Particle-Induced Chronic Inflammation is Dependent upon Lysosomal Function and Autophagy

Chronic inflammation drives the development of many debilitating pulmonary diseases. NLRP3 Inflammasome activation following lysosomal membrane permeablization (LMP) has been identified as a necessary event in the maturation of IL-1β, a critical cytokine in the development of chronic inflammation. LMP and NLRP3 activation are known to occur rapidly following particle uptake by alveolar macrophages, however the longevity of these responses has not been defined. These studies are the first to describe the persistence of the NLRP3 Inflammasome response in relation to autophagy, the primary degradation pathway for NLRP3 components, and lysosomal integrity. Alveolar macrophages were isolated from C57Bl/6 mice 7 days following silica or vehicle exposure and assessed for impaired autophagy. LC3-II and p62 were elevated in cell lysates from alveolar macrophages isolated from silica-exposed mice, as well as Inflammasome protein components NLRP3 and ASC. IL-1β levels were below detection limits in the whole lung lavage fluid at 7 days and alveolar macrophages isolated from silica-treated mice after 7 days secreted negligible amounts of IL-1β after 24 hours of ex vivo culture, suggesting suppressed Inflammasome activity. Addition of low levels of endotoxin to isolated alveolar macrophages was sufficient to cause Inflammasome reactivation, resulting in renewed IL-1β production. Inflammasome reactivation could be suppressed with the Cathepsin B inhibitor Ca-074-Me, linking Inflammasome reactivation by endotoxin with impaired lysosome function. Multi-walled Carbon Nanotubes induced responses relative to silica, indicating that these mechanisms drive most particle-induced chronic inflammation. These studies demonstrate that lysosomal function and autophagy are integral to the development of chronic inflammation, and targeting of these two integrated pathways should be considered in therapeutic approaches to preventing chronic inflammatory disease

MECHANISMS AND CONSIQENCES OF LYSOSOMAL MEMBRANE PERMEABILIZATION FOLLOWING EXPOSURE TO BIOACTIVE PARTICLES

Exposure to bioactive environmental particles and engineered nanoparticles are a significant public health concern. Inhalation of bioactive particles can result in chronic inflammation, which drives tissue remodeling and fibrosis. Furthermore, chronic inflammation can increase individual susceptibility to other diseases including cancer and autoimmune diseases. The macrophage is the critical cell in particle clearance following exposure, and is central to the inflammatory responses and tissue remodeling. Phagocytosed bioactive particles within macrophages cause cytotoxicity and activation of the NLRP3 inflammasome, outcomes that are both essential to inflammation and disease development. However, mechanisms that regulate NLRP3 inflammasome activity and cytotoxicity have not fully been elucidated. The objective of this body of work was to further define common yet critical mechanisms that cause and/or mediate NLRP3 inflammasome activity following exposure to bioactive particles. In these studies we demonstrate that bioactive particles including silica and engineered nanomaterials cause lysosome membrane permeabilization (LMP) and the release of lysosomal proteases, which precedes and facilitates NLRP3 inflammasome activation. Bioactive particles cause LMP through a mechanism that requires phagolysosome acidification. LMP and the activation of the NLRP3 inflammasome are required for secretion of pro-inflammatory cytokines and the alarmin High Mobility Group Box 1 (HMGB1). Once secreted, HMGB1 can further drive NLRP3 inflammasome activity through sterile priming, similar to the nonsterile mechanism utilized by endotoxin. A second critical pathway for regulation of the NLRP3 inflammasome was autophagy. Mice with macrophages deficient in autophagy had greater inflammation and chronic disease following silica exposure, supporting a protective anti-inflammatory role for autophagic activity. Together, these data reveal novel critical mechanisms in the regulation of NLRP3 inflammasome activity following bioactive particle exposure, and provide multiple potential therapeutic targets for the suppression of inflammation and disease

Urinary Levoglucosan as a Biomarker of Wood Smoke Exposure: Observations in a Mouse Model and in Children

BACKGROUND: Biomass smoke is an important source of particulate matter (PM), and much remains to be discovered with respect to the human health effects associated with this specific PM source. Exposure to biomass smoke can occur in one of two main categories: short-term exposures consist of periodic, seasonal exposures typified by communities near forest fires or intentional agricultural burning, and long-term exposures are chronic and typified by the use of biomass materials for cooking or heating. Levoglucosan (LG), a sugar anhydride released by combustion of cellulose-containing materials, is an attractive candidate as a biomarker of wood smoke exposure. OBJECTIVES: In the present study, Balb/c mice and children were assessed for LG in urine to determine its feasibility as a biomarker. METHODS: We performed urinary detection of LG by gas chromatography/mass spectrometry after intranasal instillations of LG or concentrated PM (mice) or biomass exposure (mice or humans). RESULTS: After instillation, we recovered most of the LG within the first 4 hr. Experiments using glucose instillation proved the specificity of our system, and instillation of concentrated PM from wood smoke, ambient air, and diesel exhaust supported a connection between wood smoke and LG. In addition, LG was detected in the urine of mice exposed to wood smoke. Finally, a pilot human study proved our ability to detect LG in urine of children. CONCLUSIONS: These results demonstrate that LG in the lungs is detectable in the urine of both mice and humans and that it is a good candidate as a biomarker of exposure to biomass smoke

Measurement of the Forward-Backward Asymmetry in the B -> K(*) mu+ mu- Decay and First Observation of the Bs -> phi mu+ mu- Decay

