STC3141 improves acute lung injury through neutralizing circulating histone in rat with experimentally-induced acute respiratory distress syndrome

Background: Acute respiratory distress syndrome (ARDS) remains a challenge because of its high morbidity and mortality. Circulation histones levels in ARDS patients were correlated to disease severity and mortality. This study examined the impact of histone neutralization in a rat model of acute lung injury (ALI) induced by a lipopolysaccharide (LPS) double-hit.Methods: Sixty-eight male Sprague-Dawley rats were randomized to sham (N = 8, received saline only) or LPS (N = 60). The LPS double-hit consisted of a 0.8 mg/kg intraperitoneal injection followed after 16 h by 5 mg/kg intra-tracheal nebulized LPS. The LPS group was then randomized into five groups: LPS only; LPS +5, 25, or 100 mg/kg intravenous STC3141 every 8 h (LPS + L, LPS + M, LPS + H, respectively); or LPS + intraperitoneal dexamethasone 2.5 mg/kg every 24 h for 56 h (LPS + D). The animals were observed for 72 h.Results: LPS animals developed ALI as suggested by lower oxygenation, lung edema formation, and histological changes compared to the sham animals. Compared to the LPS group, LPS + H and +D groups had significantly lower circulating histone levels and lung wet-to-dry ratio, and the LPS + D group also had lower BALF histone concentrations; the blood neutrophils and platelets counts in LPS + D group did not change, meanwhile, the LPS + L, +M and +H groups had significantly lower neutrophil counts and higher platelet counts in the blood; the total number of BALF WBC, platelet counts, MPO and H3 were significantly lower in the LPS + L, +M, +H and +D groups than in the LPS only group; and the degree of inflammation was significantly less in the LPS + L, +M, +H and +D groups, moreover, inflammation in the LPS + L, +M and +H animals showed a dose-dependent response; finally, the LPS + L, +M, +H and +D groups had improved oxygenation compared to the LPS group, and there were no statistical differences in PCO2 or pH among groups. All animals survived.Conclusion: Neutralization of histone using STC3141, especially at high dose, had similar therapeutic effects to dexamethasone in this LPS double-hit rat ALI model, with significantly decreased circulating histone concentration, improved acute lung injury and oxygenation

Adverse Effect of Nano-Silicon Dioxide on Lung Function of Rats with or without Ovalbumin Immunization

BACKGROUND: The great advances of nanomaterials have brought out broad important applications, but their possible nanotoxicity and risks have not been fully understood. It is confirmed that exposure of environmental particulate matter (PM), especially ultrafine PM, are responsible for many lung function impairment and exacerbation of pre-existing lung diseases. However, the adverse effect of nanoparticles on allergic asthma is seldom investigated and the mechanism remains undefined. For the first time, this work investigates the relationship between allergic asthma and nanosized silicon dioxide (nano-SiO₂). METHODOLOGY/PRINCIPAL FINDINGS: Ovalbumin (OVA)-treated and saline-treated control rats were daily intratracheally administered 0.1 ml of 0, 40 and 80 µg/ml nano-SiO₂ solutions, respectively for 30 days. Increased nano-SiO₂ exposure results in adverse changes on inspiratory and expiratory resistance (Ri and Re), but shows insignificant effect on rat lung dynamic compliance (Cldyn). Lung histological observation reveals obvious airway remodeling in 80 µg/ml nano-SiO₂-introduced saline and OVA groups, but the latter is worse. Additionally, increased nano-SiO₂ exposure also leads to more severe inflammation. With increasing nano-SiO₂ exposure, IL-4 in lung homogenate increases and IFN-γ shows a reverse but insignificant change. Moreover, at a same nano-SiO₂ exposure concentration, OVA-treated rats exhibit higher (significant) IL-4 and lower (not significant) IFN-γ compared with the saline-treated rats. The percentages of eosinophil display an unexpected result, in which higher exposure results lower eosinophil percentages. CONCLUSIONS/SIGNIFICANCE: This was a preliminary study which for the first time involved the effect of nano-SiO₂ to OVA induced rat asthma model. The results suggested that intratracheal administration of nano-SiO₂ could lead to the airway hyperresponsiveness (AHR) and the airway remolding with or without OVA immunization. This occurrence may be due to the Th1/Th2 cytokine imbalance accelerated by the nano-SiO₂ through increasing the tissue IL-4 production

