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Search Results: 1 - 10 of 308 matches for " Darrell Pilling "
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Persistent Lung Inflammation and Fibrosis in Serum Amyloid P Component (Apcs-/-) Knockout Mice
Darrell Pilling, Richard H. Gomer
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0093730
Abstract: Fibrosing diseases, such as pulmonary fibrosis, cardiac fibrosis, myelofibrosis, liver fibrosis, and renal fibrosis are chronic and debilitating conditions and are an increasing burden for the healthcare system. Fibrosis involves the accumulation and differentiation of many immune cells, including macrophages and fibroblast-like cells called fibrocytes. The plasma protein serum amyloid P component (SAP; also known as pentraxin-2, PTX2) inhibits fibrocyte differentiation in vitro, and injections of SAP inhibit fibrosis in vivo. SAP also promotes the formation of immuno-regulatory Mreg macrophages. To elucidate the endogenous function of SAP, we used bleomycin aspiration to induce pulmonary inflammation and fibrosis in mice lacking SAP. Compared to wildtype C57BL/6 mice, we find that in Apcs-/- “SAP knock-out” mice, bleomycin induces a more persistent inflammatory response and increased fibrosis. In both C57BL/6 and Apcs-/- mice, injections of exogenous SAP reduce the accumulation of inflammatory macrophages and prevent fibrosis. The types of inflammatory cells present in the lungs following bleomycin-aspiration appear similar between C57BL/6 and Apcs-/- mice, suggesting that the initial immune response is normal in the Apcs-/- mice, and that a key endogenous function of SAP is to promote the resolution of inflammation and fibrosis.
NaCl Potentiates Human Fibrocyte Differentiation
Nehemiah Cox, Darrell Pilling, Richard H. Gomer
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0045674
Abstract: Excessive NaCl intake is associated with a variety of fibrosing diseases such as renal and cardiac fibrosis. This association has been attributed to increased blood pressure as the result of high NaCl intake. However, studies in patients with high NaCl intake and fibrosis reveal a connection between NaCl intake and fibrosis that is independent of blood pressure. We find that increasing the extracellular concentration of NaCl to levels that may occur in human blood after high-salt intake can potentiate, in serum-free culture conditions, the differentiation of freshly-isolated human monocytes into fibroblast-like cells called fibrocytes. NaCl affects the monocytes directly during their adhesion. Potassium chloride and sodium nitrate also potentiate fibrocyte differentiation. The plasma protein Serum Amyloid P (SAP) inhibits fibrocyte differentiation. High levels of extracellular NaCl change the SAP Hill coefficient from 1.7 to 0.8, and cause a four-fold increase in the concentration of SAP needed to inhibit fibrocyte differentiation by 95%. Together, our data suggest that NaCl potentiates fibrocyte differentiation. NaCl-increased fibrocyte differentiation may thus contribute to NaCl-increased renal and cardiac fibrosis.
High and Low Molecular Weight Hyaluronic Acid Differentially Regulate Human Fibrocyte Differentiation
Anu S. Maharjan, Darrell Pilling, Richard H. Gomer
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026078
Abstract: Background Following tissue injury, monocytes can enter the tissue and differentiate into fibroblast-like cells called fibrocytes, but little is known about what regulates this differentiation. Extracellular matrix contains high molecular weight hyaluronic acid (HMWHA; ~2×106 Da). During injury, HMWHA breaks down to low molecular weight hyaluronic acid (LMWHA; ~0.8–8×105 Da). Methods and Findings In this report, we show that HMWHA potentiates the differentiation of human monocytes into fibrocytes, while LMWHA inhibits fibrocyte differentiation. Digestion of HMWHA with hyaluronidase produces small hyaluronic acid fragments, and these fragments inhibit fibrocyte differentiation. Monocytes internalize HMWHA and LMWHA equally well, suggesting that the opposing effects on fibrocyte differentiation are not due to differential internalization of HMWHA or LMWHA. Adding HMWHA to PBMC does not appear to affect the levels of the hyaluronic acid receptor CD44, whereas adding LMWHA decreases CD44 levels. The addition of anti-CD44 antibodies potentiates fibrocyte differentiation, suggesting that CD44 mediates at least some of the effect of hyaluronic acid on fibrocyte differentiation. The fibrocyte differentiation-inhibiting factor serum amyloid P (SAP) inhibits HMWHA-induced fibrocyte differentiation and potentiates LMWHA-induced inhibition. Conversely, LMWHA inhibits the ability of HMWHA, interleukin-4 (IL-4), or interleukin-13 (IL-13) to promote fibrocyte differentiation. Conclusions We hypothesize that hyaluronic acid signals at least in part through CD44 to regulate fibrocyte differentiation, with a dominance hierarchy of SAP>LMWHA≥HMWHA>IL-4 or IL-13.
