{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T15:37:47Z","timestamp":1791819467694,"version":"4.3.4"},"reference-count":71,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T00:00:00Z","timestamp":1764460800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Basic physiology and molecular mechanisms accounting for the maldistribution of fluid that is characteristic of the \u201cthird fluid space\u201d (Vt2) have been known for several decades but have been poorly integrated into the clinical literature. Today, the maldistribution can be quantified and simulated in living humans by using volume kinetic mathematics, which introduces possibilities to validate interventions designed to mitigate the pathophysiology. Fluid accumulation in Vt2 occurs both in fluid overload and inflammation, and both are largely influenced by interstitial fluid pressure. This is normally slightly sub-atmospheric but increases during volume loading to eventually exceed the ambient air pressure, whereby the loss of vacuum allows pools of fluid to appear in the interstitial gel. Opening of Vt2 due to fluid overload can be delayed\/minimized by lowering the infusion rate, hemorrhage, and the use of hyper-oncotic fluid. Accumulation of fluid in Vt2 during acute inflammation and tissue injury can be explained by disruption of the cell\u2013matrix interactions that actively regulate the interstitial pressure. Inflammatory mediators, mostly tissue cytokines, cause release of tensile forces that disrupt integrin-dependent adhesion between interstitial fibroblasts and collagen fibers. This disruption causes the interstitial space to expand, which results in a deep negative (suction) pressure. These events can be modulated by \u03b1-trinositol and insulin.<\/jats:p>","DOI":"10.3390\/jcm14238491","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T16:20:29Z","timestamp":1765210829000},"page":"8491","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Physiology and Molecular Mechanisms of the \u201cThird Fluid Space\u201d"],"prefix":"10.3390","volume":"14","author":[{"given":"Randal O.","family":"Dull","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, University of Arizona College of Medicine, Tucson, AZ 85724, USA"},{"name":"Department of Pathology, University of Arizona College of Medicine, Tucson, AZ 85724, USA"},{"name":"Department of Surgery, University of Arizona College of Medicine, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1528-3803","authenticated-orcid":false,"given":"Robert G.","family":"Hahn","sequence":"additional","affiliation":[{"name":"Karolinska Institute at Danderyds Hospital (KIDS), 171 77 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109525","DOI":"10.1016\/j.surg.2025.109525","article-title":"Association between cumulative fluid balance to estimated colloid oncotic pressure ratio and postoperative outcome in surgical patients requiring intensive management","volume":"185","author":"Kumar","year":"2025","journal-title":"Surgery"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1111\/joim.12274","article-title":"Association between fluid balance and survival in critically ill patients","volume":"277","author":"Lee","year":"2015","journal-title":"J. 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