Publications by authors named "Derek W Gilroy"

82 Publications

Intradermal lipopolysaccharide challenge as an acute in vivo inflammatory model in healthy volunteers.

Br J Clin Pharmacol 2021 Jul 22. Epub 2021 Jul 22.

Centre for Human Drug Research, Leiden, the Netherlands.

Aims: Whereas intravenous administration of Toll-like receptor 4 ligand lipopolysaccharide (LPS) to human volunteers is frequently used in clinical pharmacology studies, systemic use of LPS has practical limitations. We aimed to characterize the intradermal LPS response in healthy volunteers, and as such qualify the method as local inflammation model for clinical pharmacology studies.

Methods: Eighteen healthy male volunteers received 2 or 4 intradermal 10 ng LPS injections and 1 saline injection on the forearms. The LPS response was evaluated by noninvasive (perfusion, skin temperature and erythema) and invasive assessments (cellular and cytokine responses) in skin biopsy and blister exudate.

Results: LPS elicited a visible response and returned to baseline at 48 hours. Erythema, perfusion and temperature were statistically significant (P < .0001) over a 24-hour time course compared to saline. The protein response was dominated by an acute interleukin (IL)-6, IL-8 and tumour necrosis factor response followed by IL-1β, IL-10 and interferon-γ. The cellular response consisted of an acute neutrophil influx followed by different monocyte subsets and dendritic cells.

Discussion: Intradermal LPS administration in humans causes an acute, localized and transient inflammatory reaction that is well-tolerated by healthy volunteers. This may be a valuable inflammation model for evaluating the pharmacological activity of anti-inflammatory investigational compounds in proof of pharmacology studies.
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http://dx.doi.org/10.1111/bcp.14999DOI Listing
July 2021

A Randomized Trial of Albumin Infusions in Hospitalized Patients with Cirrhosis.

N Engl J Med 2021 03;384(9):808-817

From the Institute for Liver and Digestive Health (L.C., N.B.S., A.O.), the Comprehensive Clinical Trials Unit (N.F.), and the Division of Medicine, University College London (D.W.G.), Barts and the London School of Medicine and Dentistry, Queen Mary University of London (Y.K.), London, the Glasgow Royal Infirmary and the University of Glagow, Glasgow (E.F.), the National Institute for Health Research Nottingham Biomedical Research Centre at Nottingham University Hospitals NHS Trust and the University of Nottingham, Queens Medical Centre, Nottingham (S.D.R.), the Mid and South Essex NHS Foundation Trust and the Basildon and Thurrock University Hospitals NHS Foundation Trust, Basildon (G.W.), and the Bristol Royal Infirmary, Bristol (A.J.P.) - all in the United Kingdom.

Background: Infection and increased systemic inflammation cause organ dysfunction and death in patients with decompensated cirrhosis. Preclinical studies provide support for an antiinflammatory role of albumin, but confirmatory large-scale clinical trials are lacking. Whether targeting a serum albumin level of 30 g per liter or greater in these patients with repeated daily infusions of 20% human albumin solution, as compared with standard care, would reduce the incidences of infection, kidney dysfunction, and death is unknown.

Methods: We conducted a randomized, multicenter, open-label, parallel-group trial involving hospitalized patients with decompensated cirrhosis who had a serum albumin level of less than 30 g per liter at enrollment. Patients were randomly assigned to receive either targeted 20% human albumin solution for up to 14 days or until discharge, whichever came first, or standard care. Treatment commenced within 3 days after admission. The composite primary end point was new infection, kidney dysfunction, or death between days 3 and 15 after the initiation of treatment.

Results: A total of 777 patients underwent randomization, and alcohol was reported to be a cause of cirrhosis in most of these patients. A median total infusion of albumin of 200 g (interquartile range, 140 to 280) per patient was administered to the targeted albumin group (increasing the albumin level to ≥30 g per liter), as compared with a median of 20 g (interquartile range, 0 to 120) per patient administered to the standard-care group (adjusted mean difference, 143 g; 95% confidence interval [CI], 127 to 158.2). The percentage of patients with a primary end-point event did not differ significantly between the targeted albumin group (113 of 380 patients [29.7%]) and the standard-care group (120 of 397 patients [30.2%]) (adjusted odds ratio, 0.98; 95% CI, 0.71 to 1.33; P = 0.87). A time-to-event analysis in which data were censored at the time of discharge or at day 15 also showed no significant between-group difference (hazard ratio, 1.04; 95% CI, 0.81 to 1.35). More severe or life-threatening serious adverse events occurred in the albumin group than in the standard-care group.

Conclusions: In patients hospitalized with decompensated cirrhosis, albumin infusions to increase the albumin level to a target of 30 g per liter or more was not more beneficial than the current standard care in the United Kingdom. (Funded by the Health Innovation Challenge Fund; ATTIRE EudraCT number, 2014-002300-24; ISRCT number, N14174793.).
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http://dx.doi.org/10.1056/NEJMoa2022166DOI Listing
March 2021

Treating exuberant, non-resolving inflammation in the lung; Implications for acute respiratory distress syndrome and COVID-19.

Pharmacol Ther 2021 05 11;221:107745. Epub 2020 Nov 11.

Division of Medicine, University College London, London, UK.

