71 research outputs found
Effect of neutrophil elastase and its inhibitor EPI-hNE4 on transepithelial sodium transport across normal and cystic fibrosis human nasal epithelial cells
<p>Abstract</p> <p>Background</p> <p>Hyperactivity of the epithelial sodium (Na<sup>+</sup>) channel (ENaC) and increased Na<sup>+ </sup>absorption by airway epithelial cells leading to airway surface liquid dehydration and impaired mucociliary clearance are thought to play an important role in the pathogenesis of cystic fibrosis (CF) pulmonary disease. In airway epithelial cells, ENaC is constitutively activated by endogenous trypsin-like serine proteases such as Channel-Activating Proteases (CAPs). It was recently reported that ENaC activity could also be stimulated by apical treatment with human neutrophil elastase (hNE) in a human airway epithelial cell line, suggesting that hNE inhibition could represent a novel therapeutic approach for CF lung disease. However, whether hNE can also activate Na<sup>+ </sup>reabsorption in primary human nasal epithelial cells (HNEC) from control or CF patients is currently unknown.</p> <p>Methods</p> <p>We evaluated by short-circuit current (<it>I</it><sub>sc</sub>) measurements the effects of hNE and EPI-hNE4, a specific hNE inhibitor, on ENaC activity in primary cultures of HNEC obtained from control (9) and CF (4) patients.</p> <p>Results</p> <p>Neither hNE nor EPI-hNE4 treatments did modify <it>I</it><sub>sc </sub>in control and CF HNEC. Incubation with aprotinin, a Kunitz-type serine protease inhibitor that blocks the activity of endogenous CAPs, decreased <it>I</it><sub>sc </sub>by 27.6% and 54% in control and CF HNEC, respectively. In control and CF HNEC pretreated with aprotinin, hNE did significantly stimulate <it>I</it><sub>sc</sub>, an effect which was blocked by EPI-hNE4.</p> <p>Conclusions</p> <p>These results indicate that hNE does activate ENaC and transepithelial Na<sup>+ </sup>transport in both normal and CF HNEC, on condition that the activity of endogenous CAPs is first inhibited. The potent inhibitory effect of EPI-hNE4 on hNE-mediated ENaC activation observed in our experiments highlights that the use of EPI-hNE4 could be of interest to reduce ENaC hyperactivity in CF airways.</p
Matrix Metalloproteinase-8 Mediates the Unfavorable Systemic Impact of Local Irradiation on Pharmacokinetics of Anti-Cancer Drug 5-Fluorouracil
Concurrent chemoradiation with 5-fluorouracil (5-FU) is widely accepted for cancer treatment. However, the interactions between radiation and 5-FU remain unclear. Here, we evaluated the influence of local irradiation on the pharmacokinetics of 5-FU in rats. The single-fraction radiation was delivered to the whole pelvic fields of Sprague-Dawley rats after computerized tomography-based planning. 5-FU at 100 mg/kg was prescribed 24 hours after radiation. A high-performance liquid chromatography system was used to measure 5-FU in the blood. Matrix metalloproteinase-8 (MMP-8) inhibitor I was administered to examine whether or not RT modulation of 5-FU pharmacokinetic parameters could be blocked. Compared with sham-irradiated controls, whole pelvic irradiation reduced the area under the concentration versus time curve (AUC) of 5-FU in plasma and, in contrast, increased in bile with a radiation dose-dependent manner. Based on protein array analysis, the amount of plasma MMP-8 was increased by whole pelvic irradiation (2.8-fold by 0.5 Gy and 5.3-fold by 2 Gy) in comparison with controls. Pretreatment with MMP-8 inhibitor reversed the effect of irradiation on AUC of 5-FU in plasma. Our findings first indicate that local irradiation modulate the systemic pharmacokinetics of 5-FU through stimulating the release of MMP-8. The pharmacokinetics of 5-FU during concurrent chemoradiaiton therapy should be rechecked and the optimal 5-FU dose should be reevaluated, and adjusted if necessary, during CCRT
K+ channel openers restore verapamil-inhibited lung fluid resolution and transepithelial ion transport
