{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T03:29:50Z","timestamp":1791343790008,"version":"4.3.1"},"reference-count":77,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Universidad Aut\u00f3noma de Aguascalientes","award":["PIB24-4"],"award-info":[{"award-number":["PIB24-4"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: Sepsis is a life-threatening condition characterized by an uncontrolled immune response due to systemic infections. It is responsible for millions of deaths worldwide. Although inflammasomes play an important role in host defense, they have a detrimental role in sepsis induced by LPS or Gram-negative bacteria. We aimed to revise the molecular mechanisms of inflammasome activation in sepsis by LPS and Gram-negative bacteria other than cytokine release as treatments blocking TNF-\u03b1 and IL-1 cytokines have been ineffective even though cytokine storm is associated with lethality. Results: Studies with knockout mice deficient in inflammasome-derived cytokines have shown contrasting results on the role of these proinflammatory cytokines in the lethality of LPS- and Gram-negative-induced sepsis. However, DAMPs released after non-canonical inflammasome activation such as extracellular DNA, histones, HMGB1, and tissue factor result in disseminated-intravascular coagulation (DIC) and mortality in mice. Blocking these products in preclinical studies with animal models showed improved clinical scores and survival after LPS-induced sepsis or polymicrobial sepsis induced by Cecal Ligation and Puncture. Conclusions: Even though immunomodulatory drugs have shown inconclusive results as therapies for sepsis, blocking DAMPs associated with DIC may be considered for clinical trials in the future, especially in patients presenting biomarkers of coagulopathies.<\/jats:p>","DOI":"10.3390\/jcm14197102","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T07:56:29Z","timestamp":1759996589000},"page":"7102","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Role of Inflammasomes in LPS and Gram-Negative Bacterial Sepsis"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5996-9313","authenticated-orcid":false,"given":"Eduardo","family":"Hern\u00e1ndez-Cuellar","sequence":"first","affiliation":[{"name":"Laboratorio de Biolog\u00eda Celular y Tisular, Departamento de Morfolog\u00eda, Universidad Aut\u00f3noma de Aguascalientes, Aguascalientes 20100, CP, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohsuke","family":"Tsuchiya","sequence":"additional","affiliation":[{"name":"Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4432-7780","authenticated-orcid":false,"given":"Oscar","family":"Medina-Contreras","sequence":"additional","affiliation":[{"name":"Epidemiology, Endocrinology & Nutrition Research Unit, Hospital Infantil de M\u00e9xico Federico G\u00f3mez, Mexico City 06720, CP, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Valle-R\u00edos","sequence":"additional","affiliation":[{"name":"Research Division, Faculty of Medicine, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM), Mexico City 04360, CP, Mexico"},{"name":"Laboratory of Translational Research in Cellular and Molecular Biology, Hospital Infantil de M\u00e9xico Federico G\u00f3mez, Mexico City 06720, CP, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.jgar.2017.06.013","article-title":"Sepsis and septic shock: New definitions, new diagnostic and therapeutic approaches","volume":"10","author":"Esposito","year":"2017","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref_2","unstructured":"(2025, April 22). World Health Organization: Sepsis. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/sepsis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990-2017: Analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1007\/s00063-023-01088-7","article-title":"Challenges of assessing the burden of sepsis","volume":"118","author":"Rudd","year":"2023","journal-title":"Med. Klin. Intensiv. Notfmed."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Guarino, M., Perna, B., Cesaro, A.E., Maritati, M., Spampinato, M.D., Contini, C., and De Giorgio, R. (2023). Update on Sepsis and Septic Shock in Adult Patients: Management in the Emergency Department. J. Clin. Med., 12.","DOI":"10.3390\/jcm12093188"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1111\/1348-0421.12771","article-title":"Inflammasome-associated cell death: Pyroptosis, apoptosis, and physiological implications","volume":"64","author":"Tsuchiya","year":"2020","journal-title":"Microbiol. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"641750","DOI":"10.3389\/fimmu.2021.641750","article-title":"Inflammasome-Dependent Coagulation Activation in Sepsis","volume":"12","author":"Wu","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2050312119835043","DOI":"10.1177\/2050312119835043","article-title":"Sepsis: The evolution in definition, pathophysiology, and management","volume":"7","author":"Gyawali","year":"2019","journal-title":"SAGE Open Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"16045","DOI":"10.1038\/nrdp.2016.45","article-title":"Sepsis and septic shock","volume":"2","author":"Hotchkiss","year":"2016","journal-title":"Nat. Rev. Dis. Primers."