Real-time Monitoring for the Next Core-Collapse Supernova in JUNO

Core-collapse supernova (CCSN) is one of the most energetic astrophysical events in the Universe. The early and prompt detection of neutrinos before (pre-SN) and during the SN burst is a unique opportunity to realize the multi-messenger observation of the CCSN events. In this work, we describe the monitoring concept and present the sensitivity of the system to the pre-SN and SN neutrinos at the Jiangmen Underground Neutrino Observatory (JUNO), which is a 20 kton liquid scintillator detector under construction in South China. The real-time monitoring system is designed with both the prompt monitors on the electronic board and online monitors at the data acquisition stage, in order to ensure both the alert speed and alert coverage of progenitor stars. By assuming a false alert rate of 1 per year, this monitoring system can be sensitive to the pre-SN neutrinos up to the distance of about 1.6 (0.9) kpc and SN neutrinos up to about 370 (360) kpc for a progenitor mass of 30$M_{\odot}$ for the case of normal (inverted) mass ordering. The pointing ability of the CCSN is evaluated by using the accumulated event anisotropy of the inverse beta decay interactions from pre-SN or SN neutrinos, which, along with the early alert, can play important roles for the followup multi-messenger observations of the next Galactic or nearby extragalactic CCSN.Comment: 24 pages, 9 figure

Change in airway inflammatory markers in Danish energy plant workers during a working week

[b]Introduction.[/b] It is well known that exposure to organic dust can cause adverse respiratory effect. The pathogen-associated molecular patterns (PAMPS) in the organic dust, such as endotoxin from Gram-negative bacteria cell wall and fungal components, can trigger the release of cytokine (e.g. Interleukin 1β (IL-1β)) and chemokine (e.g. Interleukin 8 (IL-8)) from the immune cells in the airways. [b]Objective.[/b] To evaluate the potential inflammatory effects of organic dust exposure in energy plants in Denmark. [b]Materials and methods[/b]. Nasal lavage (NAL) and exhaled breath condensate (EBC) were sampled at Monday morning (referred to as before work) and again at Thursday afternoon (referred to as after work). NAL IL-8, EBC pH, IL-1β concentration were measured. Personal exposure to endotoxin and dust was calculated from time spent on different tasks and measured average work area exposures. [b]Results.[/b] Before work, workers from biofuel plants had a higher IL-1β and IL-8 concentration compared to conventional fuel plants (control group). Specifically, the IL-1β level of moderately and most exposed group, and IL-8 level of the least exposed group were higher compared to the control group. The changes of IL-1β, pH and IL-8 during a work week were not significant. Workers with rhinitis had a lower percentage change of IL-8 compared to healthy workers. [b]Conclusions[/b]. An increased level of EBC IL-1β in biofuel energy plant workers before work indicated a chronic or sub-chronic inflammation. The percentage change of IL-8 was lower in workers with rhinitis compared to healthy workers

IFN-γ concentrations.

<p>(A) Saline treatment plus 0 µg/ml nano-SiO₂ exposure. (B) Saline treatment plus 40 µg/ml nano-SiO₂ exposure. (C) Saline treatment plus 80 µg/ml nano-SiO₂ exposure. (D) OVA treatment plus 0 µg/ml nano-SiO₂ exposure. (E) OVA treatment plus 40 µg/ml nano-SiO₂ exposure. (F) OVA treatment plus 80 µg/ml nano-SiO₂ exposure. No significant difference among groups.</p

IL-4 concentrations.

<p>(A) Saline treatment plus 0 µg/ml nano-SiO₂ exposure. (B) Saline treatment plus 40 µg/ml nano-SiO₂ exposure. (C) Saline treatment plus 80 µg/ml nano-SiO₂ exposure. (D) OVA treatment plus 0 µg/ml nano-SiO₂ exposure. (E) OVA treatment plus 40 µg/ml nano-SiO₂ exposure. (F) OVA treatment plus 80 µg/ml nano-SiO₂ exposure. ** p<0.01, compared with (A). # p<0.05, compared with (D). <b>+</b> p<0.05, <b>++</b> p<0.01, comparisons between the same exposure concentration groups.</p

Study protocol.

<p>(A) Saline treatment plus 0 µg/ml nano-SiO₂ exposure. (B) Saline treatment plus 40 µg/ml nano-SiO₂ exposure. (C) Saline treatment plus 80 µg/ml nano-SiO₂ exposure. (D) OVA treatment plus 0 µg/ml nano-SiO₂ exposure. (E) OVA treatment plus 40 µg/ml nano-SiO₂ exposure. (F) OVA treatment plus 80 µg/ml nano-SiO₂ exposure. All rats were sacrificed on day 38.</p

Representative histological images of H&E stained rats' lung.

<p>(A) Saline treatment plus 0 µg/ml nano-SiO₂ exposure. (B) Saline treatment plus 40 µg/ml nano-SiO₂ exposure. (C) Saline treatment plus 80 µg/ml nano-SiO₂ exposure. (D) OVA treatment plus 0 µg/ml nano-SiO₂ exposure. (E) OVA treatment plus 40 µg/ml nano-SiO₂ exposure. (F) OVA treatment plus 80 µg/ml nano-SiO₂ exposure. Slices microscopically examined at original magnification of 20× (Leica DM 4000B, Germany).</p