8,738 research outputs found

    Circulating microvesicles as mediators of acute pulmonary vascular inflammation

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    Acute lung injury (ALI) resulting from remote ‘indirect’ causes is a major problem in sepsis and systemic inflammatory response syndrome (SIRS) but the underlying mechanisms are poorly understood. Circulating microvesicles (MVs) have been implicated as long-range mediators of vascular inflammation and their role as biomarkers in sepsis and SIRS has been widely investigated in clinical studies in recent years. However, the in vivo functional roles of MVs in sepsis and ALI have received less attention. Specifically, the role of in vivo MVs in the development of sepsis/SIRS-induced indirect ALI has not been previously evaluated. We hypothesised that circulating microvesicles (MVs) play a crucial role in propagating inflammation to the lungs, contributing to the development of pulmonary vascular inflammation in indirect ALI. The overall aims of this project were to: 1) evaluate MV uptake by pulmonary vascular cells and the mechanisms involved, 2) characterise the intravascular production of MVs in animal models of sepsis and sterile extrapulmonary organ injury, and 3) identify the contribution of in vivo-derived circulating MVs to the development of indirect ALI. The major findings of this work were that during sub-clinical endotoxaemia in mice, lung-marginated Ly6Chigh monocytes become a major target for circulating MV uptake via a phosphatidylserine receptor mechanism1. In mouse models of sepsis and extrapulmonary organ injury, neutrophil- and monocyte-derived MVs were the predominant MV subtypes being produced during endotoxaemia, while platelet- and endothelial-derived MVs were predominant during kidney ischaemia reperfusion injury. When MVs obtained from plasmas of endotoxaemic mice were adoptively transferred to isolated perfused lungs (IPLs), they induced significant increases in lung oedema. Depletion of intravascular lung monocytes by treatment with clodronate liposomes resulted in the reversal of the oedema, demonstrating the role of monocytes in MV-induced ALI. To investigate the contribution of different circulating MV subtypes, we immunoaffinity isolated myeloid (CD11b+) and platelet (CD41+) MVs from endotoxaemic mouse plasmas and transferred these to the IPL. We found that myeloid-MVs induced significant lung oedema and potent release of soluble mediators, whereas platelet-MVs produced a statistically significant, but much lower level of oedema and negligible release of soluble mediators. In summary, these findings indicate an important role of myeloid-derived MVs, particularly those derived from neutrophils and/or monocytes, and their interaction with lung-marginated monocytes in the pathogenesis of pulmonary vascular inflammation in indirect ALI. Further work to elucidate the specific MV molecular effectors mechanism involved will facilitate an enhanced understanding of ALI pathobiology.Open Acces

    A new method for determining small earthquake source parameters using short-period P waves

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    We developed a new technique of inverting short-period (0.5–2 Hz) P waveforms for determining small earthquake (M <3.5) focal mechanisms and moments, where magnitude ~4 events with known source mechanisms are used to calibrate the "unmodeled" structural effect. The calibration is based on a waveform cluster analysis, where we show that clustered events of different sizes, for example, M ~4 versus M ~2, display similar signals in the short-period (SP, 0.5–2 Hz) frequency band, implying propagational stability. Since both M ~4 and M ~2 events have corner frequencies higher than 2 Hz, they can be treated as point sources, and the "unmodeled" structural effect on the SP P waves can be derived from the magnitude 4 events with known source mechanisms. Similarly, well-determined magnitude 2’s can provide calibration for studying even smaller events at higher frequencies, for example, 2–8 Hz. In particular, we find that the "unmodeled" structural effect on SP P waves is mainly an amplitude discrepancy between data and 1D synthetics. The simple function of "amplitude amplification factor" (AAF) defined as the amplitude ratio between data and synthetics provides useful calibration, in that the AAFs derived from different clustered events appear consistent, hence stable and mechanism independent. We take a grid-search approach to determine source mechanisms by minimizing the misfit error between corrected data and synthetics of SP P waves. The validation tests with calibration events demonstrate the importance and usefulness of the AAF corrections in recovering reliable results. We introduce the method with the 2003 Big Bear sequence. However, it applies equally well to other source regions in southern California, because we have shown that the mechanism independence and stability of the AAFs for source regions of 10 km by 10 km are typical. By definition, the AAFs contain the effects from the station site, the path, and crustal scattering. Although isolating their contributions proves difficult, the mechanism independence and stability of the AAFs suggest that they are mainly controlled by the near-receiver structure. Moreover, the ratios between the AAFs for the vertical and radial components from various events at different locations appear consistent, suggesting that these AAF(v)/AAF(r) ratios might be simple functions of site conditions. In this study, we obtained the focal mechanisms and moments for 92 Big Bear events with M_L down to 2.0. The focal planes correlate well with the seismicity patterns, while containing abundant finer-scale fault complexity. We find a linear relationship between log(M_0) and M_L, that is, log(M_0) = 1.12M_L + 17.29, which explains all the data points spanning three orders of magnitude (2.0 < M_L < 5.5)
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