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/s41392-025-02264-1","article-title":"Pattern recognition receptors: Function, regulation and therapeutic potential","volume":"10","author":"Chen","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.it.2024.02.004","article-title":"Inflammasome diversity: Exploring novel frontiers in the innate immune response","volume":"45","author":"Yu","year":"2024","journal-title":"Trends Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1038\/cr.2015.139","article-title":"Gasdermin D is an executor of pyroptosis and required for interleukin-1\u03b2 secretion","volume":"25","author":"He","year":"2015","journal-title":"Cell Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1038\/nature15514","article-title":"Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death","volume":"526","author":"Shi","year":"2015","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1038\/ni.2263","article-title":"NLRC4-driven production of IL-1\u03b2 discriminates between pathogenic and commensal bacteria and promotes host intestinal defense","volume":"13","author":"Franchi","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3076","DOI":"10.1073\/pnas.0913087107","article-title":"Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome","volume":"107","author":"Miao","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1038\/nature10394","article-title":"Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity","volume":"477","author":"Kofoed","year":"2011","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1038\/nature10510","article-title":"The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus","volume":"477","author":"Zhao","year":"2011","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/s41423-025-01284-9","article-title":"Updated insights into the molecular networks for NLRP3 inflammasome activation","volume":"22","author":"Paik","year":"2025","journal-title":"Cell. Mol. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1109938","DOI":"10.3389\/fimmu.2022.1109938","article-title":"The mechanism of NLRP3 inflammasome activation and its pharmacological inhibitors","volume":"13","author":"Zhan","year":"2023","journal-title":"Front. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/s41590-025-02088-9","article-title":"Mechanisms of NLRP3 activation and inhibition elucidated by functional analysis of disease-associated variants","volume":"26","author":"Feng","year":"2025","journal-title":"Nat. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1038\/nature15541","article-title":"Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling","volume":"526","author":"Kayagaki","year":"2015","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/nature10558","article-title":"Non-canonical inflammasome activation targets caspase-11","volume":"479","author":"Kayagaki","year":"2011","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1126\/science.1230751","article-title":"Caspase-11 protects against bacteria that escape the vacuole","volume":"339","author":"Aachoui","year":"2013","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e13452","DOI":"10.15252\/emmm.202013452","article-title":"Interaction between the inflammasome and commensal microorganisms in gastrointestinal health and disease","volume":"13","author":"Watanabe","year":"2021","journal-title":"EMBO Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1038\/ng.3066","article-title":"Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation","volume":"46","author":"Romberg","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e391","DOI":"10.1002\/mco2.391","article-title":"Inflammasome: Structure, biological functions, and therapeutic targets","volume":"4","author":"Dai","year":"2023","journal-title":"MedComm"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1038\/nature13683","article-title":"Inflammatory caspases are innate immune receptors for intracellular LPS","volume":"514","author":"Shi","year":"2014","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4239","DOI":"10.4049\/jimmunol.177.7.4239","article-title":"The inflammatory caspases: Key players in the host response to pathogenic invasion and sepsis","volume":"177","author":"Nadiri","year":"2006","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1038\/s41467-017-02682-y","article-title":"Human caspase-4 detects tetra-acylated LPS and cytosolic Francisella and functions differently from murine caspase-11","volume":"9","author":"Lagrange","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1038\/s41586-023-06742-w","article-title":"Recognition and maturation of IL-18 by caspase-4 noncanonical inflammasome","volume":"624","author":"Shi","year":"2023","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"eaar6676","DOI":"10.1126\/sciimmunol.aar6676","article-title":"Noncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps","volume":"3","author":"Chen","year":"2018","journal-title":"Sci. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/nature18590","article-title":"Pore-forming activity and structural autoinhibition of the gasdermin family","volume":"535","author":"Ding","year":"2016","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1038\/ni.1960","article-title":"Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria","volume":"11","author":"Miao","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3468","DOI":"10.4049\/jimmunol.1900045","article-title":"Gasdermin D Protects from Melioidosis through Pyroptosis and Direct Killing of Bacteria","volume":"202","author":"Wang","year":"2019","journal-title":"J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3749","DOI":"10.4049\/jimmunol.162.7.3749","article-title":"Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: Evidence for TLR4 as the Lps gene product","volume":"162","author":"Hoshino","year":"1999","journal-title":"J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1126\/science.282.5396.2085","article-title":"Defective LPS signaling in C3H\/HeJ and C57BL\/10ScCr mice: Mutations in Tlr4 gene","volume":"282","author":"Poltorak","year":"1998","journal-title":"Science"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6978936","DOI":"10.1155\/2016\/6978936","article-title":"The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation","volume":"2016","author":"Molteni","year":"2016","journal-title":"Mediat. Inflamm."