Tumor necrosis factor-induced alterations in circulating leukocyte populations

Tumor necrosis factor is a potent agent possessing diverse biological functions. We investigated the effects of intravenous administration of human recombinant tumor necrosis factor (TNF) on immune cell populations in CBA/J mice. The animals developed a significant lymphopenia and neutrophilia both reaching a maximum at 4 hours post-injection with a trend towards resolution to normal values by 6 hours. The lymphopenia was both relative and absolute. Similarly, the neutrophilia was both relative and absolute and was due to the presence of both immature and mature neutrophils. As the neutrophilia and lymphopenia occurred concomitantly, there was no difference at any time point in the total number of peripheral blood white cells. Extensive controls were done to rule out LPS contamination in the TNF preparation. These data demonstrate the potent effects of intravenous administration of human recombinant tumor necrosis factor on peripheral blood constituents.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25943/1/0000005.pd

Tumor Necrosis Factor–Alpha Gene Expression in Human Whole Blood

Tumor necrosis factor‐alpha (TNF) is recognized as a principal mediator of a variety of pathophysiologic and immunologic events. Lipopolysaccharide (LPS) challenge, either in vitro or in vivo, results in significant TNF production. In this study we present data demonstrating LPS‐induced TNF mRNA expression and bioactivity using an in vitro tissue system of whole blood (WB). The kinetics of LPS‐induced TNF production by WB was significantly accelerated as compared to isolated cultured peripheral blood monocytes (PBM). At post‐LPS challenge, plasma from WB demonstrated a rapid rise in TNF bioactivity, peaking by 4 hr (1,021 units/ml/106 cells), plateauing between 4 and 8 hr, and then decreasing over the next 16 hr. In contrast, the highest measured TNF bioactivity from PBM did not occur until the 24‐hr time‐point (175 units/ml/106 cells). Whole blood buffy‐coat TNF mRNA was assessed by Northern blot analysis, and demonstrated significant TNF mRNA accumulation at 1 hr and a peak 2 hr post‐LPS challenge. By 8 hr TNF mRNA was undetectable. Concomitant administration of LPS with either prostaglandin E2 (10‐6M) or Dexamethasone (10‐6M) resulted in significant suppression of LPS‐induced TNF production. This data supports WB as a useful in vitro medium for the molecular and cellular analyis of TNF. As specialized connective tissue, WB may provide an important environment to study the pharmacologic manipulation of TNF mRNA and bioactivity.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141678/1/jlb0366.pd

A Multi-Parameter Dynamical Diagnostics for Upper Tropospheric and Lower Stratospheric Studies

Ozone trend estimates have shown large uncertainties in the upper troposphere/lower stratosphere (UTLS) region despite multi-decadal observations available from ground-based, balloon, aircraft, and satellite platforms. These uncertainties arise from large natural variability driven by dynamics (reflected in tropopause and jet variations) as well as the strength in constituent transport and mixing. Additionally, despite all the community efforts there is still a lack of representative high-quality global UTLS measurements to capture this variability. The Stratosphere-troposphere Processes And their Role in Climate (SPARC) Observed Composition Trends and Variability in the UTLS (OCTAV-UTLS) activity aims to reduce uncertainties in UTLS composition trend estimates by accounting for this dynamically induced variability. In this paper, we describe the production of dynamical diagnostics using meteorological information from reanalysis fields that facilitate mapping observations from several platforms into numerous geophysically-based coordinates (including tropopause and upper tropospheric jet relative coordinates). Suitable coordinates should increase the homogeneity of the air masses analyzed together, thus reducing the uncertainty caused by spatio-temporal sampling biases in the quantification of UTLS composition trends. This approach thus provides a framework for comparing measurements with diverse sampling patterns and leverages the meteorological context to derive maximum information on UTLS composition and trends and its relationships to dynamical variability. The dynamical diagnostics presented here are the first comprehensive set describing the meteorological context for multi-decadal observations by ozonesondes, lidar, aircraft, and satellite measurements in order to study the impact of dynamical processes on observed UTLS trends by different sensors on different platforms. Examples using these diagnostics to map multi-platform datasets into different geophysically-based coordinate systems are provided. The diagnostics presented can also be applied to analysis of greenhouse gases other than ozone that are relevant to surface climate and UTLS chemistry.</p

The role of TNF in diverse pathologic processes

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42481/1/10537_2005_Article_BF02172086.pd

Anti-tumor necrosis factor antibody augments edema formation in caerulein-induced acute pancreatitis,

