bluuebunny/crossref_metadata_2025 huggingface dataset:
BIOFLUIDMECHANICS OF REPRODUCTION
Authors: Fauci Lisa J. , Dillon Robert
Published: December 2005

Mammalian fertilization requires the coordinated activity of motile spermatozoa, muscular contractions of the uterus and oviduct, as well as ciliary beating. These elastic structures generate forces that drive fluid motion, but their configurations are, in turn, determined by the fluid dynamics. We review the basic fluid mechanical aspects of reproduction, including flagellar/ciliary beating and peristalsis. We report on recent biological studies that have shed light on the relative importance of the mechanical ingredients of reproduction. In particular, we examine sperm motility in the reproductive tract, ovum pickup and transport in the oviduct, as well as sperm-egg interactions. We review recent advances in understanding the internal mechanics of cilia and flagella, flagellar surface interaction, sperm motility in complex fluids, and the role of fluid dynamics in embryo transfer. We outline promising computational fluid dynamics frameworks that may be used to investigate these complex, fluid-structure interactions.
PREMELTING DYNAMICS
Authors: Wettlaufer J.S. , Worster M. Grae
Published: December 2005

When the free surfaces of most solids approach their bulk melting temperatures from below, the molecular structure of the material gives way to a disordered structure with some attributes of both the solid and liquid phases. When the temperature is sufficiently close to that of bulk transition, the surface melts and literally flows as a viscous fluid. This phenomenon, called interfacial premelting, lies at the heart of the microscopic theory of melting of solid matter, and captures the interest of condensed matter physicists and physical chemists alike. The process is ubiquitous and responsible for a wide range of consequences in materials with biological, geophysical, and technological significance. Because such systems are often exposed to spatial or temporal variations in thermodynamic forcing, there are a host of fluid mechanical phenomena that result from this underlying melting behavior. The fluid dynamics of unfrozen surfaces holds clues for understanding the bulk behavior of polycrystalline materials, from Earth's mantle to the stratosphere and beyond. In this review we focus on the fluid dynamical consequences of the premelting of solids.
AERODYNAMICS OF RACE CARS
Authors: Katz Joseph
Published: December 2005

Race car performance depends on elements such as the engine, tires, suspension, road, aerodynamics, and of course the driver. In recent years, however, vehicle aerodynamics gained increased attention, mainly due to the utilization of the negative lift (downforce) principle, yielding several important performance improvements. This review briefly explains the significance of the aerodynamic downforce and how it improves race car performance. After this short introduction various methods to generate downforce such as inverted wings, diffusers, and vortex generators are discussed. Due to the complex geometry of these vehicles, the aerodynamic interaction between the various body components is significant, resulting in vortex flows and lifting surface shapes unlike traditional airplane wings. Typical design tools such as wind tunnel testing, computational fluid dynamics, and track testing, and their relevance to race car development, are discussed as well. In spite of the tremendous progress of these design tools (due to better instrumentation, communication, and computational power), the fluid dynamic phenomenon is still highly nonlinear, and predicting the effect of a particular modification is not always trouble free. Several examples covering a wide range of vehicle shapes (e.g., from stock cars to open-wheel race cars) are presented to demonstrate this nonlinear nature of the flow field.
EXPERIMENTAL FLUID MECHANICS OF PULSATILE ARTIFICIAL BLOOD PUMPS
Authors: Deutsch Steven , Tarbell John M. , Manning Keefe B. , Rosenberg Gerson , Fontaine Arnold A.
Published: December 2005

The fluid mechanics of artificial blood pumps has been studied since the early 1970s in an attempt to understand and mitigate hemolysis and thrombus formation by the device. Pulsatile pumps are characterized by inlet jets that set up a rotational “washing” pattern during filling. Strong regurgitant jets through the closed artificial heart valves have Reynolds stresses on the order of 10,000 dynes/cm2 and are the most likely cause of red blood cell damage and platelet activation. Although the flow in the pump chamber appears benign, low wall shear stresses throughout the pump cycle can lead to thrombus formation at the wall of the smaller pumps (10–50 cc). The local fluid mechanics is critical. There is a need to rapidly measure or calculate the wall shear stress throughout the device so that the results may be easily incorporated into the design process.
NONLINEAR AND WAVE THEORY CONTRIBUTIONS OF T. BROOKE BENJAMIN (1929–1995)
Authors: Hunt J.C.R.
Published: December 2005

Brooke Benjamin's original theories of fluid mechanical phenomena changed our basic understanding of cavitation bubbles, surface and internal waves, gravity currents, instabilities of shear flow over flexible surfaces, and swirling flows. For some types of finite-amplitude wave phenomena, he generated integral constraints and derived new partial differential equations; by establishing their general properties he showed how they have wide application. He developed a complementary approach based on functional analysis that was quite new to fluid mechanics. He demonstrated methods for deriving, without detailed calculation, the essential features of nonlinear and indeterminate flow problems that are otherwise intractable.
MODELING SHAPES AND DYNAMICS OF CONFINED BUBBLES
Authors: Ajaev Vladimir S. , Homsy G.M.
Published: December 2005

