Removal of luminal content protects the small intestine during hemorrhagic shock but is not sufficient to prevent lung injury.

The small intestine plays a key role in the pathogenesis of multiple organ failure following circulatory shock. Current results show that reduced perfusion of the small intestine compromises the mucosal epithelial barrier, and the intestinal contents (including pancreatic digestive enzymes and partially digested food) can enter the intestinal wall and transport through the circulation or mesenteric lymph to other organs such as the lung. The extent to which the luminal contents of the small intestine mediate tissue damage in the intestine and lung is poorly understood in shock. Therefore, rats were assigned to three groups: No-hemorrhagic shock (HS) control and HS with or without a flushed intestine. HS was induced by reducing the mean arterial pressure (30 mmHg; 90 min) followed by return of shed blood and observation (3 h). The small intestine and lung were analyzed for hemorrhage, neutrophil accumulation, and cellular membrane protein degradation. After HS, animals with luminal contents had increased neutrophil accumulation, bleeding, and destruction of E-cadherin in the intestine. Serine protease activity was elevated in mesenteric lymph fluid collected from a separate group of animals subjected to intestinal ischemia/reperfusion. Serine protease activity was elevated in the plasma after HS but was detected in lungs only in animals with nonflushed lumens. Despite removal of the luminal contents, lung injury occurred in both groups as determined by elevated neutrophil accumulation, permeability, and lung protein destruction. In conclusion, luminal contents significantly increase intestinal damage during experimental HS, suggesting transport of luminal contents across the intestinal wall should be minimized

Theory of Interaction Effects in N-S Junctions out of Equilibrium

We consider a normal metal - superconductor (N-S) junction in the regime, when electrons in the normal metal are driven out of equilibrium. We show that the non-equilibrium fluctuations of the electron density in the N-layer cause the fluctuations of the phase of the order parameter in the S-layer. As a result, the density of states in the superconductor deviates from the BCS form, most notably the density of states in the gap becomes finite. This effect can be viewed as a result of the time reversal symmetry breaking due to the non-equilibrium, and can be described in terms of a low energy collective mode of the junction, which couples normal currents in N-layer and supercurrents. This mode is analogous to the Schmid-Sch\"{o}n mode. To interpret their measurements of the tunneling current, Pothier {\em et. al} [Phys. Rev. Lett. {\bf 79}, 3490 (1997)] had to assume that the energy relaxation rate in the normal metal is surprisingly high. The broadening of the BCS singularity of the density of states in the S-layer manifest itself similarly to the broadening of the distribution function. Mechanism suggested here can be a possible explanation of this experimental puzzle. We also propose an independent experiment to test our explanation.Comment: 16 pages, 2 .eps figure

Modelling the fluid drainage through primary lymphatic valves

This study investigates the fluid flow through tissues where lymphatic drainage occurs. Lymphatic drainage relies on two unidirectional valve systems, primary and secondary. The primary system is located in the initial lymphatics with, it is presumed, overlapping endothelial cells around the circumferential lining of lymphatic capillaries which act as unidirectional valves. The secondary lymphatic system is located in the lumen of the collecting lymphatics and is well studied in contrast to the primary system. We propose two models for the drainage of fluid by the lymphatic system that includes the primary valve system. The analysis identifies four key areas that affect lymphatic drainage. These are: the regular tissue deformations, the mechanics of the primary lymphatic valves, the fluid flow through the interstitium and that through the walls of blood capillaries. The models outline a new way of modelling the primary valve system that appears to be more relevant to experimental studies than previous models. The first model presented in this thesis describes a permeable membrane around a blood capillary, an elastic primary lymphatic valve and the interstitium lying between the two. Here we pay special attention to the mechanics of the primary valve system, by assuming that lymphatic endothelial cells (primary valve system) deflect into the lumen (allowing fluid drainage) in response to pressure differences between the interstitium and the lumen. The model predicts a piecewise linear relation between the drainage flux and the pressure difference between the blood and lymphatic capillaries. The second model presented in this thesis includes the regular tissue deformations in modelling lymphatic drainage. We propose a 'sliding door' theory of how lymphatic drainage occurs, which we base upon the premise that when the interstitium expands (due to excess fluid)the surrounding matrix pulls open the lymphatic valves creating a gap for the interstitial flid to drain into the lumen. The model predicts that after a certain number of valve cycles (close to open to close)the system relaxes to a steady state, in which the lymphatic valve stays open

Varicose Veins: Role of Mechanotransduction of Venous Hypertension

Varicose veins affect approximately one-third of the adult population and result in significant psychological, physical, and financial burden. Nevertheless, the molecular pathogenesis of varicose vein formation remains unidentified. Venous hypertension exerted on veins of the lower extremity is considered the principal factor in varicose vein formation. The role of mechanotransduction of the high venous pressure in the pathogenesis of varicose vein formation has not been adequately investigated despite a good progress in understanding the mechanomolecular mechanisms involved in transduction of high blood pressure in the arterial wall. Understanding the nature of the mechanical forces, the mechanosensors and mechanotransducers in the vein wall, and the downstream signaling pathways will provide new molecular targets for the prevention and treatment of varicose veins. This paper summarized the current understanding of mechano-molecular pathways involved in transduction of hemodynamic forces induced by blood pressure and tries to relate this information to setting of venous hypertension in varicose veins

Functionally specialized junctions between endothelial cells of lymphatic vessels

Recirculation of fluid and cells through lymphatic vessels plays a key role in normal tissue homeostasis, inflammatory diseases, and cancer. Despite recent advances in understanding lymphatic function (Alitalo, K., T. Tammela, and T.V. Petrova. 2005. Nature. 438:946–953), the cellular features responsible for entry of fluid and cells into lymphatics are incompletely understood. We report the presence of novel junctions between endothelial cells of initial lymphatics at likely sites of fluid entry. Overlapping flaps at borders of oak leaf–shaped endothelial cells of initial lymphatics lacked junctions at the tip but were anchored on the sides by discontinuous button-like junctions (buttons) that differed from conventional, continuous, zipper-like junctions (zippers) in collecting lymphatics and blood vessels. However, both buttons and zippers were composed of vascular endothelial cadherin (VE-cadherin) and tight junction–associated proteins, including occludin, claudin-5, zonula occludens–1, junctional adhesion molecule–A, and endothelial cell–selective adhesion molecule. In C57BL/6 mice, VE-cadherin was required for maintenance of junctional integrity, but platelet/endothelial cell adhesion molecule–1 was not. Growing tips of lymphatic sprouts had zippers, not buttons, suggesting that buttons are specialized junctions rather than immature ones. Our findings suggest that fluid enters throughout initial lymphatics via openings between buttons, which open and close without disrupting junctional integrity, but most leukocytes enter the proximal half of initial lymphatics

Leukocyte margination at arteriole shear rate

We numerically investigated margination of leukocytes at arteriole shear rate in straight circular channels with diameters ranging from 10 to 22 lm. Our results demonstrated that passing motion of RBCs effectively induces leukocyte margination not only in small channels but also in large channels. A longer time is needed for margination to occur in a larger channel, but once a leukocyte has marginated, passing motion of RBCs occurs continuously independent of the channel diameter, and leukocyte margination is sustained for a long duration. We also show that leukocytes rarely approach the wall surface to within a microvillus length at arteriole shear rate.Takeishi, N., Imai, Y., Nakaaki, K., Yamaguchi, T., Ishikawa, T., Leukocyte margination at arteriole shear rate, Physiol Rep, 2 ( 6), 2014, e12037, doi: 10.14814/phy2.1203