While COVID-19, the disease driven by SARS-CoV-2 has ignited interest in the host immune response to this infection, it has also highlighted the lack of treatment options for the damaging inflammatory responses driven by pathogens that precipitate the acute respiratory distress syndrome (ARDS). With the global prevalence of SARS-CoV-2 and the likelihood of a second winter spike alongside seasonal flu, the need for effective and targeted anti-inflammatory agents is even more pressing. Here we discuss the aetiology of COVID-19 and the common signalling pathways driven by SARS-CoV-2, namely p38 MAP kinase. We highlight that p38 MAP kinase becomes elevated with increasing age, thereby driving many of the inflammatory pathways that precipitate death in old people with the added drawback of impairing vaccine efficacy in this susceptible age group. Finally, we review drugs available to inhibit p38 MAP kinase, their risks-versus-benefits as well as suggested dosing regimen to combat over-exuberant innate immune responses and potentially reverse vaccine inefficacy in older patients.
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http://dx.doi.org/10.1016/j.pharmthera.2020.107745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657264PMC
May 2021

Aging immunity may exacerbate COVID-19.

Science 2020 07;369(6501):256-257

Division of Medicine, The Rayne Building, University College London, 5 University Street, London, UK.

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http://dx.doi.org/10.1126/science.abb0762DOI Listing
July 2020

Publisher Correction: Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly.

Nat Immunol 2020 06;21(6):696

Division of Medicine, University College London, London, UK.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41590-020-0686-5DOI Listing
June 2020

Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly.

Nat Immunol 2020 06 6;21(6):615-625. Epub 2020 Apr 6.

Division of Medicine, University College London, London, UK.

Increasing age alters innate immune-mediated responses; however, the mechanisms underpinning these changes in humans are not fully understood. Using a human dermal model of acute inflammation, we found that, although inflammatory onset is similar between young and elderly individuals, the resolution phase was substantially impaired in elderly individuals. This arose from a reduction in T cell immunoglobulin mucin receptor-4 (TIM-4), a phosphatidylserine receptor expressed on macrophages that enables the engulfment of apoptotic bodies, so-called efferocytosis. Reduced TIM-4 in elderly individuals was caused by an elevation in macrophage p38 mitogen-activated protein kinase (MAPK) activity. Administering an orally active p38 inhibitor to elderly individuals rescued TIM-4 expression, cleared apoptotic bodies and restored a macrophage resolution phenotype. Thus, inhibiting p38 in elderly individuals rejuvenated their resolution response to be more similar to that of younger people. This is the first resolution defect identified in humans that has been successfully reversed, thereby highlighting the tractability of targeting pro-resolution biology to treat diseases driven by chronic inflammation.
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http://dx.doi.org/10.1038/s41590-020-0646-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983074PMC
June 2020

Sestrins induce natural killer function in senescent-like CD8 T cells.

Nat Immunol 2020 06 30;21(6):684-694. Epub 2020 Mar 30.

Division of Infection and Immunity, University College London, London, UK.

Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8 T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27CD28CD8 T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands. Immunoprecipitation and imaging cytometry indicated that the NKG2D-DAP12 complex was associated with sestrin 2. The genetic inhibition of sestrin 2 resulted in decreased expression of NKG2D and DAP12 and restored TCR signaling in senescent-like CD27CD28CD8 T cells. Therefore, during aging, sestrins induce the reprogramming of non-proliferative senescent-like CD27CD28CD8 T cells to acquire a broad-spectrum, innate-like killing activity.
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http://dx.doi.org/10.1038/s41590-020-0643-3DOI Listing
June 2020

Chronic inflammation in the etiology of disease across the life span.

Nat Med 2019 12 5;25(12):1822-1832. Epub 2019 Dec 5.

Cousins Center for Psychoneuroimmunology and Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA.

Although intermittent increases in inflammation are critical for survival during physical injury and infection, recent research has revealed that certain social, environmental and lifestyle factors can promote systemic chronic inflammation (SCI) that can, in turn, lead to several diseases that collectively represent the leading causes of disability and mortality worldwide, such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease and autoimmune and neurodegenerative disorders. In the present Perspective we describe the multi-level mechanisms underlying SCI and several risk factors that promote this health-damaging phenotype, including infections, physical inactivity, poor diet, environmental and industrial toxicants and psychological stress. Furthermore, we suggest potential strategies for advancing the early diagnosis, prevention and treatment of SCI.
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http://dx.doi.org/10.1038/s41591-019-0675-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147972PMC
December 2019

Is Resolution the End of Inflammation?

Trends Mol Med 2019 03 19;25(3):198-214. Epub 2019 Feb 19.

Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, 5 University Street, University College London, London WC1E 6JF, UK. Electronic address:

Deciphering the origins of chronic inflammatory and autoimmune diseases remains elusive with reliance on therapies aimed at halting inflammation in its tracks. In recent years, an appreciation of targeting pathways by which inflammation is resolved has begun to rouse interest. Resolution of inflammation is driven by a complex set of mediators that regulate cellular events required to clear inflammatory cells from sites of infection or injury to restore tissue function. However, recent studies suggest that resolution is not the end of innate mediated immune responses to infection/injury. There is further immunological activity occurring after the resolution cascade is complete that alters the immune physiology of tissues, redefining what was once termed restorative homeostasis as adapted homeostasis.
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http://dx.doi.org/10.1016/j.molmed.2019.01.006DOI Listing
March 2019

Lipid mediators in immune regulation and resolution.

Br J Pharmacol 2019 04 1;176(8):1009-1023. Epub 2019 Mar 1.

Comparative Biological Sciences, Royal Veterinary College, University of London, London, UK.

