{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T23:36:10Z","timestamp":1792625770895,"version":"4.5.0"},"reference-count":245,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,22]],"date-time":"2021-01-22T00:00:00Z","timestamp":1611273600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000182","name":"Medical Research and Materiel Command","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000182","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>We present a brief history of the immune response and show that Metchnikoff\u2019s theory of inflammation and phagocytotic defense was largely ignored in the 20<jats:sup>th<\/jats:sup>century. For decades, the immune response was believed to be triggered centrally, until Lafferty and Cunningham proposed the initiating signal came from the tissues. This shift opened the way for Janeway\u2019s pattern recognition receptor theory, and Matzinger\u2019s danger model. All models failed to appreciate that without inflammation, there can be no immune response. The situation changed in the 1990s when cytokine biology was rapidly advancing, and the immune system\u2019s role expanded from host defense, to the maintenance of host health. An inflammatory environment, produced by immune cells themselves, was now recognized as mandatory for their attack, removal and repair functions after an infection or injury. We explore the cellular programs of the immune response, and the role played by cytokines and other mediators to tailor the right response, at the right time. Normally, the immune response is robust, self-limiting and restorative. However, when the antigen load or trauma exceeds the body\u2019s internal tolerances, as witnessed in some COVID-19 patients, excessive inflammation can lead to increased sympathetic outflows, cardiac dysfunction, coagulopathy, endothelial and metabolic dysfunction, multiple organ failure and death. Currently, there are few drug therapies to reduce excessive inflammation and immune dysfunction. We have been developing an intravenous (IV) fluid therapy comprising adenosine, lidocaine and Mg<jats:sup>2+<\/jats:sup>(ALM) that confers a survival advantage by preventing excessive inflammation initiated by sepsis, endotoxemia and sterile trauma. The multi-pronged protection appears to be unique and may provide a tool to examine the intersection points in the immune response to infection or injury, and possible ways to prevent secondary tissue damage, such as that reported in patients with COVID-19.<\/jats:p>","DOI":"10.3389\/fimmu.2020.610131","type":"journal-article","created":{"date-parts":[[2021,1,22]],"date-time":"2021-01-22T06:34:50Z","timestamp":1611297290000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Living in a Hostile World: Inflammation, New Drug Development, and Coronavirus"],"prefix":"10.3389","volume":"11","author":[{"given":"Geoffrey P.","family":"Dobson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Biros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayley L.","family":"Letson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jodie L.","family":"Morris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1007\/BF01628340","article-title":"The teleogical mechanism of living nature","volume":"15","author":"Pfluger","year":"1877","journal-title":"Pflugers Arch"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpc.2004.06.002","article-title":"Organ arrest, protection and preservation: natural hibernation to cardiac surgery: a review","volume":"139","author":"Dobson","year":"2004","journal-title":"Comp Biochem Physiol Part B"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1097\/TA.0000000000000881","article-title":"Adenosine, Lidocaine and Mg2+ (ALM): From Cardiac Surgery to Combat Casualty Care: Teaching Old Drugs New Tricks","volume":"80","author":"Dobson","year":"2016","journal-title":"J Trauma Acute Care Surg"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fsurg.2015.00043","article-title":"Addressing the global burden of trauma in major surgery","volume":"2","author":"Dobson","year":"2015","journal-title":"Front Surg"},{"key":"B5","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1152\/physrev.1929.9.3.399","article-title":"Organisation for physiological homeostasis","volume":"9","author":"Cannon","year":"1929","journal-title":"Physiol Rev"},{"key":"B6","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1080\/09647040600602805","article-title":"Theory of functional systems in the scientific school of P.K. 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