Gut Decontamination Reduces Bowel Ischemia-Induced Lung Injury in Rats*

Sorkine, Patrick; Szold, Oded; Halpern, Pinhas; Gutman, Mordechai; Greemland, M.; Rudick, Valery; Goldman, Gideon

doi:10.1378/chest.112.2.491

Cited by 62 publications

(33 citation statements)

References 22 publications

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“…The mammalian small intestine is known to be very sensitive to ischemic insults, displaying a breakdown in mucosal defense against endogenous luminal bacteria/toxins (26). We have established the ischemia/reperfusion (I/R) model in our laboratory by using a standard technique of superior mesenteric artery (SMA) ligation followed by reperfusion (27) in which we also showed that the degree of mucosal injury can be titrated based on the amount of ischemia.…”

Section: Resultsmentioning

confidence: 99%

Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition

Goldberg

Austen

Zhang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

316

323

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Under conditions of starvation and disease, the gut barrier becomes impaired, and trophic feeding to prevent gut mucosal atrophy has become a standard treatment of critically ill patients. However, the mechanisms responsible for the beneficial effects of enteral nutrition have remained a mystery. Using in vitro and in vivo models, we demonstrate that the brush-border enzyme, intestinal alkaline phosphatase (IAP), has the ability to detoxify lipopolysaccharide and prevent bacterial invasion across the gut mucosal barrier. IAP expression and function are lost with starvation and maintained by enteral feeding. It is likely that the IAP silencing that occurs during starvation is a key component of the gut mucosal barrier dysfunction seen in critically ill patients.A mong the most critical functions of the mammalian gut mucosa is to provide a barrier to luminal microbes and toxins while simultaneously allowing for the necessary digestion and absorption of dietary nutrients. The molecular mechanisms that govern barrier function are incompletely understood, but it is clear that under conditions of starvation and disease, the gut barrier becomes impaired, leading to significant morbidity and mortality (1-8). Trophic enteral feeding to prevent gut mucosal atrophy and resultant barrier dysfunction has become part of the standard treatment of intensive care unit patients (9-14). The mechanism(s) responsible for the beneficial effects of trophic feeding are not understood.Intestinal alkaline phosphatase (IAP), a brush-border protein that hydrolyzes monophosphate esters, is expressed exclusively in villus-associated enterocytes and is considered an excellent marker for crypt-villus differentiation (15-18). Narisawa et al. (19) reported that compared with their wild-type (WT) littermates, mice lacking IAP gained more weight under conditions of a high-fat diet. In addition, several studies have shown that the IAP enzyme is capable of detoxifying LPS, likely through dephosphorylation of the lipid A moiety, the primary source of its endotoxic effects (20). Despite these few reports, the physiological role of IAP within the gut has not been elucidated. Results and DiscussionTo examine the functional role of IAP, we developed in vitro model systems using intestinal cell lines (T84, HT-29, and IEC-6) that express little or no IAP under basal conditions. Stable cell lines were created that overexpress IAP (Fig. 1A), and enzyme assays were used to determine the cellular localization of the ectopically expressed IAP protein. The results in Fig. 1B show that parent cells make little, if any, endogenous IAP. In contrast, large amounts of IAP enzyme are seen in the stably transfected cells. Importantly, the vast majority of the IAP activity is in the membrane fraction as opposed to the cytosol. Fig. 1C shows the results of the control experiment used to validate our separation of membranous and cytosolic fractions, confirming that the majority of the MAPK enzyme activity exists within the cytosol rather than the membrane. This membrane ...

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Section: Resultsmentioning

confidence: 99%

Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition

Goldberg

Austen

Zhang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

316

323

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“…The mechanisms by which the lungs are affected after splanchnic damage are primarily attributed to deleterious influences of activated leukocytes on the pulmonary microcirculation (31,33,36). There are two principal mechanisms by which leukocytes may be trapped in the microcirculation of the lungs, either as preactivated cells that are trapped in the capillary network of remote organs or as nonactivated cells that adhere to activated endothelial cells in the microcirculation.…”

Section: Discussionmentioning

confidence: 99%

Effects of hyperoxia on local and remote microcirculatory inflammatory response after splanchnic ischemia and reperfusion