We review mathematical models of confined bubbles, emphasizing physical mechanisms as expressed in simple geometries. Molecular interactions between liquid, gas, and the confining solid are all important and are described through the disjoining pressure concept. Methods for finding static shapes are considered. The static solution is a springboard for discussing pressure-driven and surface-tension-driven flows, both of which involve viscous effects and macroscopic films entrained near apparent contact lines. We next discuss vapor bubbles produced by thermal effects. Vaporization localized near contact lines and condensation distributed in colder parts of the interface lead to steady vapor bubbles. Their size is determined through global constraints. Unsteady vapor bubbles are discussed and we end with thoughts on open problems.
COMPUTATIONAL PREDICTION OF FLOW-GENERATED SOUND
Authors: Wang Meng , Freund Jonathan B. , Lele Sanjiva K.
Published: December 2005

This article provides a critical review of computational techniques for flow-noise prediction and the underlying theories. Hybrid approaches, in which the turbulent noise source field is computed and/or modeled separately from the far-field calculation, are afforded particular attention. Numerical methods and modern flow simulation techniques are discussed in terms of their suitability and accuracy for flow-noise calculations. Other topics highlighted include some important formulation and computational issues in the application of aeroacoustic theories, generalized acoustic analogies with better accounts of flow-sound interaction, and recent computational investigations of noise-control strategies. The review ends with an analysis of major challenges and key areas for improvement in order to advance the state of the art of computational aeroacoustics.
CRITICAL HYPERSONIC AEROTHERMODYNAMIC PHENOMENA
Authors: Bertin John J. , Cummings Russell M.
Published: December 2005

The challenges in understanding hypersonic flight are discussed and critical hypersonic aerothermodynamics issues are reviewed. The ability of current analytical methods, numerical methods, ground testing capabilities, and flight testing approaches to predict hypersonic flow are evaluated. The areas where aerothermodynamic shortcomings restrict our ability to design and analyze hypersonic vehicles are discussed, and prospects for future capabilities are reviewed. Considerable work still needs to be done before our understanding of hypersonic flow will allow for the accurate prediction of vehicle flight characteristics throughout the flight envelope from launch to orbital insertion.
ELECTROKINETIC FLOW AND DISPERSION IN CAPILLARY ELECTROPHORESIS
Authors: Ghosal Sandip
Published: December 2005

Electrophoretic separation of a mixture of chemical species is a fundamental technique of great usefulness in biology, health care, and forensics. In capillary electrophoresis (which has evolved from its predecessor, slab-gel electrophoresis), the sample migrates through a single microcapillary instead of through the network of pores in a gel. A fundamental design problem is to minimize dispersion in the separation direction. Molecular diffusion is inevitable and sets a theoretical limit on the best separation that can be achieved. But in practice, there are a number of effects arising out of the interplay between fluid flow, chemistry, thermal effects, and electric fields that result in enhanced dispersion. This paper reviews the subject of fluid flow in such capillary microchannels and examines the various causes of enhanced dispersion that limit the efficiency of separation.
DYNAMICS AND CONTROL OF HIGH-REYNOLDS-NUMBER FLOW OVER OPEN CAVITIES
Authors: Rowley Clarence W. , Williams David R.
Published: December 2005

We review recent advances in understanding, modeling, and controlling oscillations in the flow past a cavity. The fundamental mechanisms underlying cavity flow oscillations have been known for at least 40 years, but suppressing these oscillations in a reliable and robust way is still a challenge today. Interest in controlling the flow past a cavity is motivated by aerospace applications, but in addition, cavity flows provide an attractive canonical problem for exploring general flow control techniques. The focus is on recent advances in modeling these flows, and in controlling them, using both open-loop and closed-loop techniques. A relatively new perspective is that cavity oscillations may not always be self-sustained, but under some flow conditions may be lightly damped resonances, sustained by external disturbances such as boundary layer turbulence. Areas in which our understanding is incomplete, and which deserve further study, are discussed, in particular the effects of high-frequency open-loop forcing, fundamental limitations of feedback control for a given configuration of sensors and actuators, and the development of a feedback design methodology that respects the limited range of validity of the available dynamical models.
FLUID MECHANICS AND HOMELAND SECURITY
Authors: Settles Gary S.
Published: December 2005

Homeland security involves many applications of fluid mechanics and offers many opportunities for research and development. This review explores a wide selection of fluids topics in counterterrorism and suggests future directions. Broad topics range from preparedness and deterrence of impending terrorist attacks to detection, response, and recovery. Specific topics include aircraft hardening, blast mitigation, sensors and sampling, explosive detection, microfluidics and labs-on-a-chip, chemical plume dispersal in urban settings, and building ventilation. Also discussed are vapor plumes and standoff detection, nonlethal weapons, airborne disease spread, personal protective equipment, and decontamination. Involvement in these applications requires fluid dynamicists to think across the traditional boundaries of the field and to work with related disciplines, especially chemistry, biology, aerosol science, and atmospheric science.
LONG NONLINEAR INTERNAL WAVES
Authors: Helfrich Karl R. , Melville W. Kendall
Published: December 2005

Over the past four decades, the combination of in situ and remote sensing observations has demonstrated that long nonlinear internal solitary-like waves are ubiquitous features of coastal oceans. The following provides an overview of the properties of steady internal solitary waves and the transient processes of wave generation and evolution, primarily from the point of view of weakly nonlinear theory, of which the Korteweg-de Vries equation is the most frequently used example. However, the oceanographically important processes of wave instability and breaking, generally inaccessible with these models, are also discussed. Furthermore, observations often show strongly nonlinear waves whose properties can only be explained with fully nonlinear models.
LARGE-EDDY SIMULATION OF TURBULENT COMBUSTION
Authors: Pitsch Heinz
Published: December 2005