We are all too familiar with the events that follow a bee sting-heat, redness, swelling, and pain. These are Celsus' four cardinal signs of inflammation that are driven by very well-defined signals and hormones. In fact, targeting the factors that drive this onset phase is the basis upon which most current anti-inflammatory therapies were developed. We are also very well aware that within a few hours, these cardinal signs normally disappear. In other words, inflammation resolves. When it does not, inflammation persists, resulting in damaging chronic conditions. While inflammatory onset is actively driven, so also is its resolution-years of research have identified novel internal counter-regulatory signals that work together to switch off inflammation. Among these signals, lipids are potent signalling molecules that regulate an array of immune responses including vascular hyper reactivity and pain, as well as leukocyte trafficking and clearance, so-called resolution. Here, we collate bioactive lipid research to date and summarize the major pathways involved in their biosynthesis and their role in inflammation, as well as resolution. LINKED ARTICLES: This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc.
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http://dx.doi.org/10.1111/bph.14587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451072PMC
April 2019

Pro-resolving mediators promote resolution in a human skin model of UV-killed Escherichia coli-driven acute inflammation.

JCI Insight 2018 03 22;3(6). Epub 2018 Mar 22.

Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London, United Kingdom.

While the treatment of inflammatory disorders is generally based on inhibiting factors that drive onset of inflammation, these therapies can compromise healing (NSAIDs) or dampen immunity against infections (biologics). In search of new antiinflammatories, efforts have focused on harnessing endogenous pathways that drive resolution of inflammation for therapeutic gain. Identification of specialized pro-resolving mediators (SPMs) (lipoxins, resolvins, protectins, maresins) as effector molecules of resolution has shown promise in this regard. However, their action on inflammatory resolution in humans is unknown. Here, we demonstrate using a model of UV-killed Escherichia coli-triggered skin inflammation that SPMs are biosynthesized at the local site at the start of resolution, coinciding with the expression of receptors that transduce their actions. These include receptors for lipoxin A4 (ALX/FPR2), resolvin E1 (ChemR23), resolvin D2 (GPR18), and resolvin D1 (GPR32) that were differentially expressed on the endothelium and infiltrating leukocytes. Administering SPMs into the inflamed site 4 hours after bacterial injection caused a reduction in PMN numbers over the ensuing 6 hours, the phase of active resolution in this model. These results indicate that in humans, the appearance of SPMs and their receptors is associated with the beginning of inflammatory resolution and that their therapeutic supplementation enhanced the resolution response.
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http://dx.doi.org/10.1172/jci.insight.94463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5926908PMC
March 2018

Potent Anti-Inflammatory and Pro-Resolving Effects of Anabasum in a Human Model of Self-Resolving Acute Inflammation.

Clin Pharmacol Ther 2018 10 30;104(4):675-686. Epub 2018 Jan 30.

Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London, UK.

Anabasum is a synthetic analog of Δ -tetrahydrocannabinol (THC)-11-oic acid that in preclinical models of experimental inflammation exerts potent anti-inflammatory actions with minimal central nervous system (CNS) cannabimimetic activity. Here we used a novel model of acute inflammation driven by i.d. UV-killed E. coli in healthy humans and found that anabasum (5 mg) exerted a potent anti-inflammatory effect equivalent to that of prednisolone in terms of inhibiting neutrophil infiltration, the hallmark of acute inflammation. These effects arose from the inhibition of the neutrophil chemoattractant LTB , while the inhibition of antiphagocytic prostanoids (PGE , TxB , and PGF α) resulted in enhanced clearance of inflammatory stimulus from the injected site. Anabasum at the higher dose of 20 mg possessed the additional properties of triggering the biosynthesis of specialized pro-resolving lipid mediators including LXA , LXB , RvD1, and RvD3. Collectively, we demonstrate for the first time a striking anti-inflammatory and pro-resolution effects of a synthetic analog of THC in healthy humans.
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http://dx.doi.org/10.1002/cpt.980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175297PMC
October 2018

Prolonged immune alteration following resolution of acute inflammation in humans.

PLoS One 2017 26;12(10):e0186964. Epub 2017 Oct 26.

Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London, United Kingdom.

Acute inflammation is an immediate response to infection and injury characterised by the influx of granulocytes followed by phagocytosing mononuclear phagocytes. Provided the antigen is cleared and the immune system of the host is fully functional, the acute inflammatory response will resolve. Until now it is considered that resolution then leads back to homeostasis, the physiological state tissues experienced before inflammation occurred. Using a human model of acute inflammation driven by intradermal UV killed Escherichia coli, we found that bacteria and granulocyte clearance as well as pro-inflammatory cytokine catabolism occurred by 72h. However, following a lag phase of about 4 days there was an increase in numbers of memory T cells and CD163+ macrophage at the post-resolution site up to day 17 as well as increased biosynthesis of cyclooxygenase-derived prostanoids and DHA-derived D series resolvins. Inhibiting post-resolution prostanoids using naproxen showed that numbers of tissue memory CD4 cells were under the endogenous control of PGE2, which exerts its suppressive effects on T cell proliferation via the EP4 receptor. In addition, we re-challenged the post-resolution site with a second injection of E. coli, which when compared to saline controls resulted in primarily a macrophage-driven response with comparatively fewer PMNs; the macrophage-dominated response was reversed by cyclooxygenase inhibition. Re-challenge experiments were also carried out in mice where we obtained similar results as in humans. Therefore, we report that acute inflammatory responses in both humans and rodents do not revert back to homeostasis, but trigger a hitherto unappreciated sequence of immunological events that dictate subsequent immune response to infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186964PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658111PMC
November 2017

Inflammatory Resolution Triggers a Prolonged Phase of Immune Suppression through COX-1/mPGES-1-Derived Prostaglandin E.