<p>Abstract</p> <p>Background</p> <p>Lung epithelial Na<sup>+ </sup>channels (ENaC) are regulated by cell Ca<sup>2+ </sup>signal, which may contribute to calcium antagonist-induced noncardiogenic lung edema. Although K<sup>+ </sup>channel modulators regulate ENaC activity in normal lungs, the therapeutical relevance and the underlying mechanisms have not been completely explored. We hypothesized that K<sup>+ </sup>channel openers may restore calcium channel blocker-inhibited alveolar fluid clearance (AFC) by up-regulating both apical and basolateral ion transport.</p> <p>Methods</p> <p>Verapamil-induced depression of heterologously expressed human αβγ ENaC in <it>Xenopus </it>oocytes, apical and basolateral ion transport in monolayers of human lung epithelial cells (H441), and <it>in vivo </it>alveolar fluid clearance were measured, respectively, using the two-electrode voltage clamp, Ussing chamber, and BSA protein assays. Ca<sup>2+ </sup>signal in H441 cells was analyzed using Fluo 4AM.</p> <p>Results</p> <p>The rate of <it>in vivo </it>AFC was reduced significantly (40.6 ± 6.3% of control, <it>P </it>< 0.05, n = 12) in mice intratracheally administrated verapamil. K<sub>Ca3.1 </sub>(1-EBIO) and K<sub>ATP </sub>(minoxidil) channel openers significantly recovered AFC. In addition to short-circuit current (Isc) in intact H441 monolayers, both apical and basolateral Isc levels were reduced by verapamil in permeabilized monolayers. Moreover, verapamil significantly altered Ca<sup>2+ </sup>signal evoked by ionomycin in H441 cells. Depletion of cytosolic Ca<sup>2+ </sup>in αβγ ENaC-expressing oocytes completely abolished verapamil-induced inhibition. Intriguingly, K<sub>V </sub>(pyrithione-Na), K <sub>Ca3.1 </sub>(1-EBIO), and K<sub>ATP </sub>(minoxidil) channel openers almost completely restored the verapamil-induced decrease in Isc levels by diversely up-regulating apical and basolateral Na<sup>+ </sup>and K<sup>+ </sup>transport pathways.</p> <p>Conclusions</p> <p>Our observations demonstrate that K<sup>+ </sup>channel openers are capable of rescuing reduced vectorial Na<sup>+ </sup>transport across lung epithelial cells with impaired Ca<sup>2+ </sup>signal.</p
Studies of and production in and Pb collisions
The production of and mesons is studied in proton-proton and
proton-lead collisions collected with the LHCb detector. Proton-proton
collisions are studied at center-of-mass energies of and ,
and proton-lead collisions are studied at a center-of-mass energy per nucleon
of . The studies are performed in center-of-mass rapidity
regions (forward rapidity) and
(backward rapidity) defined relative to the proton beam direction. The
and production cross sections are measured differentially as a function
of transverse momentum for and , respectively. The differential cross sections are used to
calculate nuclear modification factors. The nuclear modification factors for
and mesons agree at both forward and backward rapidity, showing
no significant evidence of mass dependence. The differential cross sections of
mesons are also used to calculate cross section ratios,
which show evidence of a deviation from the world average. These studies offer
new constraints on mass-dependent nuclear effects in heavy-ion collisions, as
well as and meson fragmentation.Comment: All figures and tables, along with machine-readable versions and any
supplementary material and additional information, are available at
https://lhcbproject.web.cern.ch/Publications/p/LHCb-PAPER-2023-030.html (LHCb
public pages
Observation of Cabibbo-suppressed two-body hadronic decays and precision mass measurement of the baryon
The first observation of the singly Cabibbo-suppressed
and decays
is reported, using proton-proton collision data at a centre-of-mass energy of
, corresponding to an integrated luminosity of , collected with the LHCb detector between 2016 and 2018. The
branching fraction ratios are measured to be
,
. In addition, using the
decay channel, the baryon
mass is measured to be , improving the
precision of the previous world average by a factor of four.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2023-011.html (LHCb
public pages
Fraction of decays in prompt production measured in pPb collisions at TeV
The fraction of and decays in the prompt
yield, , is measured by
the LHCb detector in pPb collisions at TeV. The study
covers the forward () and backward () rapidity
regions, where is the rapidity in the nucleon-nucleon
center-of-mass system. Forward and backward rapidity samples correspond to
integrated luminosities of 13.6 0.3 nb and 20.8 0.5
nb, respectively. The result is presented as a function of the
transverse momentum in the range 1 GeV/.
