10.028","volume":"125","author":"DA Khan","year":"2010","unstructured":"Khan, D. A. & Solensky, R. Drug allergy. J Allergy Clin Immunol 125, S126\u2013137 (2010).","journal-title":"J Allergy Clin Immunol"},{"key":"BFsrep33192_CR14","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/nature14022","volume":"519","author":"BD McNeil","year":"2015","unstructured":"McNeil, B. D. et al. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature 519, 237\u2013241 (2015).","journal-title":"Nature"},{"key":"BFsrep33192_CR15","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1159\/000339690","volume":"159","author":"K Farnam","year":"2012","unstructured":"Farnam, K., Chang, C., Teuber, S. & Gershwin, M. E. Nonallergic drug hypersensitivity reactions. Int Arch Allergy Immunol 159, 327\u2013345 (2012).","journal-title":"Int Arch Allergy Immunol"},{"key":"BFsrep33192_CR16","doi-asserted-by":"crossref","first-page":"268","DOI":"10.4065\/84.3.268","volume":"84","author":"B Schnyder","year":"2009","unstructured":"Schnyder, B. & Pichler, W. J. Mechanisms of drug-induced allergy. Mayo Clin Proc 84, 268\u2013272 (2009).","journal-title":"Mayo Clin Proc"},{"key":"BFsrep33192_CR17","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1111\/j.1365-2125.2011.03976.x","volume":"71","author":"DG Waller","year":"2011","unstructured":"Waller, D. G. Allergy, pseudo-allergy and non-allergy. Br J Clin Pharmacol 71, 637\u2013638 (2011).","journal-title":"Br J Clin Pharmacol"},{"key":"BFsrep33192_CR18","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S1537-1891(03)00008-9","volume":"39","author":"B Wojciak-Stothard","year":"2002","unstructured":"Wojciak-Stothard, B. & Ridley, A. J. Rho GTPases and the regulation of endothelial permeability. Vascul Pharmacol 39, 187\u2013199 (2002).","journal-title":"Vascul Pharmacol"},{"key":"BFsrep33192_CR19","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1515\/hsz-2013-0181","volume":"394","author":"E Amin","year":"2013","unstructured":"Amin, E. et al. Rho-kinase: regulation, (dys)function, and inhibition. Biol Chem 394, 1399\u20131410 (2013).","journal-title":"Biol Chem"},{"key":"BFsrep33192_CR20","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1093\/cvr\/cvq086","volume":"87","author":"V Spindler","year":"2010","unstructured":"Spindler, V., Schlegel, N. & Waschke, J. Role of GTPases in control of microvascular permeability. Cardiovasc Res 87, 243\u2013253 (2010).","journal-title":"Cardiovasc Res"},{"key":"BFsrep33192_CR21","doi-asserted-by":"crossref","first-page":"e19","DOI":"10.1017\/S1462399409001112","volume":"11","author":"P Kumar","year":"2009","unstructured":"Kumar, P. et al. Molecular mechanisms of endothelial hyperpermeability: implications in inflammation. Expert Rev Mol Med 11, e19 (2009).","journal-title":"Expert Rev Mol Med"},{"key":"BFsrep33192_CR22","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1002\/cm.20472","volume":"67","author":"M Amano","year":"2010","unstructured":"Amano, M., Nakayama, M. & Kaibuchi, K. Rho-kinase\/ROCK: A key regulator of the cytoskeleton and cell polarity. Cytoskeleton (Hoboken) 67, 545\u2013554 (2010).","journal-title":"Cytoskeleton (Hoboken)"},{"key":"BFsrep33192_CR23","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1002\/jcp.22347","volume":"226","author":"AY Ruiz-Loredo","year":"2011","unstructured":"Ruiz-Loredo, A. Y., Lopez, E. & Lopez-Colome, A. M. Thrombin promotes actin stress fiber formation in RPE through Rho\/ROCK-mediated MLC phosphorylation. J Cell Physiol 226, 414\u2013423 (2011).","journal-title":"J Cell Physiol"},{"key":"BFsrep33192_CR24","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/micc.12189","volume":"22","author":"SP Adderley","year":"2015","unstructured":"Adderley, S. P., Zhang, X. E. & Breslin, J. W. Involvement of the H1 histamine receptor, p38 MAP kinase, myosin light chains kinase, and Rho\/ROCK in histamine-induced endothelial barrier dysfunction. Microcirculation 22, 237\u2013248 (2015).","journal-title":"Microcirculation"},{"key":"BFsrep33192_CR25","doi-asserted-by":"crossref","first-page":"6725","DOI":"10.1038\/ncomms7725","volume":"6","author":"CM Mikelis","year":"2015","unstructured":"Mikelis, C. M. et al. RhoA and ROCK mediate histamine-induced vascular leakage and anaphylactic shock. Nat Commun 6, 6725 (2015).","journal-title":"Nat