Cell Rep 2017 Sep;20(13):3162-3175

Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, 5 University Street, University College London, London WC1E 6JJ, UK. Electronic address:

Acute inflammation is characterized by granulocyte infiltration followed by efferocytosing mononuclear phagocytes, which pave the way for inflammatory resolution. Until now, it was believed that resolution then leads back to homeostasis, the physiological state tissues experience before inflammation occurred. However, we discovered that resolution triggered a prolonged phase of immune suppression mediated by prostanoids. Specifically, once inflammation was switched off, natural killer cells, secreting interferon γ (IFNγ), infiltrated the post-inflamed site. IFNγ upregulated microsomal prostaglandin E synthase-1 (mPGES-1) alongside cyclo-oxygenase (COX-1) within macrophage populations, resulting in sustained prostaglandin (PG)E biosynthesis. Whereas PGE suppressed local innate immunity to bacterial infection, it also inhibited lymphocyte function and generated myeloid-derived suppressor cells, the net effect of which was impaired uptake/presentation of exogenous antigens. Therefore, we have defined a sequence of post-resolution events that dampens the propensity to develop autoimmune responses to endogenous antigens at the cost of local tissue infection.
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http://dx.doi.org/10.1016/j.celrep.2017.08.098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5639146PMC
September 2017

Administration of Albumin Solution Increases Serum Levels of Albumin in Patients With Chronic Liver Failure in a Single-Arm Feasibility Trial.

Clin Gastroenterol Hepatol 2018 05 12;16(5):748-755.e6. Epub 2017 Sep 12.

Division of Medicine, University College London, United Kingdom.

Background & Aims: Infections are life-threatening to patients with acute decompensation and acute-on-chronic liver failure (AD/ACLF). Patients with AD/ACLF have prostaglandin E2-mediated immune suppression, which can be reversed by administration of albumin; infusion of 20% human albumin solution (HAS) might improve outcomes of infections. We performed a feasibility study to determine optimal trial design, assess safety, and validate laboratory assessments of immune function to inform design of a phase 3 trial.

Methods: We performed a prospective multicenter, single-arm, open-label trial of 79 patients with AD/ACLF and levels of albumin lower than 30 g/L, seen at 10 hospitals in the United Kingdom from May through December 2015. Patients were given daily infusions of 20% HAS, based on serum levels, for 14 days or until discharge from the hospital. Rates of infection, organ dysfunction, and in-hospital mortality were recorded. The primary end point was daily serum albumin level during the treatment period. Success would be demonstrated if 60% achieved and maintained serum albumin levels at or above 30 g/L on at least one third of days with recorded levels.

Results: The patients' mean model for end-stage disease score was 20.9 ± 6.6. The primary end point (albumin ≥30 g/L on at least one third of days recorded) was achieved by 68 of the 79 patients; 75% of administrations were in accordance with suggested dosing regimen. Mean treatment duration was 10.3 days (104 ± 678 mL administered). There were 8 deaths and 13 serious adverse events, considered by the independent data-monitoring committee to be consistent with those expected. Twelve of 13 patients that developed either respiratory or cardiovascular dysfunction (based on ward-based clinical definitions) as their only organ dysfunction were alive at 30 days compared with 1 of 3 that developed renal dysfunction. Only 1 case of brain dysfunction was recorded.

Conclusions: In a feasibility trial, we found that administration of HAS increased serum levels of albumin in patients with AD/ACLF. The dosing regimen was acceptable at multiple sites and deemed safe by an independent data-monitoring committee. We also developed a robust system to record infections. The poor prognosis for patients with renal dysfunction was confirmed. However, patients with cardiovascular or respiratory dysfunction had good outcomes, which is counterintuitive. Severe encephalopathy appeared substantially under-reported, indicating that ward-based assessment of these parameters cannot be recorded with sufficient accuracy for use as a primary outcome in phase 3 trials. Trial registration no: EudraCT 2014-002300-24 and ISRCTN14174793.
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http://dx.doi.org/10.1016/j.cgh.2017.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168936PMC
May 2018

Albumin Counteracts Immune-Suppressive Effects of Lipid Mediators in Patients With Advanced Liver Disease.

Clin Gastroenterol Hepatol 2018 05 30;16(5):738-747.e7. Epub 2017 Aug 30.

Division of Medicine, University College London, London, United Kingdom.

Background & Aims: Patients with acute decompensation and acute-on-chronic liver failure (AD/ACLF) have immune dysfunction, which increases their risk for infections; however, there are no effective treatments to restore their immune function. We investigated whether the potentially immune-restorative effects of albumin are mediated by its effects on prostaglandin E (PGE) and other lipids.

Methods: We analyzed bloods samples from 45 of 79 patients with AD/ACLF and serum levels of albumin less than 30 g/L for whom infusion of 20% human albumin solution (HAS) increased serum levels of albumin 30 g/L or more in a feasibility study of effects of 20% HAS. Immune function was determined by comparison of macrophage function following addition of plasma samples. We also used samples from 12 healthy individuals. We measured binding of plasma proteins to PGE and serum levels of endotoxin (lipopolysaccharide) and cytokines; using 10 patients' samples, we investigated the effects of PGE inhibitors. We performed a comprehensive lipid metabolomic analysis using samples from 10 different patients, before and after HAS administration.

