{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T11:50:51Z","timestamp":1776858651279,"version":"3.51.2"},"reference-count":83,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) have emerged as potent modulators of immune responses during sepsis, yet their roles remain complex, alternating between protective and permissive depending on timing, tissue compartment, and inflammatory context. This review presents a historical assessment of VIP and PACAP in sepsis research, highlighting the evolution of conceptual advances across five decades. Starting in the 1980s, early studies revealed that VIP levels rise during endotoxemia and correlated with hypotension and mortality, suggesting a deleterious role. By the 1990s, research pivoted toward understanding gut-derived VIP and its interaction with nitric oxide, culminating in the classification of VIP and PACAP as \u201cmacrophage deactivating factors\u201d that downregulate TNF\u03b1 and IL-6. The 2000s further clarified their cell-specific actions through VPAC1\/2 and PAC1 receptors, showing anti-inflammatory effects on both innate and adaptive immune cells, while illuminating delivery challenges overcome by liposomal encapsulation. The 2010s expanded this narrative by dissecting receptor dynamics, gut barrier regulation, and VIP\u2019s role in neuroimmune crosstalk and thrombo-inflammation. Most recently, studies in the 2020s provide a nuanced view of how VIP suppresses inflammatory damage but also enables pathogen persistence during live bacterial infection, implicating VIP signaling in trade-offs between tolerance and clearance. Across this chronological framework, VIP and PACAP have oscillated between friend, foe, and frenemy, underscoring the importance of context in leveraging their therapeutic potential in sepsis.<\/jats:p>","DOI":"10.3390\/biology15090663","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T10:38:14Z","timestamp":1776854294000},"page":"663","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Historical Review of Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-Activating Polypeptide in Sepsis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8288-2376","authenticated-orcid":false,"given":"Razia","family":"Dawlaty","sequence":"first","affiliation":[{"name":"Plant Pathology, Microbiology, and Biotechnology, North Dakota State University, Fargo, ND 58102, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4858-8339","authenticated-orcid":false,"given":"Philomena","family":"Entsie","sequence":"additional","affiliation":[{"name":"Departments of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58102, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6321-3516","authenticated-orcid":false,"given":"Emmanuel Boadi","family":"Amoafo","sequence":"additional","affiliation":[{"name":"Departments of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58102, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5540-0456","authenticated-orcid":false,"given":"Elisabetta","family":"Liverani","sequence":"additional","affiliation":[{"name":"Departments of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58102, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5902-4347","authenticated-orcid":false,"given":"Glenn P.","family":"Dorsam","sequence":"additional","affiliation":[{"name":"Plant Pathology, Microbiology, and Biotechnology, North Dakota State University, Fargo, ND 58102, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"104363","DOI":"10.1016\/j.ebiom.2022.104363","article-title":"Immunopathophysiology of human sepsis","volume":"86","author":"Wiersinga","year":"2022","journal-title":"EBioMedicine"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1007\/s00134-021-06506-y","article-title":"Surviving sepsis campaign: International guidelines for management of sepsis and septic shock 2021","volume":"47","author":"Evans","year":"2021","journal-title":"Intensive Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2450","DOI":"10.1016\/j.immuni.2021.10.012","article-title":"The immunology of sepsis","volume":"54","author":"Wiersinga","year":"2021","journal-title":"Immunity"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1007\/s00134-020-06151-x","article-title":"Incidence and mortality of hospital- and ICU-treated sepsis: Results from an updated and expanded systematic review and meta-analysis","volume":"46","author":"Mellhammar","year":"2020","journal-title":"Intensive Care Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.mcna.2020.02.011","article-title":"Sepsis and Septic Shock\u2014Basics of diagnosis, pathophysiology and clinical decision making","volume":"104","author":"Font","year":"2020","journal-title":"Med. 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