Large-eddy simulation (LES) of turbulent combustion is a relatively new research field. Much research has been carried out over the past years, but to realize the full predictive potential of combustion LES, many fundamental questions still have to be addressed, and common practices of LES of nonreacting flows revisited. The focus of the present review is to highlight the fundamental differences between Reynolds-averaged Navier-Stokes (RANS) and LES combustion models for nonpremixed and premixed turbulent combustion, to identify some of the open questions and modeling issues for LES, and to provide future perspectives.
DROP IMPACT DYNAMICS: Splashing, Spreading, Receding, Bouncing…
Authors: Yarin A.L.
Published: December 2005

The review deals with drop impacts on thin liquid layers and dry surfaces. The impacts resulting in crown formation are referred to as splashing. Crowns and their propagation are discussed in detail, as well as some additional kindred, albeit nonsplashing, phenomena like drop spreading and deposition, receding (recoil), jetting, fingering, and rebound. The review begins with an explanation of various practical motivations feeding the interest in the fascinating phenomena of drop impact, and the above-mentioned topics are then considered in their experimental, theoretical, and computational aspects.
WALKING ON WATER: Biolocomotion at the Interface
Authors: Bush John W.M. , Hu David L.
Published: December 2005

We consider the hydrodynamics of creatures capable of sustaining themselves on the water surface by means other than flotation. Particular attention is given to classifying water walkers according to their principal means of weight support and lateral propulsion. The various propulsion mechanisms are rationalized through consideration of energetics, hydrodynamic forces applied, or momentum transferred by the driving stroke. We review previous research in this area and suggest directions for future work. Special attention is given to introductory discussions of problems not previously treated in the fluid mechanics literature, with hopes of attracting physicists, applied mathematicians, and engineers to this relatively unexplored area of fluid mechanics.
PASSIVE AND ACTIVE FLOW CONTROL BY SWIMMING FISHES AND MAMMALS
Authors: Fish F.E. , Lauder G.V.
Published: December 2005

What mechanisms of flow control do animals use to enhance hydrodynamic performance? Animals are capable of manipulating flow around the body and appendages both passively and actively. Passive mechanisms rely on structural and morphological components of the body (i.e., humpback whale tubercles, riblets). Active flow control mechanisms use appendage or body musculature to directly generate wake flow structures or stiffen fins against external hydrodynamic loads. Fish can actively control fin curvature, displacement, and area. The vortex wake shed by the tail differs between eel-like fishes and fishes with a discrete narrowing of the body in front of the tail, and three-dimensional effects may play a major role in determining wake structure in most fishes.
SCALING: Wind Tunnel to Flight
Authors: Bushnell Dennis M.
Published: December 2005

Wind tunnels have wide-ranging functionality, including many applications beyond aeronautics, and historically have been the major source of information for technological aerodynamics/aeronautical applications. There are a myriad of scaling issues/differences from flight to wind tunnel, and their study and impacts are uneven and a function of the particular type of extant flow phenomena. Typically, the most serious discrepancies are associated with flow separation. The tremendous ongoing increases in numerical simulation capability are changing and in many aspects have changed the function of the wind tunnel from a (scaled) “predictor” to a source of computational calibration/validation information with the computation then utilized as the flight prediction/scaling tool. Numerical simulations can increasingly include the influences of the various scaling issues. This wind tunnel role change has been occurring for decades as computational capability improves in all aspects. Additional issues driving this trend are the increasing cost (and time) disparity between physical experiments and computations, and increasingly stringent accuracy requirements.
FLUID MECHANICAL ASPECTS OF THE GAS-LIFT TECHNIQUE
Authors: Guet S. , Ooms G.
Published: December 2005

The gas-lift technique comprises the injection of gas bubbles in vertical oil wells to increase production. It is based on a reduction of the tubing gravitational pressure gradient. Several fluid-flow phenomena influencing such vertical gas-liquid flows are discussed. These effects include the radial distribution of void fraction and of gas and liquid velocity, flow regime changes, and system stability problems. Associated consequences for gas-lift performance and related optimization approaches are also discussed.
Imaging pancreatic β-cells in the intact pancreas
Authors: Hara Manami , Dizon Restituto F. , Glick Benjamin S. , Lee Catherine S. , Kaestner Klaus H. , Piston David W. , Bindokas Vytautas P.
Published: December 2005

We have developed a method to visualize fluorescent protein-labeled β-cells in the intact pancreas through combined reflection and confocal imaging. This method provides a 3-D view of the β-cells in situ. Imaging of the pancreas from mouse insulin I promoter (MIP)-green (GFP) and red fluorescent protein (RFP) transgenic mice shows that islets, β-cell clusters, and single β-cells are not evenly distributed but are aligned along the large blood vessels. We also observe the solitary β-cells in both fetal and adult mice and along the pancreatic and common bile ducts. We have imaged the developing endocrine cells in the embryos using neurogenin-3 (Ngn3)-GFP mice crossed with MIP-RFP mice. The dual-color-coded pancreas from embryos (E15.5) shows a large number of green Ngn3-expressing proendocrine cells with a smaller number of red β-cells. The imaging technique that we have developed, coupled with the transgenic mice in which β-cells and β-cell progenitors are labeled with different fluorescent proteins, will be useful for studying pancreatic development and function in normal and disease states.
Flow regulates intercellular communication in HAEC by assembling functional Cx40 and Cx37 gap junctional channels
Authors: Ebong Eno Essien , Kim Sanghee , DePaola Natacha
Published: December 2005

