Hepatic excretory function in sepsis: implications from biophotonic analysis of transcellular xenobiotic transport in a rodent model

INTRODUCTION: Hepatobiliary elimination of endo- and xenobiotics is affected by different variables including hepatic perfusion, hepatocellular energy state and functional integrity of transporter proteins, all of which are altered during sepsis. A particular impairment of hepatocellular transport at the canalicular pole resulting in an accumulation of potentially hepatotoxic compounds would have major implications for critical care pharmacology and diagnostics. METHODS: Hepatic transcellular transport, that is, uptake and hepatobiliary excretion, was studied in a rodent model of severe polymicrobial sepsis by two different biophotonic techniques to obtain insights into the handling of potentially toxic endo- and xenobiotics in sepsis. Direct and indirect in vivo imaging of the liver was performed by intravital multifluorescence microscopy and non-invasive whole-body near-infrared (NIRF) imaging after administration of two different, primarily hepatobiliary excreted xenobiotics, the organic anionic dyes indocyanine green (ICG) and DY635. Subsequent quantitative data analysis enabled assessment of hepatic uptake and fate of these model substrates under conditions of sepsis. RESULTS: Fifteen hours after sepsis induction, animals displayed clinical and laboratory signs of multiple organ dysfunction, including moderate liver injury, cholestasis and an impairment of sinusoidal perfusion. With respect to hepatocellular transport of both dyes, excretion into bile was significantly delayed for both dyes and resulted in net accumulation of potentially cytotoxic xenobiotics in the liver parenchyma (for example, specific dye fluorescence in liver at 30 minutes in sham versus sepsis: ICG: 75% versus 89%; DY635 20% versus 40% of maximum fluorescence; P < 0.05). Transcutaneous assessment of ICG fluorescence by whole body NIRF imaging revealed a significant increase of ICG fluorescence from the 30th minute on in the bowel region of the abdomen in sham but not in septic animals, confirming a sepsis-associated failure of canalicular excretion. CONCLUSIONS: Hepatocytes accumulate organic anions under conditions of sepsis-associated organ dysfunction. These results have potential implications for monitoring liver function, critical care pharmacology and the understanding of drug-induced liver injury in the critically ill

Do Aspirin and Other Antiplatelet Drugs Reduce the Mortality in Critically Ill Patients?

Platelet activation has been implicated in microvascular thrombosis and organ failure in critically ill patients. In the first part the present paper summarises important data on the role of platelets in systemic inflammation and sepsis as well as on the beneficial effects of antiplatelet drugs in animal models of sepsis. In the second part the data of retrospective and prospective observational clinical studies on the effect of aspirin and other antiplatelet drugs in critically ill patients are reviewed. All of these studies have shown that aspirin and other antiplatelet drugs may reduce organ failure and mortality in these patients, even in case of high bleeding risk. From the data reviewed here interventional prospective trials are needed to test whether aspirin and other antiplatelet drugs might offer a novel therapeutic option to prevent organ failure in critically ill patients

Properties of M31. II: A Cepheid disk sample derived from the first year of PS1 PAndromeda data

We present a sample of Cepheid variable stars towards M31 based on the first year of regular M31 observations of the PS1 survey in the r_P1 and i_P1 filters. We describe the selection procedure for Cepheid variable stars from the overall variable source sample and develop an automatic classification scheme using Fourier decomposition and the location of the instability strip. We find 1440 fundamental mode (classical \delta) Cep stars, 126 Cepheids in the first overtone mode, and 147 belonging to the Population II types. 296 Cepheids could not be assigned to one of these classes and 354 Cepheids were found in other surveys. These 2009 Cepheids constitute the largest Cepheid sample in M31 known so far and the full catalog is presented in this paper. We briefly describe the properties of our sample in its spatial distribution throughout the M31 galaxy, in its age properties, and we derive an apparent period-luminosity relation (PLR) in our two bands. The Population I Cepheids nicely follow the dust pattern of the M31 disk, whereas the 147 Type II Cepheids are distributed throughout the halo of M31. We outline the time evolution of the star formation in the major ring found previously and find an age gradient. A comparison of our PLR to previous results indicates a curvature term in the PLR

