Leukocyte trafficking in alveoli and airway passages

Many pulmonary diseases preferentially affect the large airways or the alveoli. Although the mechanisms are often particular to each disease process, site-specific differences in leukocyte trafficking and the regulation of inflammation also occur. Differences in the process of margination, sequestration, adhesion, and migration occur that can be attributed to differences in anatomy, hemodynamics, and the expression of proteins. The large airways are nourished by the bronchial circulation, whereas the pulmonary circulation feeds the distal lung parenchyma. The presence of different cell types in large airways from those in alveoli might contribute to site-specific differences in the molecular regulation of the inflammatory process

Dissociation by steroids of eosinophilic inflammation from airway hyperresponsiveness in murine airways

BACKGROUND: The link between eosinophils and the development of airway hyperresponsiveness (AHR) in asthma is still controversial. This question was assessed in a murine model of asthma in which we performed a dose ranging study to establish whether the dose of steroid needed to inhibit the eosinophil infiltration correlated with that needed to block AHR. METHODS: The sensitised BALB/c mice were dosed with vehicle or dexamethasone (0.01–3 mg/kg) 2 hours before and 6 hours after each challenge (once daily for 6 days) and 2 hours before AHR determination by whole-body plethysmography. At 30 minutes after the AHR to aerosolised methacholine the mice were lavaged and differential white cell counts were determined. Challenging with antigen caused a significant increase in eosinophils in the bronchoalveolar lavage (BAL) fluid and lung tissue, and increased AHR. RESULTS: Dexamethasone reduced BAL and lung tissue eosinophilia (ED(50 )values of 0.06 and 0.08 mg/kg, respectively), whereas a higher dose was needed to block AHR (ED(50 )of 0.32 mg/kg at 3 mg/ml methacholine. Dissociation was observed between the dose of steroid needed to affect AHR in comparison with eosinophilia and suggests that AHR is not a direct consequence of eosinophilia. CONCLUSION: This novel pharmacological approach has revealed a clear dissociation between eosinophilia and AHR by using steroids that are the mainstay of asthma therapy. These data suggest that eosinophilia is not associated with AHR and questions the rationale that many pharmaceutical companies are adopting in developing low-molecular-mass compounds that target eosinophil activation/recruitment for the treatment of asthma

Runx1 Loss Minimally Impacts Long-Term Hematopoietic Stem Cells

RUNX1 encodes a DNA binding subunit of the core-binding transcription factors and is frequently mutated in acute leukemia, therapy-related leukemia, myelodysplastic syndrome, and chronic myelomonocytic leukemia. Mutations in RUNX1 are thought to confer upon hematopoietic stem cells (HSCs) a pre-leukemic state, but the fundamental properties of Runx1 deficient pre-leukemic HSCs are not well defined. Here we show that Runx1 deficiency decreases both apoptosis and proliferation, but only minimally impacts the frequency of long term repopulating HSCs (LT-HSCs). It has been variously reported that Runx1 loss increases LT-HSC numbers, decreases LT-HSC numbers, or causes age-related HSC exhaustion. We attempt to resolve these discrepancies by showing that Runx1 deficiency alters the expression of several key HSC markers, and that the number of functional LT-HSCs varies depending on the criteria used to score them. Finally, we identify genes and pathways, including the cell cycle and p53 pathways that are dysregulated in Runx1 deficient HSCs

Ambient noise tomography of the Pyrenees and the surrounding regions: Inversion for a 3-D Vs model in the presence of a very heterogeneous crust