Direct cell-to-cell transfer of ions and small signaling molecules via gap junctions plays a key role in vessel wall homeostasis. Vascular endothelial gap junctional channels are formed by the connexin (Cx) proteins Cx37, Cx40, and Cx43. The mechanisms regulating connexin expression and assembly into functional channels have not been fully identified. We investigated the dynamic regulation of endothelial gap junctional intercellular communication (GJIC) by fluid flow and the participation of each vascular connexin in functional human endothelial gap junctions in vitro. Human aortic endothelial cells (HAEC) were exposed for 5, 16, and 24 h to physiological flows in a parallel-plate flow chamber. Connexin protein expression and localization were evaluated by immunocytochemistry, and functional GJIC was evaluated by dye injection. Connexin-mimetic peptide inhibitors were used to assess the specific connexin composition of functional channels. HAEC monolayers in culture exhibited baseline functional communication at a striking low level despite abundant expression of Cx43 and Cx40 localized at cell-to-cell appositions. Upon exposure to flow, GJIC by dye spread demonstrated a significant time-dependent increase from baseline levels, reaching 7.5-fold in 24 h. Inhibition studies revealed that this response was mediated primarily by Cx40, with lesser contributions of the other two vascular connexins assembled into functional homotypic and/or heterotypic channels. This is the first study to demonstrate that flow simultaneously and differentially regulates expression of the Cx37, Cx40, and Cx43 proteins and their involvement in the augmentation of intercellular communication by dye transfer in human endothelial cells in vitro.
ATP stimulates MMP-2 release from human aortic smooth muscle cells via JNK signaling pathway
Authors: Robinson William P. , Douillet Christelle D. , Milano Peter M. , Boucher Richard C. , Patterson Cam , Rich Preston B.
Published: December 2005

Aortic smooth muscle cell release of matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) has been implicated in aortic aneurysm pathogenesis, but proximal modulation of release is poorly understood. Extracellular nucleotides regulate vascular smooth muscle cell metabolism in response to physiochemical stresses, but nucleotide modulation of MMP and/or TIMP release has not been reported. We hypothesized that nucleotides modulate MMP-2 and TIMP-2 release from human aortic smooth muscle cells (HASMCs) via distinct purinergic receptors and signaling pathways. We exposed HASMCs to exogenous ATP and other nucleotides with and without interleukin-1β (IL-1β). HASMCs were pretreated in some experiments with apyrase, which degrades ATP, and inhibitors of ERK1/2, JNK, and p38 MAPK. MMP-2 and TIMP-2 released into supernatant were assessed using ELISA and Western blotting. ATP, adenosine, and UTP significantly stimulated MMP-2 release in the presence of IL-1β (300 nM ATP: 181 ± 22%, P = 0.003; 30 μm adenosine: 244 ± 150%, P = 0.001; and 200 μm UTP: 153 ± 40%, P = 0.015; vs. 100% constitutive). ATP also stimulated MMP-2 release in the absence of IL-1β (100 μm ATP: 148 ± 38% vs. 100% constitutive). Apyrase significantly reduced ATP-stimulated MMP-2 release (apyrase + 500 nM ATP: 59 ± 3% vs. 124 ± 7% with 500 nM ATP). Rank-order agonist potency for MMP-2 release was consistent with ATP activation of PAY and PAY receptors. ATP induced phosphorylation of intracellular JNK, and inhibition of the JNK pathway blocked ATP-stimulated MMP-2 release, indicating signaling via this pathway. Nucleotides are thus novel stimulants of MMP-2 release from HASMCs and may provide a mechanistic link between physiochemical stress in the aorta and aneurysms, especially in the context of inflammation.
Involvement of Rho kinase pathway in the mechanism of renal vasoconstriction and cardiac hypertrophy in rats with experimental heart failure
Authors: Winaver Joseph , Ovcharenko Elena , Rubinstein Irit , Gurbanov Konstantin , Pollesello Piero , Bishara Bishara , Hoffman Aaron , Abassi Zaid
Published: December 2005

Rho-dependent kinases serve as downstream effectors of several vasoconstrictor systems, the activities of which are upregulated in congestive heart failure (CHF). We evaluated renal and cardiac effects of Y-27632, a highly selective Rho kinase inhibitor, in an experimental model of volume-overload CHF. Effects of acute administration of Y-27632 (0.3 mg/kg) on renal hemodynamic and clearance parameters and effects of chronic treatment (10.0 mg·kg−1·day−1for 7 days via osmotic minipumps) on cardiac hypertrophy and cumulative Na+excretion were studied in male Wistar rats with aortocaval fistula and control rats. The Y-27632-induced decrease in renal vascular resistance (from 40.4 ± 4.6 to 26.0 ± 3.1 resistance units, P < 0.01) in CHF rats was associated with a significant increase in total renal blood flow (+34%) and cortical and medullary blood flow (approx +37 and +27%, respectively). These values were significantly higher than those in control rats and occurred despite a decrease in mean arterial pressure (−15 mmHg). Despite the marked renal vasodilatory effect, Y-27632 did not alter glomerular filtration rate and renal Na+excretion. Chronic administration of Y-27632 did not alter daily or cumulative renal Na+excretion in CHF rats but was associated with a significant decrease in heart-to-body weight ratio, an index of cardiac hypertrophy: 0.32 ± 0.007, 0.46 ± 0.017, and 0.37 ± 0.006% in control, CHF, and CHF + Y-27632 rats, respectively. The findings suggest that Rho kinase-dependent pathways are involved in the mechanisms of renal vasoconstriction and cardiac hypertrophy in rats with volume-overload heart failure. Selective blockade of these signaling pathways may be considered an additional tool to improve renal perfusion and attenuate cardiac hypertrophy in heart failure.
Acute responses to phytoestrogens in small arteries from men with coronary heart disease
Authors: Cruz Maria Natalia , Luksha Leonid , Logman Henareh , Poston Lucilla , Agewall Stefan , Kublickiene Karolina
Published: December 2005

