Heme oxygenase-1 plays a pro-life role in experimental brain stem death via nitric oxide synthase I/protein kinase G signaling at rostral ventrolateral medulla

<p>Abstract</p> <p>Background</p> <p>Despite its clinical importance, a dearth of information exists on the cellular and molecular mechanisms that underpin brain stem death. A suitable neural substrate for mechanistic delineation on brain stem death resides in the rostral ventrolateral medulla (RVLM) because it is the origin of a life-and-death signal that sequentially increases (pro-life) and decreases (pro-death) to reflect the advancing central cardiovascular regulatory dysfunction during the progression towards brain stem death in critically ill patients. The present study evaluated the hypothesis that heme oxygnase-1 (HO-1) may play a pro-life role as an interposing signal between hypoxia-inducible factor-1 (HIF-1) and nitric oxide synthase I (NOS I)/protein kinase G (PKG) cascade in RVLM, which sustains central cardiovascular regulatory functions during brain stem death.</p> <p>Methods</p> <p>We performed cardiovascular, pharmacological, biochemical and confocal microscopy experiments in conjunction with an experimental model of brain stem death that employed microinjection of the organophosphate insecticide mevinphos (Mev; 10 nmol) bilaterally into RVLM of adult male Sprague-Dawley rats.</p> <p>Results</p> <p>Western blot analysis coupled with laser scanning confocal microscopy revealed that augmented HO-1 expression that was confined to the cytoplasm of RVLM neurons occurred preferentially during the pro-life phase of experimental brain stem death and was antagonized by immunoneutralization of HIF-1α or HIF-1β in RVLM. On the other hand, the cytoplasmic presence of HO-2 in RVLM neurons manifested insignificant changes during both phases. Furthermore, immunoneutralization of HO-1 or knockdown of <it>ho-1 </it>gene in RVLM blunted the augmented life-and-death signals exhibited during the pro-life phase. Those pretreatments also blocked the upregulated pro-life NOS I/PKG signaling without affecting the pro-death NOS II/peroxynitrite cascade in RVLM.</p> <p>Conclusions</p> <p>We conclude that transcriptional upregulation of HO-1 on activation by HIF-1 in RVLM plays a preferential pro-life role by sustaining central cardiovascular regulatory functions during brain stem death via upregulation of NOS I/PKG signaling pathway. Our results further showed that the pro-dead NOS II/peroxynitrite cascade in RVLM is not included in this repertoire of cellular events.</p

Extracellular signal-regulated kinase 1/2 plays a pro-life role in experimental brain stem death via MAPK signal-interacting kinase at rostral ventrolateral medulla

<p>Abstract</p> <p>Background</p> <p>As the origin of a life-and-death signal detected from systemic arterial pressure, which sequentially increases (pro-life) and decreases (pro-death) to reflect progressive dysfunction of central cardiovascular regulation during the advancement towards brain stem death in critically ill patients, the rostral ventrolateral medulla (RVLM) is a suitable neural substrate for mechanistic delineation of this fatal phenomenon. The present study assessed the hypothesis that extracellular signal-regulated kinase 1/2 (ERK1/2), a member of the mitogen-activated protein kinases (MAPKs) that is important for cell survival and is activated specifically by MAPK kinase 1/2 (MEK1/2), plays a pro-life role in RVLM during brain stem death. We further delineated the participation of MAPK signal-interacting kinase (MNK), a novel substrate of ERK in this process.</p> <p>Methods</p> <p>An experimental model of brain stem death that employed microinjection of the organophosphate insecticide mevinphos (Mev; 10 nmol) bilaterally into RVLM of Sprague-Dawley rats was used, in conjunction with cardiovascular, pharmacological and biochemical evaluations.</p> <p>Results</p> <p>Results from ELISA showed that whereas the total ERK1/2 was not affected, augmented phosphorylation of ERK1/2 at Thr202 and Tyr204 in RVLM occurred preferentially during the pro-life phase of experimental brain stem death. Furthermore, pretreatment by microinjection into the bilateral RVLM of a specific ERK2 inhibitor, ERK activation inhibitor peptide II (1 nmol); a specific MEK1/2 inhibitor, U0126 (5 pmol); or a specific MNK1/2 inhibitor, CGP57380 (5 pmol) exacerbated the hypotension and blunted the augmented life-and-death signals exhibited during the pro-life phase. Those pretreatments also blocked the upregulated nitric oxide synthase I (NOS I)/protein kinase G (PKG) signaling, the pro-life cascade that sustains central cardiovascular regulatory functions during experimental brain stem death.</p> <p>Conclusions</p> <p>Our results demonstrated that activation of MEK1/2, ERK1/2 and MNK1/2 in RVLM plays a preferential pro-life role by sustaining the central cardiovascular regulatory machinery during brain stem death via upregulation of NOS I/PKG signaling cascade in RVLM.</p