Results: At baseline, AD/ACLF patient plasma induced significantly lower production of tumor necrosis factor by healthy macrophages than plasma from healthy individuals (P < .0001). Plasma from patients after HAS infusion induced significantly higher levels of tumor necrosis factor production by macrophages (19.5 ± 4.8 ng/mL) compared with plasma collected before treatment (17.7 ± 4.5 ng/mL; P = .0013). There was a significantly lower proportion of plasma protein (albumin) binding to PGE from patients with AD/ACLF plasma (mean, 61.9%) compared with plasma from control subjects (77.1%; P = .0012). AD/ACLF plasma protein binding to PGE increased following HAS treatment compared with baseline (mean increase, 8.7%; P < .0001). Circulating levels of PGE, lipopolysaccharide, and inflammatory or anti-inflammatory cytokines were higher in patients with AD/ACLF than healthy volunteers. Unexpectedly, HAS infusion had no effect on mediator levels. Principal component analysis of baseline levels of lipids that induce or resolve inflammation identified 2 distinct groups of patients that differed according to baseline plasma level of lipopolysaccharide. Sample analyses after HAS treatment indicated that albumin regulates circulating levels of lipid mediators, but this effect was distinct in each group.

Conclusions: Analysis of blood samples from patients with AD/ACLF participating in a feasibility study of 20% HAS infusions has shown that infusions to raise serum albumin above 30 g/L reversed plasma-mediated immune dysfunction by binding and inactivating PGE. We also describe a method to classify the inflammatory response in AD/ACLF, based on lipid profile, which could improve identification of patients most likely to respond to HAS treatment. A randomized controlled trial is needed to determine whether these effects of HAS reduce infections in AD/ACLF. Trial registered with European Medicines Agency (EudraCT 2014-002300-24) and adopted by NIHR (ISRCTN14174793).
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http://dx.doi.org/10.1016/j.cgh.2017.08.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168974PMC
May 2018

The fate and lifespan of human monocyte subsets in steady state and systemic inflammation.

J Exp Med 2017 Jul 12;214(7):1913-1923. Epub 2017 Jun 12.

Division of Medicine, University College London, University of London, London, England, UK

In humans, the monocyte pool comprises three subsets (classical, intermediate, and nonclassical) that circulate in dynamic equilibrium. The kinetics underlying their generation, differentiation, and disappearance are critical to understanding both steady-state homeostasis and inflammatory responses. Here, using human in vivo deuterium labeling, we demonstrate that classical monocytes emerge first from marrow, after a postmitotic interval of 1.6 d, and circulate for a day. Subsequent labeling of intermediate and nonclassical monocytes is consistent with a model of sequential transition. Intermediate and nonclassical monocytes have longer circulating lifespans (∼4 and ∼7 d, respectively). In a human experimental endotoxemia model, a transient but profound monocytopenia was observed; restoration of circulating monocytes was achieved by the early release of classical monocytes from bone marrow. The sequence of repopulation recapitulated the order of maturation in healthy homeostasis. This developmental relationship between monocyte subsets was verified by fate mapping grafted human classical monocytes into humanized mice, which were able to differentiate sequentially into intermediate and nonclassical cells.
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http://dx.doi.org/10.1084/jem.20170355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502436PMC
July 2017

Pre/pro-B cells generate macrophage populations during homeostasis and inflammation.

Proc Natl Acad Sci U S A 2017 05 1;114(20):E3954-E3963. Epub 2017 May 1.

Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London WC1E 6JJ, United Kingdom;

Most tissue-resident macrophages (Mφs) are believed to be derived prenatally and are assumed to maintain themselves throughout life by self-proliferation. However, in adult mice we identified a progenitor within bone marrow, early pro-B cell/fraction B, that differentiates into tissue Mφs. These Mφ precursors have non-rearranged B-cell receptor genes and coexpress myeloid (GR1, CD11b, and CD16/32) and lymphoid (B220 and CD19) lineage markers. During steady state, these precursors exit bone marrow, losing Gr1, and enter the systemic circulation, seeding the gastrointestinal system as well as pleural and peritoneal cavities but not the brain. While in these tissues, they acquire a transcriptome identical to embryonically derived tissue-resident Mφs. Similarly, these Mφ precursors also enter sites of inflammation, gaining CD115, F4/80, and CD16/32, and become indistinguishable from blood monocyte-derived Mφs. Thus, we have identified a population of cells within the bone marrow early pro-B cell compartment that possess functional plasticity to differentiate into either tissue-resident or inflammatory Mφs, depending on microenvironmental signals. We propose that these precursors represent an additional source of Mφ populations in adult mice during steady state and inflammation.
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http://dx.doi.org/10.1073/pnas.1616417114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441795PMC
May 2017

A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging.

Nat Immunol 2017 03 23;18(3):354-363. Epub 2017 Jan 23.

Division of Infection and Immunity, University College London, London, UK.

Mitogen-activated protein kinases (MAPKs) including Erk, Jnk and p38 regulate diverse cellular functions and are thought to be controlled by independent upstream activation cascades. Here we show that the sestrins bind to and coordinate simultaneous Erk, Jnk and p38 MAPK activation in T lymphocytes within a new immune-inhibitory complex (sestrin-MAPK activation complex (sMAC)). Whereas sestrin ablation resulted in broad reconstitution of immune function in stressed T cells, inhibition of individual MAPKs allowed only partial functional recovery. T cells from old humans (>65 years old) or mice (16-20 months old) were more likely to form the sMAC, and disruption of this complex restored antigen-specific functional responses in these cells. Correspondingly, sestrin deficiency or simultaneous inhibition of all three MAPKs enhanced vaccine responsiveness in old mice. Thus, disruption of sMAC provides a foundation for rejuvenating immunity during aging.
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http://dx.doi.org/10.1038/ni.3665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321575PMC
March 2017

Lipid Mediators in Inflammation.

Microbiol Spectr 2016 11;4(6)

Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London WC1 E6JJ, United Kingdom.