The aim of this study was to investigate acute vasodilator responses to phytoestrogens and selective estrogen receptor-α (ERα) agonist in isolated small arteries from men with established coronary heart disease (CHD) and with a history of myocardial infarction versus healthy male control subjects. As to methodology, small arteries obtained from subcutaneous fat biopsies and mounted on a wire myograph were preconstricted with norepinephrine, and dilator responses to increasing nanomolar-micromolar concentrations of the phytoestrogens resveratrol and genistein (predominantly ERβ agonists) and to propyl-[1H]-pyrazole-1,3,5-triyl-trisplenol (PPT, a selective ERα agonist) were determined. These were compared with responses to reference compound 17β-estradiol (17β-E2). Concentration-response curves were constructed before and after nitric oxide (NO) synthase inhibition with Nω-nitro-l-arginine methyl ester. As a result, relaxation induced by the investigated compounds was similar in men with CHD and control men, but in both groups PPT and genistein-induced relaxation was greater than that of resveratrol and 17β-E2. NO contributed to both phytoestrogens and PPT-induced relaxation but not to 17β-E2responses in arteries from control men. This NO-mediated component of relaxation was absent in arteries from men with established CHD. In conclusion, phytoestrogens, at concentrations achievable by ingestion of phytoestrogen-rich food products, evoke dilatation ex vivo of small peripheral arteries from normal men and those with established CHD. The contribution of NO to dilatory responses by these compounds is pertinent to arteries from control males, whereas other NO-independent dilatory mechanism(s) are involved in arteries from CHD.
Characterization of human cardiac mitochondrial ATP-sensitive potassium channel and its regulation by phorbol ester in vitro
Authors: Jiang Ming Tao , Ljubkovic Marko , Nakae Yuri , Shi Yang , Kwok Wai-Meng , Stowe David F. , Bosnjak Zeljko J.
Published: December 2005

Activation of the mitochondrial ATP-sensitive K+channel (mitoKATP) and its regulation by PKC are critical events in preconditioning induced by ischemia or pharmaceutical agents in animals and humans. The properties of the human cardiac mitoKATPchannel are unknown. Furthermore, there is no evidence that cytosolic PKC can directly regulate the mitoKATPchannel located in the inner mitochondrial membrane (IMM) due to the physical barrier of the outer mitochondrial membrane. In the present study, we characterized the human cardiac mitoKATPchannel and its potential regulation by PKC associated with the IMM. IMM fractions isolated from human left ventricles were fused into lipid bilayers in symmetrical potassium glutamate (150 mM). The conductance of native mitoKATPchannels was usually below 80 pS (∼70%), which was reduced by ATP and 5-hydroxydecanoic acid (5-HD) in a dose- and time-dependent manner. The native mitoKATPchannel is activated by diazoxide and inhibited by ATP and 5-HD. The PKC activator phorbol 12-myristate 13-acetate (2 μM) increased the cumulative open probability of the mitoKATPchannel previously inhibited by ATP ( P < 0.05), but its inactive analog 4α-phorbol 12,13-didecanoate had no effect. Western blot analysis detected an inward rectifying K+channel (Kir6.2) immunoreactive protein at 56 kDa and PKC-δ in the IMM. These data provide the first characterization of the human cardiac mitoKATPchannel and its regulation by PKC(s) in IMM. This local PKC control mechanism may represent an alternative pathway to that proposed previously for cytosolic PKC during ischemic/pharmacological preconditioning.
Effects of modulation of left ventricular contractile state and loading conditions on tissue Doppler myocardial performance index
Authors: Cannesson Maxime , Jacques Didier , Pinsky Michael R. , Gorcsan John
Published: December 2005

The Tei index is clinically useful to quantify left ventricular (LV) function, but it requires sequential Doppler recordings from two different views. A related myocardial performance index (MPI) using tissue Doppler (TD) can be rapidly calculated from a single beat; however, its ability to quantify contractility and the effects of acute changes in loading have not been determined. Our aim was to test the hypothesis that TD MPI can quantify contractile state but is affected by acute alterations in loading, using LV pressure-volume relations in an animal model. Eight dogs were studied by using mitral annular TD, high-fidelity pressure, and conductance catheters. TD MPI was calculated as ( a′ − b′)/ b′, where a′ was the duration of mitral annular velocity during diastole and b′ was the duration of the systolic wave. End-systolic elastance ( Ees), the time constant of isovolumic relaxation (τ), and peak positive and negative first derivative of pressure (dP/d tmax and dP/d tmin, respectively) were used as measures of LV function. Data were obtained at baseline, at dobutamine and esmolol infusion to alter contractile state, and at inferior vena cava and aortic occlusion to alter preload and afterload. TD MPI decreased from 0.83 (SD 0.19) to 0.62 (SD 0.20) with dobutamine and increased to 1.19 (SD 0.26) with esmolol. TD MPI significantly correlated with dP/d tmax ( r = −0.76), Ees ( r = −0.68), dP/d tmin ( r = 0.82), and τ ( r = 0.78); however, it was affected by acute decreases in preload [from 0.83 (SD 0.19) to 1.09 (SD 0.36)] and acute increases in afterload [to 1.23 (SD 0.17)]. All the above increases and decreases and r values were significant ( P < 0.05 vs. baseline). In conclusion, TD MPI can rapidly quantify alterations in LV contractile state but is affected by acute alterations in preload and afterload.
Testosterone enhances early cardiac remodeling after myocardial infarction, causing rupture and degrading cardiac function
Authors: Cavasin Maria A. , Tao Zhen-Yin , Yu Ai-Li , Yang Xiao-Ping
Published: December 2005

