{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T18:05:24Z","timestamp":1770746724989,"version":"3.49.0"},"reference-count":36,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,25]],"date-time":"2021-09-25T00:00:00Z","timestamp":1632528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM104357"],"award-info":[{"award-number":["P20GM104357"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P30GM103328"],"award-info":[{"award-number":["P30GM103328"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"publisher","award":["F31HL149257"],"award-info":[{"award-number":["F31HL149257"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"publisher","award":["R00HL130456"],"award-info":[{"award-number":["R00HL130456"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"publisher","award":["R01HL151407"],"award-info":[{"award-number":["R01HL151407"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK109133"],"award-info":[{"award-number":["R01DK109133"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Platelets, cellular mediators of thrombosis, are activated during sepsis and are increasingly recognized as mediators of the immune response. Platelet activation is significantly increased in sepsis patients compared to ICU control patients. Despite this correlation, the role of activated platelets in contributing to sepsis pathophysiology remains unclear. We previously demonstrated NOD-like receptor protein 3 inflammasome (NLRP3) inflammasome activation in sepsis-induced platelets from cecal-ligation puncture (CLP) rats. Activated platelets were associated with increased pulmonary edema and glomerular injury in CLP vs. SHAM controls. In this study, we investigated whether inhibition of platelet activation would attenuate NLRP3 activation and renal and pulmonary injury in response to CLP. CLP was performed in male and female Sprague Dawley (SD) rats (n = 10\/group) to induce abdominal sepsis and SHAM rats served as controls. A subset of CLP animals was treated with Clopidogrel (10 mg\/kg\/day, CLP + CLOP) to inhibit platelet activation. At 72 h post-CLP, platelet activation and NLRP3 inflammasome assembly were evaluated, IL-1\u03b2 and IL-18 were measured in plasma, and tissues, renal and pulmonary pathology, and renal function were assessed. Activated platelets were 7.8 \u00b1 3.6% in Sham, 22 \u00b1 6% in CLP and significantly decreased to 14.5 \u00b1 0.6% in CLP + CLOP (n = 8\u201310\/group, p &lt; 0.05). NLRP3 inflammasome assembly was inhibited in platelets of CLP + CLOP animals vs. CLP. Significant increases in plasma and kidney IL-1\u03b2 and IL-18 in response to CLP were decreased with Clopidogrel treatment. Renal injury, but not lung histology or renal function was improved in CLP + CLOP vs. CLP. These data provide evidence that activated platelets may contribute to sepsis-induced renal injury, possibly via NLRP3 activation in platelets. Platelets may be a therapeutic target to decrease renal injury in septic patients.<\/jats:p>","DOI":"10.3390\/ijms221910330","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T04:55:33Z","timestamp":1632718533000},"page":"10330","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Platelet Inhibition Prevents NLRP3 Inflammasome Activation and Sepsis-Induced Kidney Injury"],"prefix":"10.3390","volume":"22","author":[{"given":"Marivee","family":"Borges-Rodriguez","sequence":"first","affiliation":[{"name":"Departments of Pediatrics, University of Mississippi Medical Center, Jackson, MS 39212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corbin A.","family":"Shields","sequence":"additional","affiliation":[{"name":"Emergency Medicine, University of Mississippi Medical Center, Jackson, MS 39212, USA"},{"name":"Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS 39212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivia K.","family":"Travis","sequence":"additional","affiliation":[{"name":"Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS 39212, USA"},{"name":"Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS 39212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert W.","family":"Tramel","sequence":"additional","affiliation":[{"name":"Emergency Medicine, University of Mississippi Medical Center, Jackson, MS 39212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cedar H.","family":"Baik","sequence":"additional","affiliation":[{"name":"Emergency Medicine, University of Mississippi Medical Center, Jackson, MS 39212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chelsea A.","family":"Giachelli","sequence":"additional","affiliation":[{"name":"Emergency Medicine, University of Mississippi Medical Center, Jackson, MS 39212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geilda A.","family":"Tardo","sequence":"additional","affiliation":[{"name":"Emergency Medicine, University of Mississippi Medical Center, Jackson, MS 39212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan Michael","family":"Williams","sequence":"additional","affiliation":[{"name":"Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS 39212, USA"},{"name":"Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS 39212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6730-6499","authenticated-orcid":false,"given":"Denise C.","family":"Cornelius","sequence":"additional","affiliation":[{"name":"Emergency Medicine, University of Mississippi Medical Center, Jackson, MS 39212, USA"},{"name":"Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS 39212, USA"},{"name":"Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS 39212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Greco, E., Lupia, E., Bosco, O., Vizio, B., and Montrucchio, G. (2017). Platelets and Multi-Organ Failure in Sepsis. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102200"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1001\/jama.2017.13836","article-title":"Incidence and Trends of Sepsis in US Hospitals Using Clinical vs. Claims Data, 2009\u20132014","volume":"318","author":"Rhee","year":"2017","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"53","DOI":"10.4046\/trd.2016.79.2.53","article-title":"Sepsis and Acute Respiratory Distress Syndrome: Recent Update","volume":"79","author":"Kim","year":"2016","journal-title":"Tuberc. Respir. Dis. (Seoul)"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.semnephrol.2015.01.002","article-title":"Sepsis-associated acute kidney injury","volume":"35","author":"Alobaidi","year":"2015","journal-title":"Semin. Nephrol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.jinf.2015.11.008","article-title":"Recent advances in pathophysiology and biomarkers of sepsis-induced acute kidney injury","volume":"72","author":"Umbro","year":"2016","journal-title":"J. Infect."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1590\/S1413-86702001000300001","article-title":"Multiple organ failure in septic patients","volume":"5","author":"Bilevicius","year":"2001","journal-title":"Braz. J. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1001\/jama.2014.5804","article-title":"Hospital deaths in patients with sepsis from 2 independent cohorts","volume":"312","author":"Liu","year":"2014","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1378\/chest.10-1971","article-title":"Beyond thrombosis: The versatile platelet in critical illness","volume":"139","author":"Katz","year":"2011","journal-title":"Chest"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1111\/j.1538-7836.2009.03586.x","article-title":"Platelet functions beyond hemostasis","volume":"7","author":"Smyth","year":"2009","journal-title":"J. Thromb. Haemost."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1160\/TH14-02-0126","article-title":"The role of platelets in sepsis","volume":"112","year":"2014","journal-title":"Thromb. Haemost."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s001340050344","article-title":"Platelet function in septic multiple organ dysfunction syndrome","volume":"23","author":"Gawaz","year":"1997","journal-title":"Intensive Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s40635-017-0145-2","article-title":"Sepsis prediction in critically ill patients by platelet activation markers on ICU admission: A prospective pilot study","volume":"5","author":"Layios","year":"2017","journal-title":"Intensive Care Med. Exp."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1097\/00024382-200204000-00004","article-title":"Platelet and leukocyte activation correlate with the severity of septic organ dysfunction","volume":"17","author":"Russwurm","year":"2002","journal-title":"Shock"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1097\/00003246-200006000-00031","article-title":"Thrombocytopenia and prognosis in intensive care","volume":"28","author":"Vanderschueren","year":"2000","journal-title":"Crit. Care Med."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Theofani, E., Semitekolou, M., Morianos, I., Samitas, K., and Xanthou, G. (2019). Targeting NLRP3 Inflammasome Activation in Severe Asthma. J. Clin. Med., 8.","DOI":"10.3390\/jcm8101615"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1002\/mds.27874","article-title":"Targeting the microglial NLRP3 inflammasome and its role in Parkinson\u2019s disease","volume":"35","author":"Haque","year":"2020","journal-title":"Mov. Disord."