Commun"},{"key":"BFsrep33192_CR26","doi-asserted-by":"crossref","first-page":"3186","DOI":"10.1096\/fj.09-145102","volume":"24","author":"BA Bryan","year":"2010","unstructured":"Bryan, B. A. et al. RhoA\/ROCK signaling is essential for multiple aspects of VEGF-mediated angiogenesis. FASEB J 24, 3186\u20133195 (2010).","journal-title":"FASEB J"},{"key":"BFsrep33192_CR27","doi-asserted-by":"crossref","first-page":"F487","DOI":"10.1152\/ajprenal.00112.2008","volume":"296","author":"SB Campos","year":"2009","unstructured":"Campos, S. B. et al. Cytokine-induced F-actin reorganization in endothelial cells involves RhoA activation. Am J Physiol Renal Physiol 296, F487\u2013495 (2009).","journal-title":"Am J Physiol Renal Physiol"},{"key":"BFsrep33192_CR28","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s13098-015-0098-0","volume":"7","author":"XY Zhao","year":"2015","unstructured":"Zhao, X. Y. et al. Effects of high glucose on human umbilical vein endothelial cell permeability and myosin light chain phosphorylation. Diabetol Metab Syndr 7, 98 (2015).","journal-title":"Diabetol Metab Syndr"},{"key":"BFsrep33192_CR29","doi-asserted-by":"crossref","first-page":"3132","DOI":"10.1002\/jcp.22669","volume":"226","author":"NV Bogatcheva","year":"2011","unstructured":"Bogatcheva, N. V. et al. The suppression of myosin light chain (MLC) phosphorylation during the response to lipopolysaccharide (LPS): beneficial or detrimental to endothelial barrier? J Cell Physiol 226, 3132\u20133146 (2011).","journal-title":"J Cell Physiol"},{"key":"BFsrep33192_CR30","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1152\/ajplegacy.1969.216.3.675","volume":"216","author":"FB Freedman","year":"1969","unstructured":"Freedman, F. B. & Johnson, J. A. Equilibrium and kinetic properties of the Evans blue-albumin system. Am J Physiol 216, 675\u2013681 (1969).","journal-title":"Am J Physiol"},{"key":"BFsrep33192_CR31","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1093\/cvr\/cvq105","volume":"87","author":"DO Bates","year":"2010","unstructured":"Bates, D. O. Vascular endothelial growth factors and vascular permeability. Cardiovasc Res 87, 262\u2013271 (2010).","journal-title":"Cardiovasc Res"},{"key":"BFsrep33192_CR32","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1293\/tox.20.237","volume":"20","author":"H Hattori","year":"2007","unstructured":"Hattori, H. et al. Development of a novel mouse anaphylaxis model produced by intermittent intravenous injections of ovalbumin without adjuvant. J Toxicol Pathol 20, 237\u2013244 (2007).","journal-title":"J Toxicol Pathol"},{"key":"BFsrep33192_CR33","unstructured":"FDA. Guidance for industry: immunotoxicology evaluation of investigational new drugs (2002)."},{"key":"BFsrep33192_CR34","doi-asserted-by":"crossref","first-page":"S464","DOI":"10.1016\/j.jaci.2005.11.002","volume":"117","author":"PA Greenberger","year":"2006","unstructured":"Greenberger, P. A. 8. Drug allergy. J Allergy Clin Immunol 117, S464\u2013470 (2006).","journal-title":"J Allergy Clin Immunol"},{"key":"BFsrep33192_CR35","doi-asserted-by":"crossref","first-page":"269","DOI":"10.2131\/jts.14.269","volume":"14","author":"K Kubo","year":"1989","unstructured":"Kubo, K. et al. Penicillin G-induced cutaneous anaphylaxis in the guinea pig. J Toxicol Sci 14, 269\u2013277 (1989).","journal-title":"J Toxicol Sci"},{"key":"BFsrep33192_CR36","doi-asserted-by":"crossref","first-page":"72","DOI":"10.7164\/antibiotics.34.72","volume":"34","author":"O Shiho","year":"1981","unstructured":"Shiho, O. & Tsuchiya, K. IgE antibodies for penicillins and cephalosporins in rats. I. Characteristics of the IgE antibodies for penicillins and cephalosporins in rats. J Antibiot (Tokyo) 34, 72\u201378 (1981).","journal-title":"J Antibiot (Tokyo)"},{"key":"BFsrep33192_CR37","first-page":"527","volume":"7","author":"BB Levine","year":"1964","unstructured":"Levine, B. B. Studies on the immunological mechanisms of penicillin allergy. I. Antigenic specificities of guinea-pig skin sensitizing rabbit anti-benzylpenicillin antibodies. Immunology 7, 527\u2013541 (1964).","journal-title":"Immunology"},{"key":"BFsrep33192_CR38","unstructured":"FDA. Guidance for industry: estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers (2005)."