Cardiac rupture can be fatal after myocardial infarction (MI). Experiments in animals revealed gender differences in rupture rate; however, patient data are controversial. We found a significantly higher rupture rate in testosterone-treated female mice within 1 wk after MI, whereas castration in males significantly reduced rupture. We hypothesized that testosterone may adversely affect remodeling after MI, exaggerating the inflammatory response and increasing cardiac rupture, whereas estrogen may be cardioprotective, attenuating early remodeling and reducing rupture rate. We studied the effect of gender and hormone manipulation on morphological and histological changes during early remodeling after MI in 4-wk-old male and female C57BL/6J mice and how these events could affect cardiac function. Females were randomly divided into 1) sham ovariectomy + placebo (s-ovx + P), 2) s-ovx + testosterone (T), 3) ovx + P, and 4) ovx + T; males were divided into 1) sham castration + P (s-cas + P), 2) s-cas + 17β-estradiol (E), 3) cas + P, and 4) cas + E. At 6 wk after gonadectomy and hormone manipulation, MI was induced. Mice were randomly killed 1, 2, 4, 7, and 14 days after MI. The left ventricle was weighed and sectioned for evaluation of MI size, infarct expansion index (IEI), and neutrophil infiltration. Transthoracic echocardiography was performed in conscious mice in the 14-day group before organ harvest. Cardiac rupture rate and IEI were significantly higher in testosterone-treated females and noncastrated males than in controls; these effects were accompanied by enhanced neutrophil infiltration and pronounced deterioration of cardiac function and left ventricular dilatation. Ovariectomy in females and estrogen supplementation in males did not confer significant protection from cardiac rupture, IEI, or neutrophil infiltration. We concluded that, in mice, high testosterone levels enhance acute myocardial inflammation, adversely affecting myocardial healing and early remodeling, as indicated by increased cardiac rupture, and possibly causing deterioration of cardiac function after MI, and, conversely, estrogen seems to have no significant protective effect in the acute phase after MI.
Cigarette smoke disrupts VEGF165-VEGFR-2 receptor signaling complex in rat lungs and patients with COPD: morphological impact of VEGFR-2 inhibition
Authors: Marwick John A. , Stevenson Christopher S. , Giddings June , MacNee William , Butler Keith , Rahman Irfan , Kirkham Paul A.
Published: December 2005

VEGF is fundamental in the development and maintenance of the vasculature. VEGF165signaling through VEGF receptor (VEGFR)-2/kinase insert domain receptor (KDR) is a highly regulated process involving the formation of a tertiary complex with glypican (GYP)-1 and neuropilin (NRP)-1. Both VEGF and VEGFR-2 expression are reduced in emphysematous lungs; however, the mechanism of regulation of VEGF165signaling through the VEGFR-2 complex in response to cigarette smoke exposure in vivo, and in smokers with and without chronic obstructive pulmonary disease (COPD), is still unknown. We hypothesized that cigarette smoke exposure disrupts the VEGF165-VEGFR-2 complex, a potential mechanism in the pathogenesis of emphysema. We show that cigarette smoke exposure reduces NRP-1 and GYP-1 as well as VEGF and VEGFR-2 levels in rat lungs and that VEGF, VEGFR-2, GYP-1, and NRP-1 expression in the lungs of both smokers and patients with COPD are also reduced compared with nonsmokers. Moreover, our data suggest that specific inhibition of VEGFR-2 alone with NVP-AAD777 would appear not to result in emphysema in the adult rat lung. As both VEGF165and VEGFR-2 expression are reduced in emphysematous lungs, decreased GYP-1 and NRP-1 expression may yet further disrupt VEGF165-VEGFR-2 signaling. Whether or not this by itself is critical for inducing endothelial cell apoptosis and decreased vascularization of the lung seen in emphysema patients is still unclear at present. However, targeted therapies to restore VEGF165-VEGFR-2 complex may promote endothelial cell survival and help to ameliorate emphysema.
Clathrin-mediated endocytosis of FITC-albumin in alveolar type II epithelial cell line RLE-6TN
Authors: Yumoto Ryoko , Nishikawa Hiromi , Okamoto Miho , Katayama Hirokazu , Nagai Junya , Takano Mikihisa
Published: December 2005