Waisman¹,

Brod²,

Wolff³

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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. Effects of hyperoxia on local and remote microcirculatory inflammatory response after splanchnic ischemia and reperfusion. Am J Physiol Heart Circ Physiol 285: H643-H652, 2003. First published April 24, 2003 10.1152/ajpheart.00900.2002-Splanchnic ischemia-reperfusion (I/R) causes tissue hypoxia that triggers local and systemic microcirculatory inflammatory responses. We evaluated the effects of hyperoxia in I/R induced by 40-min superior mesenteric artery (SMA) occlusion and 120-min reperfusion in four groups of rats: 1) control (anesthesia only), 2) sham operated (all surgical procedures without vascular occlusion; air ventilation), 3) SMA I/R and air, 4) SMA I/R and 100% oxygen ventilation started 10 min before reperfusion. Leukocyte rolling and adhesion in mesenteric microvessels, pulmonary microvascular blood flow velocity (BFV), and macromolecular (FITC-albumin) flux into lungs were monitored by intravital videomicroscopy. We also determined pulmonary leukocyte infiltration. SMA I/R caused marked decreases in mean arterial blood pressure (MABP) and blood flow to the splanchnic and hindquarters vascular beds and pulmonary BFV and shear rates, followed by extensive increase in leukocyte rolling and adhesion and plugging of Ͼ50% of the mesenteric microvasculature. SMA I/R also caused marked increase in pulmonary sequestration of leukocytes and macromolecular leak with concomitant decrease in circulating leukocytes. Inhalation of 100% oxygen maintained MABP at significantly higher values (P Ͻ 0.001) but did not change regional blood flows. Oxygen therapy attenuated the increase in mesenteric leukocyte rolling and adherence (P Ͻ 0.0001) and maintained microvascular patency at values not significantly different from sham-operated animals. Hyperoxia also attenuated the decrease in pulmonary capillary BFV and shear rates, reduced leukocyte infiltration in the lungs (P Ͻ 0.001), and prevented the increase in pulmonary macromolecular leak (P Ͻ 0.001), maintaining it at values not different from sham-operated animals. The data suggest that beneficial effects of normobaric hyperoxia in splanchnic I/R are mediated by attenuation of both local and remote inflammatory microvascular responses. reperfusion injury; acute lung injury; reoxygenation injury; intravital videomicroscopy; multiorgan failure; systemic inflammatory response syndrome HYPOPERFUSION AND ISCHEMIA of the bowel is a common, important pathological process that affects adults and infants. In both groups the morbidity and mortality related to these processes are high. In adults, occlusive and nonocclusive conditions may reduce splanchnic blood flow (8,35

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“…8,9 Enteric bacteria have a crucial role in the pathogenesis of I/R-induced local inflammation and remote organ dysfunction. 10,11 It is known that increased intestinal permeability may result from disruption of tight junctions in the epithelial cells because of energy depletion and cell death. [12][13][14] Clear evidence of cell apoptosis can be seen in I/R-challenged intestinal mucosa.…”

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confidence: 99%

Anti-apoptotic PI3K/Akt signaling by sodium/glucose transporter 1 reduces epithelial barrier damage and bacterial translocation in intestinal ischemia

Huang

Hsiao

et al. 2011

Laboratory Investigation

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Intestinal ischemia/reperfusion (I/R) causes mucosal barrier damage and bacterial translocation (BT), leading to septic complications. Previous in vitro studies showed that activation of sodium/glucose transporter 1 (SGLT1) prevented the epithelial apoptosis and permeability rise induced by microbial products. Our aim was to investigate whether luminal glucose uptake by SGLT1 protects against ischemia-induced epithelial cell death and barrier dysfunction, and to explore the glucose-mediated cellular survival pathways in vivo. Rat jejunum was luminally instilled with either vehicle, a pancaspase inhibitor ZVAD, or glucose prior to I/R challenge (occlusion of the superior mesenteric artery for 20 min and reperfusion for 60 min). Histopathology and apoptosis in the jejunum were examined by TUNEL staining and caspase-3 cleavage. Intestinal permeability was evaluated using in vivo assays measuring luminal-to-blood passage of fluoresceindextran and portal drainage of enterally administered gadodiamide by magnetic resonance imaging. BT was determined by culturing liver and spleen homogenates. Immunofluorescent analysis and kinase assay were used to study PI3K/Akt signaling pathways. Intestinal I/R caused enterocyte apoptosis and villous destruction. Intestinal infusion with ZVAD decreased the I/R-triggered gut permeability rise and BT, suggesting that the barrier damage was partly dependent on cell apoptosis. Enteral instillation of glucose attenuated the epithelial apoptosis, barrier damage, and mucosal inflammation caused by I/R. Phloridzin (a SGLT1 inhibitor) reduced the protective effect of glucose in a dose-dependent manner. Enteral glucose increased the mucosal Akt kinase activity as evidenced by the augmented phosphorylation of exogenous GSK3. Enhanced membrane translocation and phosphorylation of Akt in epithelial cells were associated with elevated phosphorylation of mTOR, Bad, and FoxO1/3a following glucose uptake. Inhibition of PI3K/Akt signaling by LY294002 and wortmannin partially blocked the glucose-mediated rescue of cell apoptosis and barrier damage. In conclusion, SGLT1 glucose uptake alleviated I/R-induced barrier dysfunction and BT, partly by inhibiting epithelial apoptosis via activation of PI3K/Akt signaling.

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Gut Decontamination Reduces Bowel Ischemia-Induced Lung Injury in Rats*

Cited by 62 publications

References 22 publications

Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition

Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition

Effects of hyperoxia on local and remote microcirculatory inflammatory response after splanchnic ischemia and reperfusion

Anti-apoptotic PI3K/Akt signaling by sodium/glucose transporter 1 reduces epithelial barrier damage and bacterial translocation in intestinal ischemia

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