},{"key":"BFsrep33192_CR39","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1089\/jpm.2008.9817","volume":"11","author":"HE Woodall","year":"2008","unstructured":"Woodall, H. E., Chiu, A. & Weissman, D. E. Opioid allergic reactions #175. J Palliat Med 11, 1340\u20131341 (2008).","journal-title":"J Palliat Med"},{"key":"BFsrep33192_CR40","doi-asserted-by":"crossref","first-page":"666","DOI":"10.2214\/AJR.07.2872","volume":"190","author":"J Trcka","year":"2008","unstructured":"Trcka, J. et al. Anaphylaxis to iodinated contrast material: nonallergic hypersensitivity or IgE-mediated allergy? AJR Am J Roentgenol 190, 666\u2013670 (2008).","journal-title":"AJR Am J Roentgenol"},{"key":"BFsrep33192_CR41","first-page":"54","volume":"17","author":"R Jurakic Toncic","year":"2009","unstructured":"Jurakic Toncic, R., Marinovic, B. & Lipozencic, J. Nonallergic hypersensitivity to nonsteroidal antiinflammatory drugs, angiotensin-converting enzyme inhibitors, radiocontrast media, local anesthetics, volume substitutes and medications used in general anesthesia. Acta Dermatovenerol Croat 17, 54\u201369 (2009).","journal-title":"Acta Dermatovenerol Croat"},{"key":"BFsrep33192_CR42","first-page":"E523","volume":"44","author":"B Adams","year":"2015","unstructured":"Adams, B., Roboubi, B. & Henshaw, R. Acute onset of vancomycin anaphylaxis with disseminated intravascular coagulation in an orthopedic patient despite prior repeated exposure. Am J Orthop (Belle Mead NJ) 44, E523\u2013525 (2015).","journal-title":"Am J Orthop (Belle Mead NJ)"},{"key":"BFsrep33192_CR43","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1002\/phar.1493","volume":"35","author":"JA Justo","year":"2015","unstructured":"Justo, J. A. & Bosso, J. A. Adverse reactions associated with systemic polymyxin therapy. Pharmacotherapy 35, 28\u201333 (2015).","journal-title":"Pharmacotherapy"},{"key":"BFsrep33192_CR44","doi-asserted-by":"crossref","first-page":"2332","DOI":"10.1161\/ATVBAHA.107.152322","volume":"27","author":"GP van Nieuw Amerongen","year":"2007","unstructured":"van Nieuw Amerongen, G. P. et al. Involvement of Rho kinase in endothelial barrier maintenance. Arterioscler Thromb Vasc Biol 27, 2332\u20132339 (2007).","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"BFsrep33192_CR45","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.devcel.2009.01.004","volume":"16","author":"E Dejana","year":"2009","unstructured":"Dejana, E., Tournier-Lasserve, E. & Weinstein, B. M. The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. Dev Cell 16, 209\u2013221 (2009).","journal-title":"Dev Cell"},{"key":"BFsrep33192_CR46","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.bbamem.2007.07.012","volume":"1778","author":"A Hartsock","year":"2008","unstructured":"Hartsock, A. & Nelson, W. J. Adherens and tight junctions: structure, function and connections to the actin cytoskeleton. Biochim Biophys Acta 1778, 660\u2013669 (2008).","journal-title":"Biochim Biophys Acta"},{"key":"BFsrep33192_CR47","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1093\/toxsci\/kft336","volume":"138","author":"S Kustermann","year":"2014","unstructured":"Kustermann, S. et al. A real-time impedance-based screening assay for drug-induced vascular leakage. Toxicol Sci 138, 333\u2013343 (2014).","journal-title":"Toxicol Sci"},{"key":"BFsrep33192_CR48","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1126\/science.279.5350.509","volume":"279","author":"A Hall","year":"1998","unstructured":"Hall, A. Rho GTPases and the actin cytoskeleton. Science 279, 509\u2013514 (1998).","journal-title":"Science"},{"key":"BFsrep33192_CR49","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1152\/physrev.00012.2005","volume":"86","author":"D Mehta","year":"2006","unstructured":"Mehta, D. & Malik, A. B. Signaling mechanisms regulating endothelial permeability. Physiol Rev 86, 279\u2013367 (2006).","journal-title":"Physiol Rev"},{"key":"BFsrep33192_CR50","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1242\/jcs.114.7.1343","volume":"114","author":"B Wojciak-Stothard","year":"2001","unstructured":"Wojciak-Stothard, B., Potempa, S., Eichholtz, T. & Ridley, A. J. Rho and Rac but not Cdc42 regulate endothelial cell permeability. J Cell Sci 114, 1343\u20131355 (2001).","journal-title":"J Cell Sci"},{"key":"BFsrep33192_CR51","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1038\/nrm1128","volume":"4","author":"K