Defunct brain stem cardiovascular regulation underlies cardiovascular collapse associated with methamphetamine intoxication

<p>Abstract</p> <p>Background</p> <p>Intoxication from the psychostimulant methamphetamine (METH) because of cardiovascular collapse is a common cause of death within the abuse population. For obvious reasons, the heart has been taken as the primary target for this METH-induced toxicity. The demonstration that failure of brain stem cardiovascular regulation, rather than the heart, holds the key to cardiovascular collapse induced by the pesticide mevinphos implicates another potential underlying mechanism. The present study evaluated the hypothesis that METH effects acute cardiovascular depression by dampening the functional integrity of baroreflex via an action on brain stem nuclei that are associated with this homeostatic mechanism.</p> <p>Methods</p> <p>The distribution of METH in brain and heart on intravenous administration in male Sprague-Dawley rats, and the resultant changes in arterial pressure (AP), heart rate (HR) and indices for baroreflex-mediated sympathetic vasomotor tone and cardiac responses were evaluated, alongside survival rate and time.</p> <p>Results</p> <p>Intravenous administration of METH (12 or 24 mg/kg) resulted in a time-dependent and dose-dependent distribution of the psychostimulant in brain and heart. <b/>The distribution of METH to neural substrates associated with brain stem cardiovascular regulation was significantly larger than brain targets for its neurological and psychological effects; the concentration of METH in cardiac tissues was the lowest among all tissues studied. In animals that succumbed to METH, the baroreflex-mediated sympathetic vasomotor tone and cardiac response were defunct, concomitant with cessation of AP and HR. On the other hand, although depressed, those two indices in animals that survived were maintained, alongside sustainable AP and HR. Linear regression analysis further revealed that the degree of dampening of brain stem cardiovascular regulation was positively and significantly correlated with the concentration of METH in key neural substrate involved in this homeostatic mechanism.</p> <p>Conclusions</p> <p>We conclude that on intravenous administration, METH exhibits a preferential distribution to brain stem nuclei that are associated with cardiovascular regulation. We further found that the concentration of METH in those brain stem sites dictates the extent that baroreflex-mediated sympathetic vasomotor tone and cardiac responses are compromised, which in turn determines survival or fatality because of cardiovascular collapse.</p

Differential protection against oxidative stress and nitric oxide overproduction in cardiovascular and pulmonary systems by propofol during endotoxemia

<p>Abstract</p> <p>Background</p> <p>Both overproduction of nitric oxide (NO) and oxidative injury of cardiovascular and pulmonary systems contribute to fatal cardiovascular depression during endotoxemia. We investigated in the present study the relative contribution of oxidative stress and NO to cardiovascular depression during different stages of endotoxemia, and delineated their roles in cardiovascular protective effects of a commonly used anesthetic propofol during endotoxemia.</p> <p>Methods</p> <p>Experimental endotoxemia was induced by systemic injection of <it>E. coli </it>lipopolysaccharide (LPS, 15 mg/kg) to Sprague-Dawley rats that were maintained under propofol (15 or 30 mg/kg/h, i.v.) anesthesia. Mean systemic arterial pressure (MSAP) and heart rate (HR) were monitored for 6 h after the endotoxin. Tissue level of NO was measured by chemical reduction-linked chemiluminescence and oxidative burst activity was determined using dihydroethidium method. Expression of NO synthase (NOS) was determined by immunoblotting. The Scheffé multiple range test was used for post hoc statistical analysis.</p> <p>Results</p> <p>Systemic injection of LPS (15 mg/kg) induced biphasic decreases in MSAP and HR. In the heart, lung and aorta, an abrupt increase in lipid peroxidation, our experimental index of oxidative tissue injury, was detected in early stage and sustained during late stage cardiovascular depression. LPS injection, on the other hand, induced a gradual increase in tissue nitrite and nitrate levels in the same organs that peaked during late stage endotoxemia. Propofol infusion (15 or 30 mg/kg/h, i.v.) significantly attenuated lipid peroxidation in the heart, lung and aorta during early and late stage endotoxemia. High dose (30 mg/kg/h, i.v.) propofol also reversed the LPS-induced inducible NO synthase (iNOS) upregulation and NO production in the aorta, alongside a significant amelioration of late stage cardiovascular depression and increase in survival time during endotoxemia.</p> <p>Conclusion</p> <p>Together these results suggest that oxidative injury and NO may play a differential role in LPS-induced cardiovascular depression. Oxidative tissue injury is associated with both early and late stage; whereas NO is engaged primarily in late stage cardiovascular depression. Moreover, propofol anesthesia may protect against fatal cardiovascular depression during endotoxemia by attenuating the late stage NO surge in the aorta, possibly via inhibition of iNOS upregulation by the endotoxin.</p