We examined mechanisms of FITC-albumin uptake by alveolar type II epithelial cells using cultured RLE-6TN cells. Alkaline phosphatase activity and the expression of cytokeratin 19 mRNA, which are characteristic features of alveolar type II epithelial cells, were detected in RLE-6TN cells. The uptake of FITC-albumin by the cells was time and temperature dependent and showed the saturation kinetics of high- and low-affinity transport systems. FITC-albumin uptake was inhibited by native albumin, by chemically modified albumin, and by metabolic inhibitors and bafilomycin A1, an inhibitor of vacuolar H+-ATPase. Confocal laser scanning microscopic analysis after FITC-albumin uptake showed punctate localization of fluorescence in the cells, which was partly localized in lysosomes. FITC-albumin taken up by the cells gradually degraded over time, as shown by fluoroimage analyzer after SDS-PAGE. The uptake of FITC-albumin by RLE-6TN cells was not inhibited by nystatin, indomethacin, or methyl-β-cyclodextrin (inhibitors of caveolae-mediated endocytosis) but was inhibited by phenylarsine oxide and chlorpromazine (inhibitors of clathrin-mediated endocytosis) in a concentration-dependent manner. Uptake was also inhibited by potassium depletion and hypertonicity, conditions known to inhibit clathrin-mediated endocytosis. These results indicate that the uptake of FITC-albumin in cultured alveolar type II epithelial cells, RLE-6TN, is mediated by clathrin-mediated but not by caveolae-mediated endocytosis, and intracellular FITC-albumin is gradually degraded in lysosomes. Possible receptors involved in this endocytic system are discussed.
Differential protease, innate immunity, and NF-κB induction profiles during lung inflammation induced by subchronic cigarette smoke exposure in mice
Authors: Vlahos R. , Bozinovski S. , Jones J. E. , Powell J. , Gras J. , Lilja A. , Hansen M. J. , Gualano R. C. , Irving L. , Anderson G. P.
Published: December 2005

Cigarette smoke exposure is a major determinant of adverse lung health, but the molecular processes underlying its effects on inflammation and immunity remain poorly understood. Therefore, we sought to understand whether inflammatory and host defense determinants are affected during subchronic cigarette smoke exposure. Dose-response and time course studies of lungs from Balb/c mice exposed to smoke generated from 3, 6, and 9 cigarettes/day for 4 days showed macrophage- and S100A8-positive neutrophil-rich inflammation in lung tissue and bronchoalveolar lavage (BAL) fluid, matrix metalloproteinase (MMP) and serine protease induction, sustained NF-κB translocation and binding, and mucus cell induction but very small numbers of CD3+CD4+ and CD3+CD8+ lymphocytes. Cigarette smoke had no effect on phospho-Akt but caused a small upregulation of phospho-Erk1/2. Activator protein-1 and phospho-p38 MAPK could not be detected. Quantitative real-time PCR showed upregulation of chemokines (macrophage inflammatory protein-2, monocyte chemoattractant protein-1), inflammatory mediators (TNF-α, IL-1β), leukocyte growth and survival factors [granulocyte-macrophage colony-stimulating factor, colony-stimulating factor (CSF)-1, CSF-1 receptor], transforming growth factor-β, matrix-degrading MMP-9 and MMP-12, and Toll-like receptor (TLR)2, broadly mirroring NF-κB activation. No upregulation was observed for MMP-2, urokinase-type plasminogen activator, tissue-type plasminogen activator, and TLRs 3, 4, and 9. In mouse strain comparisons the rank order of susceptibility was Balb/c > C3H/HeJ > 129SvJ > C57BL6. Partition of responses into BAL macrophages vs. lavaged lung strongly implicated macrophages in the inflammatory responses. Strikingly, except for IL-10 and MMP-12, macrophage and lung gene profiles in Balb/c and C57BL/6 mice were very similar. The response pattern we observed suggests that subchronic cigarette smoke exposure may be useful to understand pathogenic mechanisms triggered by cigarette smoke in the lungs including inflammation and alteration of host defense.
Downregulation of type II bone morphogenetic protein receptor in hypoxic pulmonary hypertension
Authors: Takahashi Hideki , Goto Naoto , Kojima Yuko , Tsuda Yasunari , Morio Yoshiteru , Muramatsu Masashi , Fukuchi Yoshinosuke
Published: December 2005

Heterozygous mutations in the type II receptor for bone morphogenetic protein (BMPR-II) and dysfunction of BMPR-II have been implicated in patients with primary pulmonary hypertension (PH). To clarify the possible involvement of BMP and BMPR-II in the development of hypoxic PH, the expression of BMP-2, BMPR-II, and their downstream signals were investigated in rat lung under normal and hypoxic conditions by RT-PCR, immunoblot, and immunohistochemical methods. In rats under normal conditions, BMP-2 is localized in the endothelium of the pulmonary artery, whereas BMPR-II is abundantly expressed in the endothelium, smooth muscle cells, and adventitial fibroblasts. After 0.5 and 3 days of exposure to hypoxia, upregulation of BMP-2 was observed in the intrapulmonary arteries. The change was accompanied by activation of its downstream signaling, p38 MAPK, and Erk1/2 MAPK, and the apoptotic process, measured by caspase-3 activity and TdT-mediated dUTP nick end labeling-positive cells. In contrast, a significant decrease in the expression of BMPR-II and inactivation of p38 MAPK and caspase-3 were observed in the pulmonary vasculature after 7–21 days of hypoxia exposure. Because BMP-2 is known to inhibit proliferation of vascular smooth muscle cells and promote cellular apoptosis, disruption of BMP signaling pathway through downregulation of BMPR-II in chronic hypoxia may result in pulmonary vascular remodeling due to the failure of critical antiproliferative/differentiation programs in the pulmonary vasculature. These results suggest abrogation of BMP signaling may be a common molecular pathogenesis in the development of PH with various pathophysiological events, including primary and hypoxic PH.
Adenosine A2Areceptors promote adenosine-stimulated wound healing in bronchial epithelial cells
Authors: Allen-Gipson D. S. , Wong J. , Spurzem J. R. , Sisson J. H. , Wyatt T. A.
Published: December 2005