The fraction at forward rapidity is compatible with the LHCb
measurement performed in collisions at TeV, whereas the
result at backward rapidity is 2.4 larger than in the forward region
for GeV/. The increase of at low at backward rapidity is compatible with the suppression of the
(2S) contribution to the prompt yield. The lack of in-medium
dissociation of states observed in this study sets an upper limit of
180 MeV on the free energy available in these pPb collisions to dissociate or
inhibit charmonium state formation.Comment: All figures and tables, along with machine-readable versions and any
supplementary material and additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2023-028.html (LHCb
public pages
Helium identification with LHCb
The identification of helium nuclei at LHCb is achieved using a method based on measurements of ionisation losses in the silicon sensors and timing measurements in the Outer Tracker drift tubes. The background from photon conversions is reduced using the RICH detectors and an isolation requirement. The method is developed using pp collision data at √(s) = 13 TeV recorded by the LHCb experiment in the years 2016 to 2018, corresponding to an integrated luminosity of 5.5 fb-1. A total of around 105 helium and antihelium candidates are identified with negligible background contamination. The helium identification efficiency is estimated to be approximately 50% with a corresponding background rejection rate of up to Script O(1012). These results demonstrate the feasibility of a rich programme of measurements of QCD and astrophysics interest involving light nuclei
Momentum scale calibration of the LHCb spectrometer
For accurate determination of particle masses accurate knowledge of the momentum scale of the detectors is crucial. The procedure used to calibrate the momentum scale of the LHCb spectrometer is described and illustrated using the performance obtained with an integrated luminosity of 1.6 fb-1collected during 2016 in pp running. The procedure uses large samples of J/ψ → μ+μ- and B+ → J/ψK+ decays and leads to a relative accuracy of 3 × 10-4 on the momentum scale
Measurement of boson production cross-section in collisions at TeV
The first measurement of the boson production cross-section at
centre-of-mass energy TeV in the forward region is reported,
using collision data collected by the LHCb experiment in year 2017,
corresponding to an integrated luminosity of . The
production cross-section is measured for final-state muons in the
pseudorapidity range . The integrated cross-section is determined to be for the di-muon invariant
mass in the range . This result and the
differential cross-section results are in good agreement with theoretical
predictions at next-to-next-to-leading order in the strong coupling.
Based on a previous LHCb measurement of the boson production
cross-section in Pb collisions at TeV, the nuclear
modification factor is measured for the first time at this
energy. The measured values are in the forward region () and
in the backward region
(), where represents the muon rapidity in
the centre-of-mass frame.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2023-010.html (LHCb
public pages
Enhanced production of baryons in high-multiplicity collisions at TeV
The production rate of baryons relative to mesons
in collisions at a center-of-mass energy TeV is measured
by the LHCb experiment. The ratio of to production
cross-sections shows a significant dependence on both the transverse momentum
and the measured charged-particle multiplicity. At low multiplicity, the ratio
measured at LHCb is consistent with the value measured in
collisions, and increases by a factor of with increasing multiplicity.
At relatively low transverse momentum, the ratio of to
cross-sections is higher than what is measured in
collisions, but converges with the ratio as the momentum
increases. These results imply that the evolution of heavy quarks into
final-state hadrons is influenced by the density of the hadronic environment
produced in the collision. Comparisons with a statistical hadronization model
and implications for the mechanisms enforcing quark confinement are discussed.Comment: All figures and tables, along with machine-readable versions and any
supplementary material and additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2023-027.html (LHCb
public pages
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