Effective Rheology of Bubbles Moving in a Capillary Tube

We calculate the average volumetric flux versus pressure drop of bubbles moving in a single capillary tube with varying diameter, finding a square-root relation from mapping the flow equations onto that of a driven overdamped pendulum. The calculation is based on a derivation of the equation of motion of a bubble train from considering the capillary forces and the entropy production associated with the viscous flow. We also calculate the configurational probability of the positions of the bubbles.Comment: 4 pages, 1 figur

Particle identification in ALICE : a Bayesian approach

Peer reviewe

Flow Dominance and Factorization of Transverse Momentum Correlations in Pb-Pb Collisions at the LHC

We present the first measurement of the two-particle transverse momentum differential correlation function, P2≡ ΔpTΔpT/ pT2, in Pb-Pb collisions at sNN=2.76 TeV. Results for P2 are reported as a function of the relative pseudorapidity (Δη) and azimuthal angle (Δφ) between two particles for different collision centralities. The Δφ dependence is found to be largely independent of Δη for |Δη|≥0.9. In the 5% most central Pb-Pb collisions, the two-particle transverse momentum correlation function exhibits a clear double-hump structure around Δφ=π (i.e., on the away side), which is not observed in number correlations in the same centrality range, and thus provides an indication of the dominance of triangular flow in this collision centrality. Fourier decompositions of P2, studied as a function of the collision centrality, show that correlations at |Δη|≥0.9 can be well reproduced by a flow ansatz based on the notion that measured transverse momentum correlations are strictly determined by the collective motion of the system

K*(892)(0) and phi(1020)meson production at high transverse momentum in pp and Pb-Pb collisions at root sNN=2.76 TeV

The production of K∗(892)0 and φ(1020) mesons in proton-proton (pp) and lead-lead (Pb-Pb) collisions at √sNN = 2.76 TeV has been analyzed using a high luminosity data sample accumulated in 2011 with the ALICE detector at the Large Hadron Collider (LHC). Transverse momentum (pT) spectra have been measured for K∗(892)0 and φ(1020) mesons via their hadronic decay channels for pT up to 20 GeV/c. The measurements in pp collisions have been compared to model calculations and used to determine the nuclear modification factor and particle ratios. The K∗(892)0/K ratio exhibits significant reduction from pp to central Pb-Pb collisions, consistent with the suppression of the K∗(892)0 yield at low pT due to rescattering of its decay products in the hadronic phase. In central Pb-Pb collisions the pT dependent φ(1020)/π and K∗(892)0/π ratios show an enhancement over pp collisions for pT ≈ 3 GeV/c, consistent with previous observations of strong radial flow. At high pT, particle ratios in Pb-Pb collisions are similar to those measured in pp collisions. In central Pb-Pb collisions, the production of K∗(892)0 and φ(1020) mesons is suppressed for pT &gt; 8 GeV/c. This suppression is similar to that of charged pions, kaons, and protons, indicating that the suppression does not depend on particle mass or flavor in the light quark sector

J/psi production as a function of charged-particle pseudorapidity density in p-Pb collisions at root s(NN)=5.02 TeV

We report measurements of the inclusive J/ψ yield and average transverse momentum as a function of charged-particle pseudorapidity density dNch/dη in p–Pb collisions at sNN=5.02TeV with ALICE at the LHC. The observables are normalised to their corresponding averages in non-single diffractive events. An increase of the normalised J/ψ yield with normalised dNch/dη, measured at mid-rapidity, is observed at mid-rapidity and backward rapidity. At forward rapidity, a saturation of the relative yield is observed for high charged-particle multiplicities. The normalised average transverse momentum at forward and backward rapidities increases with multiplicity at low multiplicities and saturates beyond moderate multiplicities. In addition, the forward-to-backward nuclear modification factor ratio is also reported, showing an increasing suppression of J/ψ production at forward rapidity with respect to backward rapidity for increasing charged-particle multiplicity