Lipids are potent signaling molecules that regulate a multitude of cellular responses, including cell growth and death and inflammation/infection, via receptor-mediated pathways. Derived from polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), each lipid displays unique properties, thus making their role in inflammation distinct from that of other lipids derived from the same PUFA. This diversity arises from their synthesis, which occurs via discrete enzymatic pathways and because they elicit responses via different receptors. This review will collate the bioactive lipid research to date and summarize the major pathways involved in their biosynthesis and role in inflammation. Specifically, lipids derived from AA (prostanoids, leukotrienes, 5-oxo-6,8,11,14-eicosatetraenoic acid, lipoxins, and epoxyeicosatrienoic acids), EPA (E-series resolvins), and DHA (D-series resolvins, protectins, and maresins) will be discussed herein.
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http://dx.doi.org/10.1128/microbiolspec.MCHD-0035-2016DOI Listing
November 2016

A Comparison of Human Neutrophils Acquired from Four Experimental Models of Inflammation.

PLoS One 2016 25;11(10):e0165502. Epub 2016 Oct 25.

Centre for Clinical Pharmacology, Division of Medicine, University College London, London, United Kingdom.

Defects in neutrophil function have been implicated in a wide spectrum of clinical conditions. Several models are employed to study activated human neutrophils akin to those found at a site of inflammation. These include whole blood (WB) ex vivo stimulation with lipopolysaccharide (LPS) and in vivo techniques: cantharidin blister, skin windows and intra-dermal injection of UV-killed E.coli (UVKEc). Neutrophils obtained from these have never been compared. We compared the activation status of neutrophils from each technique in order to inform the optimal model for use in human studies. Healthy male volunteers were randomised to undergo one of the four techniques (n = 5/group). LPS: WB stimulated with 1ng/ml of LPS for 4 hours. Cantharidin: 12.5μl of 0.1% cantharidin elicited a single blister, aspirated at 24 hours. Skin windows: four 6mm mechanical-suction blisters created, de-roofed and an exudate-collection chamber placed over the windows for 4 hours before aspiration. UVKEc: 1.5 x 107 UVKEc injected intra-dermally. A single 10mm mechanical-suction blister formed and aspirated at 4 hours. Unstimulated WB used as the control. Flow cytometry was used to determine activation status using CD16, CD11b, CD54, CD62L and CD88. Functional status was assessed with a phagocytosis assay. The pattern of neutrophil activation was similar in all models. Neutrophil CD11b was elevated in all models, most markedly in UVKEc (p<0.0001), and CD54 was also elevated but only significant in the LPS model (p = 0.001). CD62L was significantly reduced in all 4 models (p<0.0001) and CD88 was also suppressed in all. There were no changes in CD16 in any model, neither was there any significant difference in the phagocytic capacity of the neutrophils. In summary, there are no significant differences in activation marker expression or phagocytic capacity in the neutrophils obtained from each technique. Therefore we believe whole blood stimulation is the best model in experimentally challenging inpatient populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165502PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079626PMC
June 2017

Novel translational model of resolving inflammation triggered by UV-killed E. coli.

J Pathol Clin Res 2016 Jul 4;2(3):154-65. Epub 2016 May 4.

Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, 5 University Street University College London London WC1E 6JF UK.

Whilst numerous studies investigating the aetiology of inflammatory diseases have been performed in rodents, the applicability of these data to human pathophysiology is frequently debated. Regardless of the strengths and weaknesses of rodent models in biomedical research, there is a need to develop models of experimental inflammation in humans. Here, we describe a self-resolving acute inflammatory response triggered by the intradermal injection of UV-killed Escherichia coli into the forearm of healthy volunteers. Cells and exudates were harvested from onset to resolution by applying negative pressure over the inflamed site. Onset was characterized by high blood flow, neutrophilia and peak levels of pro-inflammatory cytokines, whilst resolution showed a decline in blood blow, reduction in neutrophils, increase in monocytes/macrophages and waning of classic pro-inflammatory cytokine levels. An anti-inflammatory effect, defined as suppression of onset phase events, was demonstrated by administering naproxen, a conventional non-steroidal anti-inflammatory drug. In summary, this model of resolving acute inflammation is minimally invasive, highly tractable and allows simultaneous investigation of the vascular response, cellular trafficking and chemical mediator profile of onset and resolution phases of acute inflammation in humans. It can serve as a translational platform to provide mechanistic insights and to test the clinical efficacy of novel anti-inflammatory and pro-resolving drugs, and also as a tool in patients to explore inherent defects in resolution pathways.
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http://dx.doi.org/10.1002/cjp2.43DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958736PMC
July 2016

CYP450-derived oxylipins mediate inflammatory resolution.

Proc Natl Acad Sci U S A 2016 Jun 25;113(23):E3240-9. Epub 2016 May 25.

Comparative Biomedical Sciences, Royal Veterinary College, London NW1 0TU, United Kingdom

Resolution of inflammation has emerged as an active process in immunobiology, with cells of the mononuclear phagocyte system being critical in mediating efferocytosis and wound debridement and bridging the gap between innate and adaptive immunity. Here we investigated the roles of cytochrome P450 (CYP)-derived epoxy-oxylipins in a well-characterized model of sterile resolving peritonitis in the mouse. Epoxy-oxylipins were produced in a biphasic manner during the peaks of acute (4 h) and resolution phases (24-48 h) of the response. The epoxygenase inhibitor SKF525A (epoxI) given at 24 h selectively inhibited arachidonic acid- and linoleic acid-derived CYP450-epoxy-oxlipins and resulted in a dramatic influx in monocytes. The epoxI-recruited monocytes were strongly GR1(+), Ly6c(hi), CCR2(hi), CCL2(hi), and CX3CR1(lo) In addition, expression of F4/80 and the recruitment of T cells, B cells, and dendritic cells were suppressed. sEH (Ephx2)(-/-) mice, which have elevated epoxy-oxylipins, demonstrated opposing effects to epoxI-treated mice: reduced Ly6c(hi) monocytes and elevated F4/80(hi) macrophages and B, T, and dendritic cells. Ly6c(hi) and Ly6c(lo) monocytes, resident macrophages, and recruited dendritic cells all showed a dramatic change in their resolution signature following in vivo epoxI treatment. Markers of macrophage differentiation CD11b, MerTK, and CD103 were reduced, and monocyte-derived macrophages and resident macrophages ex vivo showed greatly impaired phagocytosis of zymosan and efferocytosis of apoptotic thymocytes following epoxI treatment. These findings demonstrate that epoxy-oxylipins have a critical role in monocyte lineage recruitment and activity to promote inflammatory resolution and represent a previously unidentified internal regulatory system governing the establishment of adaptive immunity.
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http://dx.doi.org/10.1073/pnas.1521453113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988604PMC
June 2016