Riento","year":"2003","unstructured":"Riento, K. & Ridley, A. J. Rocks: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol 4, 446\u2013456 (2003).","journal-title":"Nat Rev Mol Cell Biol"},{"key":"BFsrep33192_CR52","doi-asserted-by":"crossref","first-page":"3823","DOI":"10.1007\/s00018-010-0460-1","volume":"67","author":"KP Nunes","year":"2010","unstructured":"Nunes, K. P., Rigsby, C. S. & Webb, R. C. RhoA\/Rho-kinase and vascular diseases: what is the link? Cell Mol Life Sci 67, 3823\u20133836 (2010).","journal-title":"Cell Mol Life Sci"},{"key":"BFsrep33192_CR53","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1093\/cvr\/cvq115","volume":"87","author":"FR Curry","year":"2010","unstructured":"Curry, F. R. & Adamson, R. H. Vascular permeability modulation at the cell, microvessel, or whole organ level: towards closing gaps in our knowledge. Cardiovasc Res 87, 218\u2013229 (2010).","journal-title":"Cardiovasc Res"},{"key":"BFsrep33192_CR54","doi-asserted-by":"crossref","first-page":"e0132367","DOI":"10.1371\/journal.pone.0132367","volume":"10","author":"K Ashina","year":"2015","unstructured":"Ashina, K. et al. Histamine induces vascular hyperpermeability by increasing blood flow and endothelial barrier disruption in vivo. Plos one 10, e0132367 (2015).","journal-title":"Plos one"},{"key":"BFsrep33192_CR55","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1111\/j.1476-5381.1996.tb15547.x","volume":"118","author":"M Feletou","year":"1996","unstructured":"Feletou, M., Bonnardel, E. & Canet, E. Bradykinin and changes in microvascular permeability in the hamster cheek pouch: role of nitric oxide. Br J Pharmacol 118, 1371\u20131376 (1996).","journal-title":"Br J Pharmacol"},{"key":"BFsrep33192_CR56","doi-asserted-by":"crossref","first-page":"405","DOI":"10.4065\/80.3.405","volume":"80","author":"MA Park","year":"2005","unstructured":"Park, M. A. & Li, J. T. Diagnosis and management of penicillin allergy. Mayo Clin Proc 80, 405\u2013410 (2005).","journal-title":"Mayo Clin Proc"},{"key":"BFsrep33192_CR57","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.3390\/ijms16012252","volume":"16","author":"Q Lian","year":"2015","unstructured":"Lian, Q., Cheng, Y., Zhong, C. & Wang, F. Inhibition of the IgE-mediated activation of RBL-2H3 cells by TIPP, a novel thymic immunosuppressive pentapeptide. Int J Mol Sci 16, 2252\u20132268 (2015).","journal-title":"Int J Mol Sci"},{"key":"BFsrep33192_CR58","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1158\/1535-7163.MCT-06-0689","volume":"6","author":"L Yin","year":"2007","unstructured":"Yin, L. et al. Fasudil inhibits vascular endothelial growth factor-induced angiogenesis in vitro and in vivo. Mol Cancer Ther 6, 1517\u20131525 (2007).","journal-title":"Mol Cancer Ther"},{"key":"BFsrep33192_CR59","doi-asserted-by":"crossref","first-page":"2436","DOI":"10.1016\/j.peptides.2011.10.001","volume":"32","author":"LY Wang","year":"2011","unstructured":"Wang, L. Y. et al. Apelin-13 passes through the ADMA-damaged endothelial barrier and acts on vascular smooth muscle cells. Peptides 32, 2436\u20132443 (2011).","journal-title":"Peptides"},{"key":"BFsrep33192_CR60","doi-asserted-by":"crossref","first-page":"H1057","DOI":"10.1152\/ajpheart.00841.2003","volume":"286","author":"JW Breslin","year":"2004","unstructured":"Breslin, J. W. & Yuan, S. Y. Involvement of RhoA and Rho kinase in neutrophil-stimulated endothelial hyperpermeability. Am J Physiol Heart Circ Physiol 286, H1057\u20131062 (2004).","journal-title":"Am J Physiol Heart Circ Physiol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep33192.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep33192","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep33192.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T00:32:43Z","timestamp":1672878763000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep33192"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,9,13]]},"references-count":60,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,12,16]]}},"alternative-id":["BFsrep33192"],"URL":"https:\/\/doi.org\/10.1038\/srep33192","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,9,13]]},"assertion":[{"value":"15 April 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 August 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 September 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"33192"}}