Toll-like receptor 2 agonists inhibit human fibrocyte differentiation
Anu S Maharjan, Darrell Pilling, Richard H Gomer
Fibrogenesis & Tissue Repair , 2010, DOI: 10.1186/1755-1536-3-23
Abstract: When human peripheral blood mononuclear cells (PBMCs) were cultured with TLR3, TLR4, TLR5, TLR7, TLR8 or TLR9 agonists, there was no significant effect on fibrocyte differentiation, even though enhanced extracellular tumor necrosis factor (TNF)-α accumulation and/or increased cell surface CD86 or major histocompatibility complex (MHC) class II levels were observed. However, all TLR2 agonists tested inhibited fibrocyte differentiation without any significant effect on cell survival. Adding TLR2 agonists to purified monocytes had no effect on fibrocyte differentiation. However, some TLR2 agonists caused PBMCs to secrete a factor that inhibits the differentiation of purified monocytes into fibrocytes. This factor is not interferon (IFN)-α, IFN-γ, interleukin (IL)-12, aggregated immunoglobulin G (IgG) or serum amyloid P (SAP), factors known to inhibit fibrocyte differentiation. TLR2 agonist-treated PBMCs secrete low levels of IL-6, TNF-α, IFN-γ, granulocyte colony-stimulating factor and tumor growth factor β1, but combinations of these factors had no effect on fibrocyte differentiation from purified monocytes.Our results indicate that TLR2 agonists indirectly inhibit fibrocyte differentiation and that, for some TLR2 agonists, this inhibition involves other cell types in the PBMC population secreting an unknown factor that inhibits fibrocyte differentiation. Together, these data suggest that the presence of some bacterial signals can inhibit fibrocyte differentiation and may thus slow wound closure.Following injury, circulating peripheral blood cells such as neutrophils, monocytes, dendritic cells and lymphocytes leave the bloodstream and enter the injured site. Once monocytes are in the injured site, they can differentiate into fibroblast-like cells called fibrocytes [1-8]. Fibrocytes have a distinct spindle-shaped appearance. Fibrocytes express hematopoietic markers, including CD45, major histocompatibility complex (MHC) class II, and CD34, along with stromal markers i
Identification of Markers that Distinguish Monocyte-Derived Fibrocytes from Monocytes, Macrophages, and Fibroblasts
Darrell Pilling,Ted Fan,Donna Huang,Bhavika Kaul,Richard H. Gomer
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0007475
Abstract: The processes that drive fibrotic diseases are complex and include an influx of peripheral blood monocytes that can differentiate into fibroblast-like cells called fibrocytes. Monocytes can also differentiate into other cell types, such as tissue macrophages. The ability to discriminate between monocytes, macrophages, fibrocytes, and fibroblasts in fibrotic lesions could be beneficial in identifying therapies that target either stromal fibroblasts or fibrocytes.
New symmetry current for massive spin-3/2 fields
Terry Pilling
Physics , 2004, DOI: 10.1142/S0217732304014975
Abstract: We present several new results which will be of value to theorists working with massive spin-3/2 vector-spinor fields as found, for example, in low and intermediate energy hadron physics and also linearized supergravity. The general lagrangian and propagator for a vector-spinor field in d-dimensions is given. It is shown that the observables of the theory are invariant under a novel continuous symmetry group which is also extended to an algebra. A new technique is developed for exploring the consequences of the symmetry and a previously unknown conserved vector current and charge are found. The current leads to new interactions involving spin-3/2 particles and may have important experimental consequences.