Intravenous Endotoxin Challenge in Healthy Humans: An Experimental Platform to Investigate and Modulate Systemic Inflammation.

J Vis Exp 2016 05 16(111). Epub 2016 May 16.

Centre for Clinical Pharmacology, Division of Medicine, University College London.

Activation of inflammatory pathways represents a central mechanism in multiple disease states both acute and chronic. Triggered via either pathogen or tissue damage-associated molecular motifs, common biochemical pathways lead to conserved yet variable physiological and immunological alterations. Dissection and delineation of the determinants and mechanisms underlying phenotypic variance in response is expected to yield novel therapeutic advances. Intravenous (IV) administration of endotoxin (gram-negative bacterial lipopolysaccharide), a specific Toll-like receptor 4 agonist, represents an in vivo model of systemic inflammation in man. National Institutes for Health Clinical Center Reference Endotoxin (CCRE, Escherichia coli O:113:H10:K negative) is employed to reliably and reproducibly generate vascular, hematological, endocrine, immunological and organ-specific functional effects that parallel, to varying degrees, those seen in the early stages of pathological states. Alteration of dose (0.06 - 4 ng/kg) and time-scale of exposure (bolus vs. infusion) allows replication of either acute or chronic inflammation and a range of severity to be elicited, with higher doses (2 - 4 ng/kg) frequently being used to create a 'sepsis-like' state. Established and novel medicinal compounds may additionally be administered prior to or post endotoxin exposure to appreciate their effect on the inflammatory cascade. Despite limitations in scope and generalizability, human IV endotoxin challenge offers a unique platform to gain mechanistic insights into inducible physiological responses and inflammatory pathways. Rationally employed it may aid translation of this knowledge into therapeutic innovations.
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http://dx.doi.org/10.3791/53913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942172PMC
May 2016

Resolution of inflammation: a new therapeutic frontier.

Nat Rev Drug Discov 2016 08 29;15(8):551-67. Epub 2016 Mar 29.

Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, 5 University Street, University College London, London WC1E 6JJ, UK.

Dysregulated inflammation is a central pathological process in diverse disease states. Traditionally, therapeutic approaches have sought to modulate the pro- or anti-inflammatory limbs of inflammation, with mixed success. However, insight into the pathways by which inflammation is resolved has highlighted novel opportunities to pharmacologically manipulate these processes - a strategy that might represent a complementary (and perhaps even superior) therapeutic approach. This Review discusses the state of the art in the biology of resolution of inflammation, highlighting the opportunities and challenges for translational research in this field.
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http://dx.doi.org/10.1038/nrd.2016.39DOI Listing
August 2016

ATTIRE: Albumin To prevenT Infection in chronic liveR failurE: study protocol for a single-arm feasibility trial.

BMJ Open 2016 Jan 25;6(1):e010132. Epub 2016 Jan 25.

Division of Medicine, University College London (UCL), London, UK.

Introduction: Circulating prostaglandin E2 levels are elevated in acutely decompensated cirrhosis and have been shown to contribute to immune suppression. Albumin binds and inactivates this hormone. Human albumin solution could thus be repurposed as an immune restorative drug in these patients.This feasibility study aims to determine whether it is possible and safe to restore serum albumin to >30 g/L and maintain it at this level in patients admitted with acute decompensated cirrhosis using repeated 20% human albumin infusions according to daily serum albumin levels.

Methods And Analysis: Albumin To prevenT Infection in chronic liveR failurE (ATTIRE) stage 1 is a multicentre, open label dose feasibility trial. Patients with acutely decompensated cirrhosis admitted to hospital with a serum albumin of <30 g/L are eligible, subject to exclusion criteria. Daily intravenous human albumin solution will be infused, according to serum albumin levels, for up to 14 days or discharge in all patients. The primary end point is daily serum albumin levels for the duration of the treatment period and the secondary end point is plasma-induced macrophage dysfunction. The trial will recruit 80 patients. Outcomes will be used to assist with study design for an 866 patient randomised controlled trial at more than 30 sites across the UK.

Ethics And Dissemination: Research ethics approval was given by the London-Brent research ethics committee (ref: 15/LO/0104). The clinical trials authorisation was issued by the medicines and healthcare products regulatory agency (ref: 20363/0350/001-0001).

Results: Will be disseminated through peer reviewed journals and international conferences. Recruitment of the first participant occurred on 26/05/2015.

Trial Registration Number: The trial is registered with the European Medicines Agency (EudraCT 2014-002300-24) and has been adopted by the NIHR (ISRCTN 14174793). This manuscript refers to V.4.0 of the protocol; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2015-010132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735307PMC
January 2016

Sex-specific regulation of chemokine Cxcl5/6 controls neutrophil recruitment and tissue injury in acute inflammatory states.