We reconstruct the rare decays $B^+ \to K^+\mu^+\mu^-$, $B^0 \to K^{*}(892)^0\mu^+\mu^-$, and $B^0_s \to \phi(1020)\mu^+\mu^-$ in a data sample corresponding to $4.4 {\rm fb^{-1}}$ collected in $p\bar{p}$ collisions at $\sqrt{s}=1.96 {\rm TeV}$ by the CDF II detector at the Fermilab Tevatron Collider. Using $121 \pm 16$ $B^+ \to K^+\mu^+\mu^-$ and $101 \pm 12$ $B^0 \to K^{*0}\mu^+\mu^-$ decays we report the branching ratios. In addition, we report the measurement of the differential branching ratio and the muon forward-backward asymmetry in the $B^+$ and $B^0$ decay modes, and the $K^{*0}$ longitudinal polarization in the $B^0$ decay mode with respect to the squared dimuon mass. These are consistent with the theoretical prediction from the standard model, and most recent determinations from other experiments and of comparable accuracy. We also report the first observation of the $B^0_s \to \phi\mu^+\mu^- decay and measure its branching ratio${\mathcal{B}}(B^0_s \to \phi\mu^+\mu^-) = [1.44 \pm 0.33 \pm 0.46] \times 10^{-6}$using$27 \pm 6$signal events. This is currently the most rare$B^0_s$ decay observed.Comment: 7 pages, 2 figures, 3 tables. Submitted to Phys. Rev. Let

Search for a New Heavy Gauge Boson Wprime with Electron + missing ET Event Signature in ppbar collisions at sqrt(s)=1.96 TeV

We present a search for a new heavy charged vector boson $W^\prime$ decaying to an electron-neutrino pair in $p\bar{p}$ collisions at a center-of-mass energy of 1.96\unit{TeV}. The data were collected with the CDF II detector and correspond to an integrated luminosity of 5.3\unit{fb}^{-1}. No significant excess above the standard model expectation is observed and we set upper limits on $\sigma\cdot{\cal B}(W^\prime\to e\nu)$. Assuming standard model couplings to fermions and the neutrino from the $W^\prime$ boson decay to be light, we exclude a $W^\prime$ boson with mass less than 1.12\unit{TeV/}c^2 at the 95\unit{%} confidence level.Comment: 7 pages, 2 figures Submitted to PR

Measurements of the properties of Lambda_c(2595), Lambda_c(2625), Sigma_c(2455), and Sigma_c(2520) baryons

We report measurements of the resonance properties of Lambda_c(2595)+ and Lambda_c(2625)+ baryons in their decays to Lambda_c+ pi+ pi- as well as Sigma_c(2455)++,0 and Sigma_c(2520)++,0 baryons in their decays to Lambda_c+ pi+/- final states. These measurements are performed using data corresponding to 5.2/fb of integrated luminosity from ppbar collisions at sqrt(s) = 1.96 TeV, collected with the CDF II detector at the Fermilab Tevatron. Exploiting the largest available charmed baryon sample, we measure masses and decay widths with uncertainties comparable to the world averages for Sigma_c states, and significantly smaller uncertainties than the world averages for excited Lambda_c+ states.Comment: added one reference and one table, changed order of figures, 17 pages, 15 figure

Search for heavy bottom-like quarks decaying to an electron or muon and jets in ppˉp\bar{p} collisions at s=1.96\sqrt{s}=1.96 TeV

We report the most sensitive direct search for pair production of fourth-generation bottom-like chiral quarks ($b'$) each decaying promptly to $tW$. We search for an excess of events with an electron or muon, at least five jets (one indentified as due to a $b$ or $c$ quark) and an imbalance of transverse momentum using data from $p\bar{p}$ collisions collected by the CDF II detector at Fermilab with an integrated luminosity of 4.8 fb$^{-1}$. We observe events consistent with background expectation and calculate upper limits on the $b'$ pair production cross section ($\sigma_{b\bar{b'}}\lesssim 30$ fb for $m_{b'}>$375 GeV/$c^2$) and exclude $m_{b'}<372$ \gevcc at 95% confidence level.Comment: For submission to PR

First Measurement of the Angular Coefficients of Drell-Yan e(+)e(-) Pairs in the Z Mass Region from p(p)over-bar Collisions at root s=1.96 TeV

We report on the first measurement of the angular distributions of final state electrons in p (p) over bar -> gamma*/Z -> e(+)e(-) + X events produced in the Z boson mass region at root s = 1.96 TeV. The data sample collected by the CDF II detector for this result corresponds to 2.1 fb(-1) of integrated luminosity. The angular distributions are studied as a function of the transverse momentum of the electron-positron pair and show good agreement with the Lam-Tung relation, consistent with a spin-1 description of the gluon, and demonstrate that, at high values of the transverse momentum, Z bosons are produced via quark-antiquark annihilation and quark-gluon Compton processes

First Search for Multijet Resonances in root s=1.96 TeV p(p)over-bar Collisions

We present the first model independent search for three-jet hadronic resonances within multijet events in root s = 1.96 TeV p (p) over bar collisions at the Fermilab Tevatron using the CDF II detector. Pair production of supersymmetric gluinos and squarks with hadronic R-parity violating decays is employed as an example of a new physics benchmark for this signature. Selection criteria based on the kinematic properties of an ensemble of jet combinations within each event help to extract signal from copious QCD background. No significant excess outside the top quark mass window is observed in data with an integrated luminosity of 3.2 fb(-1). We place 95% confidence level limits on the production cross section sigma(p (p) over bar -> XX') X BR((g) over tilde(g) over tilde -> 3 jet + 3 jet) where X, X' = (g) over tilde, (q) over tilde, or (sic), with (q) over tilde, (sic) -> (g) over tilde + jet, as a function of gluino mass, in the range of 77 GeV/c(2) to 240 GeV/c(2)