Symmetry of massive Rarita-Schwinger fields
Terry Pilling
Physics , 2004, DOI: 10.1142/S0217751X05021300
Abstract: We derive the general lagrangian and propagator for a vector-spinor field in $d$-dimensions and show that the physical observables are invariant under the so-called point transformation symmetry. Until now the symmetry has not been exploited in any non-trival way, presumably because it is not an invariance of the classical action nor is it a gauge symmetry. Nevertheless, we develop a technique for exploring the consequences of the symmetry leading to a conserved vector current and charge. The current and charge are identically zero in the free field case and only contribute in a background such as a electromagnetic or gravitational field. The current can couple spin-3/2 fields to vector and scalar fields and may have important consequences in intermediate energy hadron physics as well as linearized supergravity. The consistency problem which plagues higher spin field theories is then discussed and and some ideas regarding the possiblity of solutions are presented.
Black Hole Thermodynamics and the Factor of 2 Problem
Terry Pilling
Physics , 2007, DOI: 10.1016/j.physletb.2008.01.015
Abstract: We show that the recent tunneling formulas for black hole radiation in static, spherically symmetric spacetimes follow as a consequence of the first law of black hole thermodynamics and the area-entropy relation based on the radiation temperature. A tunneling formula results even if the radiation temperature is different from the one originally derived by Hawking and this is discussed in the context of the recent factor of 2 problem. In particular, it is shown that if the radiation temperature is higher than the Hawking temperature by a factor of two, thermodynamics then leads to a tunneling formula which is exactly the one recently found to be canonically invariant.
Synovial fluid leukocyte apoptosis is inhibited in patients with very early rheumatoid arthritis
Karim Raza, Dagmar Scheel-Toellner, Chi-Yeung Lee, Darrell Pilling, S John Curnow, Francesco Falciani, Victor Trevino, Kanta Kumar, Lakhvir K Assi, Janet M Lord, Caroline Gordon, Christopher D Buckley, Mike Salmon
Arthritis Research & Therapy , 2006, DOI: 10.1186/ar2009
Abstract: Inhibition of T-cell apoptosis in the synovium of patients with established rheumatoid arthritis (RA) was first described in 1995 [1]. Subsequent work contrasted the virtually complete inhibition of T-cell apoptosis in RA with high levels of T-cell apoptosis in gout [2]. The phenotype of rheumatoid synovial T cells (Bcl-XL high, Bcl-2low) demonstrated that their survival was maintained by stromal mechanisms rather than by the common γ-chain cytokines, and IFN-β was identified as a key fibroblast-derived survival signal [3]. In addition to their effects on T cells, both IFN-β and synovial fluid from RA patients delay neutrophil apoptosis [4,5]. These observations led to the concept that inhibition of leukocyte apoptosis, mediated by an expanded fibroblast network in the rheumatoid joint, was an important mechanism that maintains the leukocyte infiltrate in RA and perpetuates disease [6].We recently showed that patients with very early RA, within the first 3 months of symptom onset, have a synovial fluid cytokine profile that is distinct from those of patients with other forms of very early synovitis and of patients with established RA [7]. The synovial fluid of patients with very early RA is characterized by elevated levels of cytokines that are survival factors for T cells (IL-2, IL-4 and IL-15) and neutrophils (granulocyte-macrophage colony-stimulating factor [GM-CSF] and granulocyte colony-stimulating factor [G-CSF]). We therefore sought to determine whether synovial fluid neutrophil and lymphocyte apoptosis was inhibited in patients with very early RA compared with patients with other very early inflammatory arthritides. We found that patients with very early RA had significantly lower levels of neutrophil apoptosis than did patients who developed non-RA persistent arthritis and those with a resolving disease course. Similarly, lymphocyte apoptosis was absent in patients with early RA, whereas it was seen in patients with other early arthritides. The inhibition o
Archetypal Literary Theory in the Postmodern Era
Dobson, Darrell
JUNG: the e-Journal of the Jungian Society for Scholarly Study , 2005,
Abstract: I propose that differentiating the archetype and the archetypal image provides a means of responding to some postmodern critiques of archetypal theory. I consider the literary theories of Northrop Frye and a postmodern feminist critique of his work. I hypothesize that a more fully Jungian perspective on archetypal theory provides a means of responding to the critiques levelled at Frye. This analysis hopes to contribute to positioning archetypal theory in such a manner as to allow it to remain cogent and relevant in light of postmodern critiques, and to do so without marginalizing or ignoring postmodern theoretical insights.
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