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/0092-8674(95)90490-5","article-title":"Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock","volume":"80","author":"Li","year":"1995","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"R146","DOI":"10.1186\/cc8041","article-title":"VX-166: A novel potent small molecule caspase inhibitor as a potential therapy for sepsis","volume":"13","author":"Weber","year":"2009","journal-title":"Crit. Care."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/nature04515","article-title":"Cryopyrin activates the inflammasome in response to toxins and ATP","volume":"440","author":"Mariathasan","year":"2006","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/nature02664","article-title":"Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf","volume":"430","author":"Mariathasan","year":"2004","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/S0092-8674(00)80943-5","article-title":"Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE","volume":"92","author":"Wang","year":"1998","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1126\/science.1240988","article-title":"Cytoplasmic LPS activates caspase-11: Implications in TLR4-independent endotoxic shock","volume":"341","author":"Hagar","year":"2013","journal-title":"Science"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1126\/science.1240248","article-title":"Noncanonical inflammasome activation by intracellular LPS independent of TLR4","volume":"341","author":"Kayagaki","year":"2013","journal-title":"Science"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"108887","DOI":"10.1016\/j.celrep.2021.108887","article-title":"Gasdermin D mediates the maturation and release of IL-1\u03b1 downstream of inflammasomes","volume":"34","author":"Tsuchiya","year":"2021","journal-title":"Cell Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4385","DOI":"10.4049\/jimmunol.1000803","article-title":"Inflammasome-dependent release of the alarmin HMGB1 in endotoxemia","volume":"185","author":"Lamkanfi","year":"2010","journal-title":"J. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1038\/348550a0","article-title":"Interleukin-1 receptor antagonist reduces mortality from endotoxin shock","volume":"348","author":"Ohlsson","year":"1990","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3364","DOI":"10.4049\/jimmunol.159.7.3364","article-title":"Phenotypic and functional characterization of mice that lack the type I receptor for IL-1","volume":"159","author":"Glaccum","year":"1997","journal-title":"J. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1111\/j.1600-0463.2010.02684.x","article-title":"Differential susceptibility to lethal endotoxaemia in mice deficient in IL-1\u03b1, IL-1\u03b2 or IL-1 receptor type I","volume":"118","author":"Joosten","year":"2010","journal-title":"APMIS"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"291","DOI":"10.4049\/jimmunol.157.1.291","article-title":"Effect of endotoxin in IL-1 beta-deficient mice","volume":"157","author":"Fantuzzi","year":"1996","journal-title":"J. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.immuni.2018.08.016","article-title":"The Endotoxin Delivery Protein HMGB1 Mediates Caspase-11-Dependent Lethality in Sepsis","volume":"49","author":"Deng","year":"2018","journal-title":"Immunity"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.blre.2015.12.004","article-title":"DAMP and DIC: The role of extracellular DNA and DNA-binding proteins in the pathogenesis of DIC","volume":"30","author":"Liaw","year":"2016","journal-title":"Blood Rev."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1038\/nm.2053","article-title":"Extracellular histones are major mediators of death in sepsis","volume":"15","author":"Xu","year":"2009","journal-title":"Nat. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"15880","DOI":"10.1073\/pnas.1005743107","article-title":"Extracellular DNA traps promote thrombosis","volume":"107","author":"Fuchs","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1182\/blood-2016-09-741298","article-title":"Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice","volume":"129","author":"McDonald","year":"2017","journal-title":"Blood"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1016\/j.immuni.2019.11.005","article-title":"Bacterial Endotoxin Activates the Coagulation Cascade through Gasdermin D-Dependent Phosphatidylserine Exposure","volume":"51","author":"Yang","year":"2019","journal-title":"Immunity"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1097\/SHK.0000000000000509","article-title":"Circulating microparticles, blood cells, and endothelium induce procoagulant activity in sepsis through phosphatidylserine exposure","volume":"45","author":"Zhang","year":"2016","journal-title":"Shock"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1016\/j.immuni.2019.04.003","article-title":"Inflammasome Activation Triggers Blood Clotting and Host Death through Pyroptosis","volume":"50","author":"Wu","year":"2019","journal-title":"Immunity"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1001\/archsurg.1996.01430240027003","article-title":"Prevention of endotoxin-induced mortality by antitissue factor immunization","volume":"131","author":"Dackiw","year":"1996","journal-title":"Arch. Surg."