The Wendelstein Calar Alto Pixellensing Project(WeCAPP): First MACHO Candidates

We report the detection of the first 2 microlensing candidates from the Wendelstein Calar Alto Pixellensing Project (WeCAPP). Both are detected with a high signal-to-noise-ratio and were filtered out from 4.5 mill. pixel light curves using a variety of selection criteria. Here we only consider well-sampled events with timescales of 1 d < t_fwhm < 20 d, high amplitude, and low chi^2 of the microlensing fit. The two-color photometry (R,I) shows that the events are achromatic and that giant stars with colors of (R-I) ~ 1.1 mag in the bulge of M31 have been lensed. The magnification factors are 64 and 10 which are obtained for typical giant luminosities of M_I = -2.5 mag. Both lensing events lasted for only a few days (t_fwhm^GL1 = 1.7 d and t_fwhm^GL2 = 5.4 d). The event GL1 is likely identical with PA-00-S3 reported by the POINT-AGAPE project. Our calculations favor in both cases the possibility that MACHOs in the halo of M31 caused the lensing events. The most probable masses, 0.08 M_sun for GL1 and 0.02 M_sun for GL2, are in the range of the brown dwarf limit of hydrogen burning. Solar mass objects are a factor of two less likely.Comment: Accepted for publication in ApJ Letters (28 Oct 2003), 4 pages, 2 color figures, uses emulateapj styl

Interleukin 20 regulates dendritic cell migration and expression of co-stimulatory molecules

BACKGROUND: Psoriasis is an inflammatory disease characterized by leukocyte skin infiltration. Interestingly, recent works suggest that the migration of dendritic cells (DCs) is abnormal in psoriatic skin. DCs have significant role in regulating the function of T lymphocytes, at least in part influenced by the local environment of cytokines. In psoriatic skin lesions the expression of IL-20 is highly up-regulated. It is unclear if this cytokine has any influence on DCs. METHODS: Here, we investigated the influence of IL-20 in monocyte-derived dendritic cell (MDDCs) in vitro. This work addressed IL-20 effects on DC maturation, receptor expression and signaling. By use of extra cellular matrix components mimicking the skin environment, we also studied the functional effects of IL-20 on the chemotactic migration of DCs. Based on the recent finding that CD18 integrin are shed during migration of myeloid leukocytes, the concentration of these adhesion molecules was measured in MDDCs culture supernatants post migration. RESULTS: Following stimulation with IL-20, immature human MDDCs enhanced the expression of the co-stimulatory molecule CD86, further enabling activation of the p38 MAPK, but not the STAT3, pathway. IL-20 increased the migration of MDDCs in a biphasic response narrowly controlled by the interleukin concentration. A concomitant change in the shedding of CD18 integrins suggested that these adhesion molecules play a role in the migration of the MDDCs through the extracellular matrix layer. CONCLUSION: Taken together, our findings points to a possible, yet subtle, role of IL-20 in DCs migration. The biphasic response suggests that the aberrant IL-20 expression in psoriasis impedes DC migration, which could be a part of the processes that precipitates the dysregulated inflammatory response associated with this disease

Activation of Sphingomyelinase-Ceramide-Pathway in COVID-19 Purposes Its Inhibition for Therapeutic Strategies

Effective treatment strategies for severe coronavirus disease (COVID-19) remain scarce. Hydrolysis of membrane-embedded, inert sphingomyelin by stress responsive sphingomyelinases is a hallmark of adaptive responses and cellular repair. As demonstrated in experimental and observational clinical studies, the transient and stress-triggered release of a sphingomyelinase, SMPD1, into circulation and subsequent ceramide generation provides a promising target for FDA-approved drugs. Here, we report the activation of sphingomyelinase-ceramide pathway in 23 intensive care patients with severe COVID-19. We observed an increase of circulating activity of sphingomyelinase with subsequent derangement of sphingolipids in serum lipoproteins and from red blood cells (RBC). Consistent with increased ceramide levels derived from the inert membrane constituent sphingomyelin, increased activity of acid sphingomyelinase (ASM) accurately distinguished the patient cohort undergoing intensive care from healthy controls. Positive correlational analyses with biomarkers of severe clinical phenotype support the concept of an essential pathophysiological role of ASM in the course of SARS-CoV-2 infection as well as of a promising role for functional inhibition with anti-inflammatory agents in SARS-CoV-2 infection as also proposed in independent observational studies. We conclude that large-sized multicenter, interventional trials are now needed to evaluate the potential benefit of functional inhibition of this sphingomyelinase in critically ill patients with COVID-19