title: Loss of the intestinal mucus layer in the normal rat causes gut injury but not toxic mesenteric lymph nor lung injury.
abstract: There is substantial evidence that gut barrier failure is associated with distant organ injury and systemic inflammation. After major trauma or stress, the factors and mechanisms involved in gut injury are unknown. Our primary hypothesis is that loss of the intestinal mucus layer will result in injury of the normal gut that is exacerbated by the presence of luminal pancreatic proteases. Our secondary hypothesis is that the injury produced in the gut will result in the production of biologically active mesenteric lymph and consequently distant organ (i.e., lung) injury. To test this hypothesis, five groups of rats were studied: 1) uninstrumented naive rats; 2) control rats in which a ligated segment of distal ileum was filled with saline; 3) rats with pancreatic proteases placed in their distal ileal segments; 4) rats with the mucolytic N-acetylcysteine (NAC) placed in their distal ileal segments; and 5) rats exposed to NAC and pancreatic proteases in their ileal segments. The potential systemic consequences of gut injury induced by NAC and proteases were assessed by measuring the biological activity of mesenteric lymph as well as gut-induced lung injury. Exposure of the normal intestine to NAC, but not saline or proteases, led to increased gut permeability, loss of mucus hydrophobicity, a decrease in the mucus layer, as well as morphological evidence of villous injury. Although proteases themselves did not cause gut injury, the combination of pancreatic proteases with NAC caused more severe injury than NAC alone, suggesting that once the mucus barrier is impaired, luminal proteases can injure the now vulnerable gut. Because comparable levels of gut injury caused by systemic insults are associated with gut-induced lung injury, which is mediated by biologically active factors in mesenteric lymph, we next tested whether this local model of gut injury would produce active mesenteric lymph or lead to lung injury. It did not, suggesting that gut injury by itself may not be sufficient to induce distant organ dysfunction. Therefore, loss of the intestinal mucus layer, especially in the presence of intraluminal pancreatic proteases, is sufficient to lead to injury and barrier dysfunction of the otherwise normal intestine but not to produce gut-induced distant organ dysfunction.
authors.affiliation: Department of Surgery, UMDNJ-New Jersey Medical School, Newark, New Jersey 07103, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Sharpe
authors.forename: Xiaofa
authors.initials: X
authors.lastname: Qin
authors.forename: Qi
authors.initials: Q
authors.lastname: Lu
authors.forename: Eleonora
authors.initials: E
authors.lastname: Feketeova
authors.forename: David C
authors.initials: DC
authors.lastname: Palange
authors.forename: Wei
authors.initials: W
authors.lastname: Dong
authors.forename: Sharvil U
authors.initials: SU
authors.lastname: Sheth
authors.forename: Marlon A
authors.initials: MA
authors.lastname: Lee
authors.forename: Diego
authors.initials: D
authors.lastname: Reino
authors.forename: Da-Zhong
authors.initials: DZ
authors.lastname: Xu
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Deitch
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology / Q000633:toxicity; D055371:Acute Lung Injury / Q000209:etiology*; D000818:Animals; D018988:Bacterial Translocation / Q000502:physiology; D005070:Evans Blue / Q000493:pharmacokinetics; D005100:Expectorants / Q000494:pharmacology / Q000633:toxicity; D057927:Hydrophobic and Hydrophilic Interactions; D007082:Ileum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008026:Ligation; D008168:Lung / Q000378:metabolism; D008196:Lymph / Q000502:physiology*; D008297:Male; D008643:Mesentery; D008954:Models, Biological; D009093:Mucus / Q000502:physiology*; D010179:Pancreas / Q000201:enzymology; D010447:Peptide Hydrolases / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016897:Respiratory Burst
chemical_list: D005100:Expectorants; D005070:Evans Blue; D010447:Peptide Hydrolases; D000111:Acetylcysteine