Breakdown of Mucin as Barrier to Digestive Enzymes in the Ischemic Rat Small Intestine

Loss of integrity of the epithelial/mucosal barrier in the small intestine has been associated with different pathologies that originate and/or develop in the gastrointestinal tract. We showed recently that mucin, the main protein in the mucus layer, is disrupted during early periods of intestinal ischemia. This event is accompanied by entry of pancreatic digestive enzymes into the intestinal wall. We hypothesize that the mucin-containing mucus layer is the main barrier preventing digestive enzymes from contacting the epithelium. Mucin breakdown may render the epithelium accessible to pancreatic enzymes, causing its disruption and increased permeability. The objective of this study was to investigate the role of mucin as a protection for epithelial integrity and function. A rat model of 30 min splanchnic arterial occlusion (SAO) was used to study the degradation of two mucin isoforms (mucin 2 and 13) and two epithelial membrane proteins (E-cadherin and toll-like receptor 4, TLR4). In addition, the role of digestive enzymes in mucin breakdown was assessed in this model by luminal inhibition with acarbose, tranexamic acid, or nafamostat mesilate. Furthermore, the protective effect of the mucin layer against trypsin-mediated disruption of the intestinal epithelium was studied in vitro. Rats after SAO showed degradation of mucin 2 and fragmentation of mucin 13, which was not prevented by protease inhibition. Mucin breakdown was accompanied by increased intestinal permeability to FITC-dextran as well as degradation of E-cadherin and TLR4. Addition of mucin to intestinal epithelial cells in vitro protected against trypsin-mediated degradation of E-cadherin and TLR4 and reduced permeability of FITC-dextran across the monolayer. These results indicate that mucin plays an important role in the preservation of the mucosal barrier and that ischemia but not digestive enzymes disturbs mucin integrity, while digestive enzymes actively mediate epithelial cell disruption

New Historical Jurisprudence: Legal History as Critical Analysis of Law

This modest manifesto--or minifesto--portrays legal history as a mode of critical analysis of law, using the historical analysis of American penality as an illustration and the fullfledged manifestos by Piketty and Guldi & Armitage as points of reference. Historical analysis of law, in this light, appears as one mode of critical analysis among others, including, notably, comparative analysis of law, along with economic, philosophical, sociological, or ethical analysis of law, and so on. Historical analysis of law, in other words, is itself a mode of legal scholarship, not a subspecies of law or history. It is a comprehensive view of law from a particular critical vantage point: a way of doing law, rather than of doing things with law. Historical analysis of law in this sense is less “law and history” than “law as history,” less legal history than historical jurisprudence

The American Model Penal Code: A Brief Overview

If there can be said to be an American criminal code, the Model Penal Code is it. Nonetheless, there remains an enormous diversity among the fifty-two American penal codes, including some that have never adopted a modern code format or structure. Yet, even within the minority of states without a modern code, the Model Penal Code has great influence, as courts regularly rely upon it to fashion the law that the state\u27s criminal code fails to provide. In this essay we provide a brief introduction to this historic document, its history and its content. Available for download at http://ssrn.com/abstract=66116