Adenosine produces a wide variety of physiological effects through the activation of specific adenosine receptors (A1, A2A, A2B, A3). Adenosine, acting particularly at the A2Aadenosine receptor (A2AAR), is a potent endogenous anti-inflammatory agent and sensor of inflammatory tissue damage. The complete healing of wounds is the final step in a highly regulated response to injury. Recent studies on epidermal wounds have identified the A2AAR as the main adenosine receptor responsible for altering the kinetics of wound closure. We hypothesized that A2AAR promotes wound healing in bronchial epithelial cells (BECs). To test this hypothesis, the human BEC line BEAS-2B and bovine BECs (BBECs) were used. Real-time RT-PCR of RNA from unstimulated BEAS-2B cells revealed transcriptional expression of A1, A2A, A2Band A3receptors. Western blot analysis of lysates from BEAS-2B cells and BBECs detected a single band at 44.7 kDa in both the BECs, indicating the presence of A2AAR. In a wound healing model, we found that adenosine stimulated wound repair in cultured BBECs in a concentration-dependent manner, with an optimal closure rate observed between 4 and 6 h. Similarly, the A2AAR agonist 5′-( N-cyclopropyl)carboxamidoadenosine (CPCA) augmented wound closure, with a maximal closure rate occurring between 4 and 6 h. Inhibition of A2AAR with ZM-241385, a known A2AAR antagonist, impeded wound healing. In addition, ZM-241385 also attenuated adenosine-mediated wound repair. Kinase studies revealed that adenosine-stimulated airway repair activates PKA by ligating A2AAR. Collectively, the data suggest that the A2AAR is involved in BEC adenosine-stimulated wound healing and may prove useful in understanding purinergic-mediated actions on airway epithelial repair.
Estrogen receptor regulation of pulmonary alveolar dimensions: alveolar sexual dimorphism in mice
Authors: Massaro Donald , Massaro Gloria DeCarlo
Published: December 2005

Female rats and mice have smaller and, per body mass (BM), more alveoli and alveolar surface area (Sa) than males of their respective species. This sexual dimorphism becomes apparent about the time of sexual maturity. It is prevented in rats (not tested in mice) by ovariectomy at age 3 wk. In female mice, estrogen receptor (ER)-α and ER-β are required for formation of alveoli of appropriate size and number. We now report the average volume of an alveolus (v̄a) and the number of alveoli per body mass (Na/BM) were not statistically different between ER-α−/− and wild type (wt) males. However, the combination of a larger value for v̄a and a smaller value for Na/BM, though neither parameter achieved a statistically significant intergroup difference, resulted in a statistically significant lower Sa/BM in ER-α−/− males compared with wt males. In ER-β−/− males, v̄a was bigger and Na/BM and Sa/BM were lower compared with wt males. Wt males had larger alveoli and lower Na/BM and Sa/BM than wt females. The wt sexual dimorphism of v̄a, Na/BM, and Sa/BM was absent in ER-α−/− mice. Alveolar size did not differ between ER-β−/− females and males but Na/BM and Sa/BM were greater in ER-β−/− females than in ER-β−/− males. The results in male mice, with prior findings in female mice, 1) demonstrate estrogen receptors have a smaller effect on alveolar dimensions in male than female mice, 2) show ER-α and ER-β are required for the sexual dimorphism of alveolar size, and 3) show ER-α is needed for the sexual dimorphism of body mass-specific alveolar number and surface area.
TLR7 ligand prevents allergen-induced airway hyperresponsiveness and eosinophilia in allergic asthma by a MYD88-dependent and MK2-independent pathway
Authors: Moisan J. , Camateros P. , Thuraisingam T. , Marion D. , Koohsari H. , Martin P. , Boghdady M. L. , Ding A. , Gaestel M. , Guiot M. C. , Martin J. G. , Radzioch D.
Published: December 2005

Asthma is one of the leading causes of childhood hospitalization, and its incidence is on the rise throughout the world. Currently, the standard treatment for asthma is the use of corticosteroids to try to suppress the inflammatory reaction taking place in the bronchial tree. Using a murine model of atopic allergic asthma employing a methacholine-hyperresponsive (A/J) as well as a hyporesponsive (C57BL/6) strain of mice sensitized and challenged with ovalbumin, we show that treatment with a synthetic Toll-like receptor 7 (TLR7) ligand (S-28463, a member of the imidazoquinoline family) prevents development of the asthmatic phenotype. Treatment with S-28463 resulted in a reduction of airway resistance and elastance following ovalbumin sensitization and challenge. This was accompanied by a dramatic reduction in infiltration of leukocytes, especially eosinophils, into the lungs of both C57BL/6 and A/J mice following OVA challenge. Treatment with S-28463 also abolished both the elevation in serum IgE level as well as the induction of IL-4, IL-5, and IL-13 by OVA challenge. The protective effects of S-28463 were also observed in MK2 knockout, but not MYD88 knockout, mice. We did not observe a switch in cytokine profile from TH2 to TH1, as both IL-12p70 and IFN-γ levels were reduced following S-28463 treatment. These results clearly demonstrate the anti-inflammatory effect of imidazoquinolines in an allergic asthma model as well as the clinical potential of TLR7 ligands in the treatment of allergic diseases.