The pathogenesis of acute pancreatitis is incompletely defined, but the outcome is determined in part by an acute inflammatory process. Pancreatitis-associated inflammation appears to play a role in the local retroperitoneal injury as well as in the associated dysfunction of remote organs such as the lung. Tumor necrosis factor (TNF) appears to be a proximal mediator of the inflammatory response. In this study, anti-TNF antibody was administered to rats with caerulein-induced pancreatitis to determine if the observed increases in pancreatic and pulmonary microvascular permeability were related to plasma TNF activity. In contrast to the expected findings, blockade of TNF activity was found to increase the amount of edema formation in both the pulmonary and pancreatic microvascular beds. The mechanism is not known; however, blockade of TNF-induced down regulation of phagocytic cell activity, ablation of TNF-dependent feedback inhibition of other cytokines, failure of induction of endogenous antioxidant systems, or inactivation of the TNF control of microvascular tone are all possible explanations. This is potentially an important observation as clinical strategies are now being developed to modify the inflammatory response in ways presumed advantageous to an injured host.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29016/1/0000045.pd

Modeling Cell Gradient Sensing and Migration in Competing Chemoattractant Fields

Directed cell migration mediates physiological and pathological processes. In particular, immune cell trafficking in tissues is crucial for inducing immune responses and is coordinated by multiple environmental cues such as chemoattractant gradients. Although the chemotaxis mechanism has been extensively studied, how cells integrate multiple chemotactic signals for effective trafficking and positioning in tissues is not clearly defined. Results from previous neutrophil chemotaxis experiments and modeling studies suggested that ligand-induced homologous receptor desensitization may provide an important mechanism for cell migration in competing chemoattractant gradients. However, the previous mathematical model is oversimplified to cell gradient sensing in one-dimensional (1-D) environment. To better understand the receptor desensitization mechanism for chemotactic navigation, we further developed the model to test the role of homologous receptor desensitization in regulating both cell gradient sensing and migration in different configurations of chemoattractant fields in two-dimension (2-D). Our results show that cells expressing normal desensitizable receptors preferentially orient and migrate toward the distant gradient in the presence of a second local competing gradient, which are consistent with the experimentally observed preferential migration of cells toward the distant attractant source and confirm the requirement of receptor desensitization for such migratory behaviors. Furthermore, our results are in qualitative agreement with the experimentally observed cell migration patterns in different configurations of competing chemoattractant fields

Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxofylline

Tumor necrosis factor-alpha (TNF), a mononuclear phagocyte (MO)-derived peptide, is increasingly being recognized for its pleomorphic immunologic effects. A number of investigations have demonstrated that lipopolysaccharide (LPS) can induce TNF synthesis, yet mechanisms that regulate TNF expression at the cellular and molecular levels have not been fully elucidated. In this study, we present data demonstrating pentoxifylline, a methylxanthine, is efficacious in suppressing LPS-induced MO-derived TNF at the level of both TNF mRNA accumulation and TNF supernatant bioactivity. Pentoxifylline, at a dose of 1 x 10-5M, suppressed the production of both biologically active TNF and TNF mRNA expression by more than 50%. Furthermore, additional methylxanthines and dibutyryl cAMP have similar effects on TNF expression. These data support the mechanism for this suppressive effect is via the generation of intracellular cAMP.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27135/1/0000128.pd

Statistical Properties of Turbulence: An Overview

We present an introductory overview of several challenging problems in the statistical characterisation of turbulence. We provide examples from fluid turbulence in three and two dimensions, from the turbulent advection of passive scalars, turbulence in the one-dimensional Burgers equation, and fluid turbulence in the presence of polymer additives.Comment: 34 pages, 31 figure

Ursolic Acid Increases Skeletal Muscle and Brown Fat and Decreases Diet-Induced Obesity, Glucose Intolerance and Fatty Liver Disease

Skeletal muscle Akt activity stimulates muscle growth and imparts resistance to obesity, glucose intolerance and fatty liver disease. We recently found that ursolic acid increases skeletal muscle Akt activity and stimulates muscle growth in non-obese mice. Here, we tested the hypothesis that ursolic acid might increase skeletal muscle Akt activity in a mouse model of diet-induced obesity. We studied mice that consumed a high fat diet lacking or containing ursolic acid. In skeletal muscle, ursolic acid increased Akt activity, as well as downstream mRNAs that promote glucose utilization (hexokinase-II), blood vessel recruitment (Vegfa) and autocrine/paracrine IGF-I signaling (Igf1). As a result, ursolic acid increased skeletal muscle mass, fast and slow muscle fiber size, grip strength and exercise capacity. Interestingly, ursolic acid also increased brown fat, a tissue that shares developmental origins with skeletal muscle. Consistent with increased skeletal muscle and brown fat, ursolic acid increased energy expenditure, leading to reduced obesity, improved glucose tolerance and decreased hepatic steatosis. These data support a model in which ursolic acid reduces obesity, glucose intolerance and fatty liver disease by increasing skeletal muscle and brown fat, and suggest ursolic acid as a potential therapeutic approach for obesity and obesity-related illness