BACKGROUND Intestinal alkaline phosphatase (IAP) plays a pivotal role in maintaining gut health and well-being. Oral supplementation with IAP in mice improves gut barrier function and prevents luminal proinflammatory factors from gaining access to the circulation. In this study, we sought to explore the relationship between IAP and tight junction protein (TJP) expression and function. STUDY DESIGN The effect of IAP deletion on TJP levels was studied in mouse embryonic fibroblasts (MEFs) generated from IAP-knockout and wild type mice. Regulation of TJPs by IAP was assayed in the human colon cancer Caco-2 and T84 cells by overexpressing the human IAP gene. Tight junction protein levels and localization were measured by using RT q-PCR and antibodies targeting the specific TJPs. Finally, the effect of IAP on inflammation-induced intestinal permeability was measured by in vitro trans-well epithelial electrical resistance (TEER). RESULTS Intestinal alkaline phosphatase gene deletion in MEFs resulted in significantly lower levels of ZO-1, ZO-2, and Occludin compared with levels in wild-type control cells; IAP over-expression in Caco-2 and T84 cells resulted in approximate 2-fold increases in the mRNA levels of ZO-1 and ZO-2. The IAP treatment ameliorated lipopolysaccharide-induced increased permeability in the Caco-2 trans-well system. Furthermore, IAP treatment preserved the localization of the ZO-1 and Occludin proteins during inflammation and was also associated with improved epithelial barrier function. CONCLUSIONS Intestinal alkaline phosphatase is a major regulator of gut mucosal permeability and appears to work at least partly through improving TJP levels and localization. These data provide a strong foundation to develop IAP as a novel therapy to maintain gut barrier function.

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Backgrounds & Aims Bacterially-derived factors from the gut play a major role in the activation of inflammatory pathways in the liver and in the pathogenesis of alcoholic liver disease. The intestinal brush-border enzyme intestinal alkaline phosphatase (IAP) detoxifies a variety of bacterial pro-inflammatory factors and also functions to preserve gut barrier function. The aim of this study was to investigate whether oral IAP supplementation could protect against alcohol-induced liver disease. Methods Mice underwent acute binge or chronic ethanol exposure to induce alcoholic liver injury and steatosis +/− IAP supplementation. Liver tissue was assessed for biochemical, inflammatory and histopathological changes. An ex vivo co-culture system was used to examine the effects of alcohol and IAP treatment in regard to the activation of hepatic stellate cells and their role in the development of alcoholic liver disease. Results Pretreatment with IAP resulted in significantly lower serum alanine aminotransferase (ALT) compared to the ethanol alone group in the acute binge model. IAP treatment attenuated the development of alcohol-induced fatty liver, lowered hepatic pro-inflammatory cytokine and serum LPS levels, and prevented alcohol-induced gut barrier dysfunction. Finally, IAP ameliorated the activation of hepatic stellate cells and prevented their lipogenic effect on hepatocytes. Conclusions IAP treatment protected mice from alcohol-induced hepatotoxicity and steatosis. Oral IAP supplementation could represent a novel therapy to prevent alcoholic-related liver disease in humans.

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Landslide early warning systems (EWS) are an important tool to reduce landslide risks, especially where the potential for structural protection measures is limited. However, design, implementation, and successful operation of a landslide EWS is complex and has not been achieved in many cases. Critical problems are uncertainties related to landslide triggering conditions, successful implementation of emergency protocols, and the response of the local population. We describe here the recent implementation of a landslide EWS for the Combeima valley in Colombia, a region particularly affected by landslide hazards. As in many other cases, an insufficient basis of data (rainfall, soil measurements, landslide event record) and related uncertainties represent a difficult complication. To be able to better assess the influence of the different EWS components, we developed a numerical model that simulates the EWS in a simplified yet integrated way. The results show that the expected landslide-induced losses depend nearly exponentially on the errors in precipitation measurements. Stochastic optimization furthermore suggests an increasing adjustment of the rainfall landslide-triggering threshold for an increasing observation error. These modeling studies are a first step toward a more generic and integrated approach that bears important potential for substantial improvements in design and operation of a landslide EWS.

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