PMN transendothelial migration decreases nuclear NFκB in IL-1β–activated endothelial cells: role of PECAM-1

During the systemic inflammatory response, circulating cytokines interact with the vascular endothelium, resulting in activation and nuclear accumulation of the nuclear transcription factor, nuclear factor kappa B (NFκB). In turn, NFκB transactivates relevant proinflammatory genes, resulting in an amplification of the inflammatory response. Because this scenario is potentially detrimental to the host, mechanisms exist to limit this amplification. Using an in vitro system that mimics the vascular–interstitial interface during inflammation (cell culture inserts), we provide evidence for the existence of a novel negative feedback mechanism on NFκB activity. We show that the interleukin 1β–induced accumulation of nuclear NFκB in human umbilical vein endothelial cell monolayers is dramatically reduced when polymorphonuclear leukocytes (PMN) are allowed to migrate across these monolayers. This effect does not appear to be due to PMN-derived elastase or nitric oxide. Fixed PMN (adhere but do not migrate) did not affect nuclear NFκB. Furthermore, cross-linking of platelet-endothelial cell adhesion molecule-1 (PECAM-1), but not intercellular adhesion molecule-1, reduces human umbilical vein endothelial cell nuclear NFκB induced by interleukin 1β. Finally, interaction of PMN with PECAM-1–deficient endothelial cells does not reduce nuclear NFκB. These observations indicate that engagement of PECAM-1 by emigrating PMN is a pivotal event in this negative feedback on NFκB activity

Cardiac Fibroblasts Contribute to Myocardial Dysfunction in Mice with Sepsis: The Role of NLRP3 Inflammasome Activation

Myocardial contractile dysfunction in sepsis is associated with the increased morbidity and mortality. Although the underlying mechanisms of the cardiac depression have not been fully elucidated, an exaggerated inflammatory response is believed to be responsible. Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome is an intracellular platform that is involved in the maturation and release of interleukin (IL)-1 beta. The aim of the present study is to evaluate whether sepsis activates NLRP3 inflammasome/caspase-1/IL-1 beta pathway in cardiac fibroblasts (CFs) and whether this cytokine can subsequently impact the function of cardiomyocytes (cardiac fibroblast-myocyte crosstalk). We show that treatment of CFs with lipopolysaccharide (LPS) induces upregulation of NLRP3, activation of caspase-1, as well as the maturation (activation) and release of IL-1 beta. In addition, the genetic (small interfering ribonucleic acid [siRNA]) and pharmacological (glyburide) inhibition of the NLRP3 inflammasome in CFs can block this signaling pathway. Furthermore, the inhibition of the NLRP3 inflammasome in cardiac fibroblasts ameliorated the ability of LPS-chalenged CFs to impact cardiomyocyte function as assessed by intracellular cyclic adenosine monophosphate (cAMP) responses in cardiomyocytes. Salient features of this the NLP3 inflammasome/ caspase-1 pathway were confirmed in in vivo models of endotoxemia/sepsis. We found that inhibition of the NLRP3 inflammasome attenuated myocardial dysfunction in mice with LPS and increased the survival rate in mice with feces-induced peritonitis. Our results indicate that the activation of the NLRP3 inflammasome in cardiac fibroblasts is pivotal in the induction of myocardial dysfunction in sepsis

Interstitial Glucose and Physical Exercise in Type 1 Diabetes: Integrative Physiology, Technology, and the Gap In-Between

Continuous and flash glucose monitoring systems measure interstitial fluid glucose concentrations within a body compartment that is dramatically altered by posture and is responsive to the physiological and metabolic changes that enable exercise performance in individuals with type 1 diabetes. Body fluid redistribution within the interstitial compartment, alterations in interstitial fluid volume, changes in rate and direction of fluid flow between the vasculature, interstitium and lymphatics, as well as alterations in the rate of glucose production and uptake by exercising tissues, make for caution when interpreting device read-outs in a rapidly changing internal environment during acute exercise. We present an understanding of the physiological and metabolic changes taking place with acute exercise and detail the blood and interstitial glucose responses with different forms of exercise, namely sustained endurance, high-intensity, and strength exercises in individuals with type 1 diabetes. Further, we detail novel technical information on currently available patient devices. As more health services and insurance companies advocate their use, understanding continuous and flash glucose monitoring for its strengths and limitations may offer more confidence for patients aiming to manage glycemia around exercise

Sound-induced artifact in cochlear blood flow measurements using the laser Doppler flowmeter

The laser Doppler flowmeter has been shown to give a response from the cochlea during high intensity acoustic stimulation which is not related to blood flow through the cochlea. The magnitude of this response depends upon the intensity and frequency of stimulation and the location of the probe on the cochlea. Evidence is presented that the response is derived from the vibration of cochlear tissue and/or the bony cochlear shell during acoustic stimulation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26467/1/0000001.pd

Investigation of the Mechanisms Underlying the Gastroprotective Effect of Cymbopogon Citratus Essential Oil

Cymbopogon citratus is a medicinal plant popularly used in Brazil for the treatment of various diseases, and the research interest in this plant is justifiable because of its potential medicinal value in stomachache and gastric ulcer. This study was aimed to test the validity of this practice by using experimental models of gastric ulcer and to clarify the mechanisms of gastroprotection by C. citratus leaves essential oil (EOCC). EOCC was evaluated for the ability to protect the gastric mucosa against injuries caused by necrotizing agents (absolute ethanol and aspirin) in rodents. The results of this study revealed that EOCC posses a dose-independent anti-ulcer effect against the different experimental models. EOCC pretreatment depicted a higher preventive index in ethanol-(88%) and aspirin-induced (76%) acute ulceration. On pretreatment of mice with indomethacin, the cyclooxygenase inhibitor slightly suppressed the gastroprotective effect of EOCC (48.5%). Furthermore, EOCC gastroprotection was not attenuated in mice pretreated with L-NAME (85.2%), glibenclamide (100%), or yohimbine (79.7%), the respective inhibitors of nitric oxide synthase, K+ATP channel activation, and α2 receptors. These results confirmed the traditional use of C. citratus for the treatment of gastric ulcer. Thus, we provide the first evidence that EOCC reduces gastric damage induced by ethanol, at least in part, by mechanisms that involve endogenous prostaglandins