},{"key":"ref_17","first-page":"737","article-title":"The Pathogenic Role of NLRP3 Inflammasome Activation in Inflammatory Bowel Diseases of Both Mice and Humans","volume":"11","author":"Liu","year":"2017","journal-title":"J. Crohns Colitis"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1007\/s10753-019-01124-9","article-title":"The NLRP3 Inflammasome and Its Role in Sepsis Development","volume":"43","author":"Danielski","year":"2020","journal-title":"Inflammation"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.intimp.2014.02.017","article-title":"Hemin inhibits NLRP3 inflammasome activation in sepsis-induced acute lung injury, involving heme oxygenase-1","volume":"20","author":"Luo","year":"2014","journal-title":"Int. Immunopharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1172\/JCI78253","article-title":"UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis","volume":"125","author":"Moon","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2132","DOI":"10.1002\/mnfr.201500316","article-title":"Curcumin suppresses NLRP3 inflammasome activation and protects against LPS-induced septic shock","volume":"59","author":"Gong","year":"2015","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"20595","DOI":"10.3390\/ijms160920595","article-title":"Exogenous Carbon Monoxide Decreases Sepsis-Induced Acute Kidney Injury and Inhibits NLRP3 Inflammasome Activation in Rats","volume":"16","author":"Wang","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3997","DOI":"10.1096\/fj.201600728R","article-title":"Complement-induced activation of the cardiac NLRP3 inflammasome in sepsis","volume":"30","author":"Kalbitz","year":"2016","journal-title":"FASEB J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1056\/NEJM200103083441001","article-title":"and Recombinant human protein CWEiSSsg. Efficacy and safety of recombinant human activated protein C for severe sepsis","volume":"344","author":"Bernard","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/s12185-015-1904-z","article-title":"Present and future of anticoagulant therapy using antithrombin and thrombomodulin for sepsis-associated disseminated intravascular coagulation: A perspective from Japan","volume":"103","author":"Iba","year":"2016","journal-title":"Int. J. Hematol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e14073","DOI":"10.14814\/phy2.14073","article-title":"NLRP3 inflammasome activation in platelets in response to sepsis","volume":"7","author":"Cornelius","year":"2019","journal-title":"Physiol. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Cornelius, D.C., Travis, O.K., Tramel, R.W., Borges-Rodriguez, M., Baik, C.H., Greer, M., Giachelli, C.A., Tardo, G.A., and Williams, J.M. (2020). NLRP3 inflammasome inhibition attenuates sepsis-induced platelet activation and prevents multi-organ injury in cecal-ligation puncture. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0234039"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1097\/CCM.0b013e31819ceb71","article-title":"Platelets support pulmonary recruitment of neutrophils in abdominal sepsis","volume":"37","author":"Asaduzzaman","year":"2009","journal-title":"Crit. Care Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1056\/NEJMra032401","article-title":"Acute renal failure and sepsis","volume":"351","author":"Schrier","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"S313","DOI":"10.1097\/00003246-200205001-00022","article-title":"Platelet function in sepsis","volume":"30","author":"Vincent","year":"2002","journal-title":"Crit. Care Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1161\/ATVBAHA.116.307401","article-title":"P2Y12 Receptor Modulates Sepsis-Induced Inflammation","volume":"36","author":"Liverani","year":"2016","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1097\/SHK.0b013e318188bd06","article-title":"Elevated serum angiopoietin 2 levels are associated with increased mortality in sepsis","volume":"31","author":"Siner","year":"2009","journal-title":"Shock"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1097\/01.CCM.0000198525.82124.74","article-title":"Endocan, a new endothelial marker in human sepsis","volume":"34","author":"Scherpereel","year":"2006","journal-title":"Crit Care Med."},{"key":"ref_34","first-page":"782573","article-title":"Outcomes of severe sepsis and septic shock patients on chronic antiplatelet treatment: A historical cohort study","volume":"2013","author":"Jaffer","year":"2013","journal-title":"Crit. Care Res. Pract."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1007\/s00210-006-0067-0","article-title":"Pharmacological profile and toxicity of fluorescein-labelled sinistrin, a novel marker for GFR measurements","volume":"373","author":"Pill","year":"2006","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1016\/j.ejmech.2005.03.020","article-title":"Fluorescein-labeled sinistrin as marker of glomerular filtration rate","volume":"40","author":"Pill","year":"2005","journal-title":"Eur. J. Med. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10330\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:05:00Z","timestamp":1760166300000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10330"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,25]]},"references-count":36,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ijms221910330"],"URL":"https:\/\/doi.org\/10.3390\/ijms221910330","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,25]]}}}