Biol Sex Differ 2015 26;6:27. Epub 2015 Nov 26.

Centre for Microvascular Research, London, EC1M 6BQ UK.

Background: Tissue infiltration by neutrophils during acute inflammatory states causes substantial tissue injury. While the magnitude of tissue neutrophil accumulation in innate immune responses is profoundly greater in males than females, fundamental aspects of the molecular mechanisms underlying these sex differences remain largely unknown.

Methods: We investigated sex differences in neutrophil stimulation and recruitment in ischemia/reperfusion (I/R; mesenteric or renal) or carrageenan pleurisy in rats or mice, as well as skin injury in human volunteers. The induction of potent chemoattractive mediators (chemokines) and neutrophil adhesion molecules were measured by real-time PCR, flow cytometry, and protein assays.

Results: Mesenteric I/R in age-matched Wistar rats resulted in substantially more neutrophil accumulation and tissue injury at 2 h reperfusion in males than females. Using intravital microscopy, we show that the immediate (<30 min) neutrophil response to I/R is similar in males and females but that prolonged neutrophil recruitment occurs in males at sites local and distal to inflammatory insult partly due to an increase in circulating neutrophil populations with elevated surface expression of adhesion molecules. Sex differences in neutrophil kinetics were correlated with sustained induction of chemokine Cxcl5 in the tissue, circulation, and bone marrow of males but not females. Furthermore, blockade of Cxcl5 in males prior to ischemia resulted in neutrophil responses that were similar in magnitude to those in females. Conversely, administration of Cxcl5 to males in the absence of I/R was sufficient to increase levels of systemic neutrophils. Cxcl5 treatment of bone marrow neutrophils in vitro caused substantial induction of neutrophil-mobilizing cytokine granulocyte colony-stimulating factor (GCSF) and expression of β2 integrin that accounts for sexual dimorphism in circulating neutrophil populations in I/R. Moreover, male Cxcl5-stimulated bone marrow neutrophils had an increased capacity to adhere to β2 integrin ligand ICAM-1, implicating a greater sensitivity of male leukocytes to Cxcl5-mediated activation. Differential induction of Cxcl5 (human CXCL6) between the sexes was also evident in murine renal I/R, rat pleurisy, and human skin blisters and correlated with the magnitude of neutrophil accumulation in tissues.

Conclusions: Our study reveals that sex-specific induction of chemokine Cxcl5/CXCL6 contributes to sexual dimorphism in neutrophil recruitment in diverse acute inflammatory responses partly due to increased stimulation and trafficking of bone marrow neutrophils in males.
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http://dx.doi.org/10.1186/s13293-015-0047-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661984PMC
November 2015

Macrophage development and polarization in chronic inflammation.

Semin Immunol 2015 Aug 26;27(4):257-66. Epub 2015 Jul 26.

Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, 5 University Street, University College London, London WC1E 6JJ, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.smim.2015.07.002DOI Listing
August 2015

Bile duct-ligated mice exhibit multiple phenotypic similarities to acute decompensation patients despite histological differences.

Liver Int 2016 06 22;36(6):837-46. Epub 2015 Jun 22.

Manchester Pharmacy School, Faculty of Medical and Human Sciences, the University of Manchester, Manchester, UK.

Background & Aims: Patients with decompensated cirrhosis are susceptible to infection. Innate immune dysfunction and development of organ failure are considered to underlie this. A rodent model of liver disease sharing these phenotypic features would assist in vivo study of underlying mechanisms and testing of therapeutics. We evaluated three models to identify which demonstrated the greatest clinical and immunological phenotypic similarity to patients with acutely decompensated (AD) cirrhosis.

Methods: We selected Bile Duct Ligation (BDL) rats at 4 weeks, BDL mice at 14 days and Carbon tetrachloride (CCl4 ) mice at 10 weeks (with studies performed 7 days after final CCl4 infection). We examined organ dysfunction, inflammatory response to carrageenan-in-paw, plasma eicosanoid concentrations, macrophage cytokine production and responses to peritoneal infection.

Results: Bile duct ligation caused sarcopenia, liver, cardiovascular and renal dysfunction whereas CCl4 mice demonstrated no clinical abnormalities. BDL rodents exhibited depressed response to carrageenan-in-paw unlike CCl4 mice. BDL rats have slightly elevated plasma eicosanoid levels and plasma showed partial PGE2 -mediated immune suppression whereas CCl4 mice did not. Plasma NOx was elevated in patients with acute or chronic liver failure (AoCLF) compared to healthy volunteers and BDL rodents but not CCl4 mice. Elevated nitric oxide (NO) via inducible nitric oxide synthase (iNOS) mediates defective leucocyte trafficking in BDL rodent models.

Conclusions: We conclude that BDL mice and rats are not simply models of cholestatic liver injury but may be used to study mechanisms underlying poor outcome from infection in AD and have identified elevated NO as a potential mediator of depressed leucocyte trafficking.
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http://dx.doi.org/10.1111/liv.12876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869675PMC
June 2016

HIF1α allows monocytes to take a breather during sepsis.

Immunity 2015 Mar;42(3):397-9

Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, 5 University Street, University College London, London WC1E 6JJ, UK. Electronic address:

How the immune system is negatively affected by sepsis is not fully understood. In this issue of Immunity, Shalova et al. (2015) show that during human sepsis monocytes upregulate hypoxia-inducible factor-α (HIF1-α) activity and acquire an immunosuppressive phenotype while retaining anti-bacterial and wound-healing properties.
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http://dx.doi.org/10.1016/j.immuni.2015.02.016DOI Listing
March 2015
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