The lithospheric architecture of the Pyrenees is still uncertain and highly debated. Here, we provide new constraints from a high-resolution 3-D S-wave velocity model of the Pyrenees and the adjacent foreland basins. This model is obtained from ambient noise tomography on records of temporary and permanent seismic arrays installed in southwestern France and northern Spain. We first computed group velocity maps for Rayleigh waves in the 5 to 55 s period range using noise correlation stacks at 1500-8500 station pairs. As the crust is very heterogeneous, poor results were obtained using a single starting model in a linearized inversion of group velocity dispersion curves for the shear wave structure. We therefore built a starting model for each grid node by full exploration of the model space. The resulting 3-D shear wave velocity model is compared to data from previous geophysical studies as a validation test. Despite the poor sensitivity of surface waves to seismic discontinuities, the geometry of the top of the basement and the Moho depth are retrieved well, except along the Cantabrian coast. Major reflectors of the ECORS deep seismic sounding profiles in the central and western Pyrenees coincide with sharp velocity gradients in our velocity model.We retrieve the difference between the thicker Iberian crust and the thinner European crust, the presence of low-velocity material of the Iberian crust underthrust beneath the European crust in the central Pyrenees, and the structural dissymmetry between the South Pyrenean Zone and the North Pyrenean Zone at the shallow crustal level. In the Labourd-Mauléon-Arzacq region (western Pyrenees), there is a high S-wave velocity anomaly at 20-30 km in depth, which might explain the positive Bouguer anomaly of the Labourd Massif. This high-velocity lower crust, which is also detected beneath the Parentis area, might be an imprint of the Albian-Aptian rifting phase. The southeastern part of the Massif Central has an unusual velocity structure, with a very shallowMoho (21-25 km) above an uppermost mantle with anomalously low shear wave velocity.We thank all participants in the fieldwork, and the municipalities and landlords that hosted a PYROPE temporary station. We also acknowledge SISMOB, the French seismic mobile pool (a com- ponent of the RESIF Research Facility), for providing us with the seismological instrumentation for the temporary deployments. We used data from the FR and RD (RESIF), G (Geoscope) and CA (‘Institut Cartogr ` afic i Geol ` ogic de Catalunya’) permanent net- works. RESIF ( http://portal.resif.fr/ ) is a national Research Infras- tructure, recognized as such by the French Ministry of Higher Education and Research. RESIF is managed by the RESIF Con- sortium, composed of 18 Research Institutions and Universities in France. RESIF additionally supported by a public grant overseen by the French National Research Agency (ANR) as part of the «Investissements d’Avenir» program (reference: ANR-11-EQPX- 0040)andtheFrenchMinistryofEcology,SustainableDevelopment and Energy. The PYROPE experiment was supported by the French Research Agency “ANR blanc” program (project PYROPE, ANR-09-BLAN-0229). This is a contribution of the Team Consolider-Ingenio 2010 TOPO-IBERIA (CSD2006–00041). CPeer reviewe

Lipid pattern in middle-aged inhabitants of the Lower Silesian region of Poland. The PURE Poland sub-study

Introduction. A decreased serum high density lipoprotein-cholesterol (HDL-C) is a strong predictor of cardiovascular risk. However, total HDL is a very dynamic, changeable fraction, and does not perform the function of atherosclerosis markers. In the presented study, the pattern of serum lipids, including HDL-C subclasses (HDL2- and HDL3-cholesterol), in a middleaged Polish Lower Silesia population was defined. Materials and method. A group of 746 males and 1,298 females, aged 35–70, were investigated. All subjects were participants in the PURE study. Mean serum lipid levels were determined for groups selected on the basis of gender, age, cigarette smoking, drinking alcohol and place of residence (urban/rural area). The data were analyzed using STATISTICA 6.0 PL. Results. In multiple linear regression models, age was the most important independent and consistent predictor of total cholesterol (TC) and LDL cholesterol (LDL-C). The prevalence of low HDL-C (threshold 40 mg/dL in males, 50 mg/dL in females) was 16.5% for males and 22.6% for females. This gender-conditioned difference in the prevalence of low HDL-C was greater in rural (20.0% vs. 30.9%, respectively, in males and females) in comparison to urban (14.4% vs. 17.1%) areas. The lipid pattern was significantly worse in rural than in urban females. Female rural inhabitants showed higher triglycerides (TG) and lower HDL cholesterol (total and contained in subclasses HDL2 and HDL3). Simultaneously, a higher BMI, higher percent of smokers and drinkers and lower age of smoking female rural inhabitants in comparison to urban females were estimated. In the total population, cigarette smoking or drinking alcohol were associated with significant increases in TC, LDL-C and TG, also with decreased HDL-C (smoking) or HDL2-C (drinking). Two-way analysis of variance showed the existence of interaction between these risk factors in their influence on HDL-C and HDL3-C. Conclusion. In the middle-aged population of the Lower Silesian region in Poland the place of residence (urban/rural area) had a significant impact on the lipid pattern. This pattern is more atherogenic in rural women than in urban women