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1172\/JCI115748","article-title":"Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia","volume":"89","author":"Fischer","year":"1992","journal-title":"J. Clin. Invest."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.4049\/jimmunol.1601745","article-title":"Deletion of Nlrp3 Augments Survival during Polymicrobial Sepsis by Decreasing Autophagy and Enhancing Phagocytosis","volume":"198","author":"Jin","year":"2017","journal-title":"J. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1164\/rccm.200604-546OC","article-title":"Caspase-1 regulates Escherichia coli sepsis and splenic B cell apoptosis independently of interleukin-1beta and interleukin-18","volume":"174","author":"Sarkar","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1038\/82741","article-title":"Caspase inhibitors improve survival in sepsis: A critical role of the lymphocyte","volume":"1","author":"Hotchkiss","year":"2000","journal-title":"Nat. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/s41435-024-00293-4","article-title":"Integrated analysis reveals NLRC4 as a potential biomarker in sepsis pathogenesis","volume":"25","author":"Jiang","year":"2024","journal-title":"Genes Immun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1038\/nm.2729","article-title":"Lethal inflammasome activation by a multidrug-resistant pathobiont upon antibiotic disruption of the microbiota","volume":"18","author":"Ayres","year":"2012","journal-title":"Nat. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.18632\/aging.202379","article-title":"NLRC4 gene silencing-dependent blockade of NOD-like receptor pathway inhibits inflammation, reduces proliferation and increases apoptosis of dendritic cells in mice with septic shock","volume":"13","author":"Wang","year":"2021","journal-title":"Aging"},{"key":"ref_67","first-page":"127","article-title":"Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody","volume":"33","author":"Taylor","year":"1991","journal-title":"Circ. Shock."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1007\/s00134-011-2353-7","article-title":"Recombinant human milk fat globule-EGF factor 8 produces dose-dependent benefits in sepsis","volume":"38","author":"Shah","year":"2012","journal-title":"Intensive Care Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1016\/S0140-6736(05)60602-2","article-title":"Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group","volume":"351","author":"Abraham","year":"1998","journal-title":"Lancet"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1097\/00003246-199609000-00002","article-title":"INTERSEPT: An international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. International Sepsis Trial Study Group","volume":"24","author":"Cohen","year":"1996","journal-title":"Crit. Care Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1111\/ijcp.12382","article-title":"Anti-TNF-\u03b1 therapy for patients with sepsis: A systematic meta-analysis","volume":"68","author":"Lv","year":"2014","journal-title":"Int. J. Clin. Pract."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1097\/01.CCM.0000110730.38696.9C","article-title":"Should we continue to target the platelet-activating factor pathway in septic patients?","volume":"32","author":"Minneci","year":"2004","journal-title":"Crit. Care Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1097\/CCM.0000000000001402","article-title":"Interleukin-1 Receptor Blockade Is Associated with Reduced Mortality in Sepsis Patients with Features of Macrophage Activation Syndrome: Reanalysis of a Prior Phase III Trial","volume":"44","author":"Shakoory","year":"2016","journal-title":"Crit. Care Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1097\/00003246-199707000-00010","article-title":"Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: A phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group","volume":"25","author":"Opal","year":"1997","journal-title":"Crit. Care Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1111\/anae.16263","article-title":"Immunomodulatory drugs in sepsis: A systematic review and meta-analysis","volume":"79","author":"Robey","year":"2024","journal-title":"Anaesthesia"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1016\/S2213-2600(23)00158-3","article-title":"Prospective evaluation of the efficacy, safety, and optimal biomarker enrichment strategy for nangibotide, a TREM-1 inhibitor, in patients with septic shock (ASTONISH): A double-blind, randomised, controlled, phase 2b trial","volume":"11","author":"Lambden","year":"2023","journal-title":"Lancet. Respir. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1186\/s12879-016-1823-5","article-title":"The efficacy of thymosin \u03b11 as immunomodulatory treatment for sepsis: A systematic review of randomized controlled trials","volume":"16","author":"Liu","year":"2016","journal-title":"BMC Infect. Dis."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/19\/7102\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T04:37:44Z","timestamp":1760157464000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/19\/7102"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,9]]},"references-count":77,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["jcm14197102"],"URL":"https:\/\/doi.org\/10.3390\/jcm14197102","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,9]]}}}