{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T22:11:20Z","timestamp":1769119880112,"version":"3.49.0"},"reference-count":37,"publisher":"American Physiological Society","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"published-print":{"date-parts":[[2005,5]]},"abstract":"<jats:p>Protein-losing enteropathy (PLE), the excessive loss of plasma proteins through the intestine, often correlates with the episodic loss of heparan sulfate (HS) proteoglycans (HSPG) from the basolateral surface of intestinal epithelial cells. PLE onset is often associated with a proinflammatory state. We investigated whether loss of HS or treatment with the proinflammatory cytokine TNF-\u03b1 directly causes protein leakage and whether a combination of both exacerbates this process. We established the first in vitro model of PLE and measured the flux of albumin\/FITC through a monolayer of intestinal HT29 or Caco-2 cells grown on transwells and determined the integrity by transepithelial electrical resistance (TER). Loss of HS from the basolateral surface, either by heparanase digestion or by inhibition of HS synthesis, increased albumin flux 1.58 \u00b1 0.09-fold and reduced TER by 23.4 \u00b1 6.5%. TNF-\u03b1 treatment increased albumin flux 4.04 \u00b1 0.03-fold and reduced TER by 75.7 \u00b1 4.7% but only slightly decreased HS content. The combined effects of HS loss and TNF-\u03b1 treatment were not only additive, but synergistic, with a 7.00 \u00b1 0.11-fold increase in albumin flux and a 83.9 \u00b1 8.1% reduction of TER. Coincubation of TNF-\u03b1 with soluble HS or heparin abolished these synergistic effects. Loss of basolateral HS directly causes protein leakage and amplifies the effects of the proinflammatory cytokine TNF-\u03b1. Our findings imply that loss of HSPGs renders patients more susceptible to PLE and offer a potential explanation for the favorable response some PLE patients have to heparin therapy.<\/jats:p>","DOI":"10.1152\/ajpgi.00461.2004","type":"journal-article","created":{"date-parts":[[2004,12,17]],"date-time":"2004-12-17T01:24:23Z","timestamp":1103246663000},"page":"G1015-G1023","source":"Crossref","is-referenced-by-count":50,"title":["Heparan sulfate depletion amplifies TNF-\u03b1-induced protein leakage in an in vitro model of protein-losing enteropathy"],"prefix":"10.1152","volume":"288","author":[{"given":"Lars","family":"Bode","sequence":"first","affiliation":[]},{"given":"Erik A.","family":"Eklund","sequence":"additional","affiliation":[]},{"given":"Simon","family":"Murch","sequence":"additional","affiliation":[]},{"given":"Hudson H.","family":"Freeze","sequence":"additional","affiliation":[]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"crossref","unstructured":"Beeken WL, Busch HJ, and Sylwester DL.Intestinal protein loss in Crohn's disease.Gastroenterology62: 207\u2013215, 1972.","DOI":"10.1016\/S0016-5085(72)80171-9"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.11.6164"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1111\/j.1348-0421.1999.tb02438.x"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(98)09267-8"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(97)70214-2"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1016\/S0945-053X(02)00012-4"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1097\/00075198-200304000-00011"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1136\/gut.45.2.191"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.20068"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.86.2.688"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.4065\/73.8.777"},{"key":"R12","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.60.070191.002303"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90173-V"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115530"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1186\/cc2166"},{"key":"R16","doi-asserted-by":"publisher","DOI":"10.1097\/00008480-200210000-00010"},{"key":"R17","doi-asserted-by":"publisher","DOI":"10.1097\/00042737-200104000-00026"},{"key":"R18","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(93)90485-Y"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(96)90941-1"},{"key":"R20","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00066.2003"},{"key":"R21","doi-asserted-by":"publisher","DOI":"10.1172\/JCI2350"},{"key":"R22","doi-asserted-by":"crossref","unstructured":"Ostrow Aand Rychik J.Investigations into possible mechanisms of protein-losing enteropathy after Fontan operation (Abstract).J Am Coll Cardiol, 2004. 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