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Search Results: 1 - 10 of 298136 matches for " Theodore J Standiford "
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PPARs in Lung Biology and Disease
Theodore J. Standiford,Jesse Roman
PPAR Research , 2007, DOI: 10.1155/2007/28765
PPARs in Alveolar Macrophage Biology
Monica R. Smith,Theodore J. Standiford,Raju C. Reddy
PPAR Research , 2007, DOI: 10.1155/2007/23812
Abstract: PPARs, most notably PPAR-γ, play a crucial role in regulating the activation of alveolar macrophages, which in turn occupy a pivotal place in the immune response to pathogens and particulates drawn in with inspired air. In this review, we describe the dual role of the alveolar macrophage as both a first-line defender through its phagocytotic activity and a regulator of the immune response. Depending on its state of activation, the alveolar macrophage may either enhance or suppress different aspects of immune function in the lung. We then review the role of PPAR-γ and its ligands in deactivating alveolar macrophages—thus limiting the inflammatory response that, if unchecked, could threaten the essential respiratory function of the alveolus—while upregulating the cell's phagocytotic activity. Finally, we examine the role that inadequate or inappropriate PPAR-γ responses play in specific lung diseases.
Cooperative Interactions between TLR4 and TLR9 Regulate Interleukin 23 and 17 Production in a Murine Model of Gram Negative Bacterial Pneumonia
Urvashi Bhan,Megan N. Ballinger,Xianying Zeng,Michael J. Newstead,Matthew D. Cornicelli,Theodore J. Standiford
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0009896
Abstract: Toll like receptors play an important role in lung host defense against bacterial pathogens. In this study, we investigated independent and cooperative functions of TLR4 and TLR9 in microbial clearance and systemic dissemination during Gram-negative bacterial pneumonia. To access these responses, wildtype Balb/c mice, mice with defective TLR4 signaling (TLR4lps-d), mice deficient in TLR9 (TLR9?/?) and TLR4/9 double mutant mice (TLR4lps-d/TLR9?/?) were challenged with K. pneumoniae, then time-dependent lung bacterial clearance and systemic dissemination determined. We found impaired lung bacterial clearance in TLR4 and TLR9 single mutant mice, whereas the greatest impairment in clearance was observed in TLR4lps-d/TLR9?/? double mutant mice. Early lung expression of TNF-α, IL-12, and chemokines was TLR4 dependent, while IFN-γ production and the later expression of TNF-α and IL-12 was dependent on TLR9. Classical activation of lung macrophages and maximal induction of IL-23 and IL-17 required both TLR4 and TLR9. Finally, the i.t. instillation of IL-17 partially restored anti-bacterial immunity in TLR4lps-d/TLR9?/? double mutant mice. In conclusion, our studies indicate that TLR4 and TLR9 have both non-redundant and cooperative roles in lung innate responses during Gram-negative bacterial pneumonia and are both critical for IL-17 driven antibacterial host response.
Pioglitazone is as effective as dexamethasone in a cockroach allergen-induced murine model of asthma
Venkata R Narala, Rajesh Ranga, Monica R Smith, Aaron A Berlin, Theodore J Standiford, Nicholas W Lukacs, Raju C Reddy
Respiratory Research , 2007, DOI: 10.1186/1465-9921-8-90
Abstract: We compared the effectiveness of the PPAR-γ agonist pioglitazone (PIO) to the established effectiveness of a glucocorticoid receptor agonist, dexamethasone (DEX), in a murine model of asthma induced by cockroach allergen (CRA). After sensitization to CRA and airway localization by intranasal instillation of the allergen, Balb/c mice were challenged twice at 48-h intervals with intratracheal CRA. Either PIO (25 mg/kg/d), DEX (1 mg/kg/d), or vehicle was administered throughout the period of airway CRA exposure.PIO and DEX demonstrated similar abilities to reduce airway hyperresponsiveness, pulmonary recruitment of inflammatory cells, serum IgE, and lung levels of IL-4, IL-5, TNF-α, TGF-β, RANTES, eotaxin, MIP3-α, Gob-5, and Muc5-ac. Likewise, intratracheal administration of an adenovirus containing a constitutively active PPAR-γ expression construct blocked CRA induction of Gob-5 and Muc5-ac.Given the potent effectiveness shown by PIO, we conclude that PPAR-γ agonists deserve investigation as potential therapies for human asthma.Asthma incidence and morbidity continues to rise worldwide. Prominent characteristics of allergic asthma include reduced airflow, airway hyperresponsiveness (AHR), accumulation of eosinophils, mast cells, and other inflammatory cells in peribronchiolar regions, and hyperplasia of goblet cells with excessive mucus secretion [1,2]. These effects are accompanied, in part, by the overproduction of a variety of cytokines and chemokines that attract inflammatory cells and stimulate a TH2- and IgE-dominated immune response.Glucocorticoids, inhaled or oral, are currently the most effective treatments for asthma [3]. Side effects remain a significant problem, however, especially since individuals may begin using these medications in childhood and continue them for life. Furthermore, some patients, especially those with severe disease, may respond poorly to steroids or not at all [4]. Consequently, the need remains for medications that are safer and equ
IRAK-M Regulates Chromatin Remodeling in Lung Macrophages during Experimental Sepsis
Kenneth Lyn-Kew,Eric Rich,Xianying Zeng,Haitao Wen,Steven L. Kunkel,Michael W. Newstead,Urvashi Bhan,Theodore J. Standiford
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011145
Abstract: Sepsis results in a profound state of immunosuppression, which is temporally associated with impaired leukocyte function. The mechanism of leukocyte reprogramming in sepsis is incompletely understood. In this study, we explored mechanisms contributing to dysregulated inflammatory cytokine expression by pulmonary macrophages during experimental sepsis. Pulmonary macrophages (PM) recovered from the lungs of mice undergoing cecal ligation and puncture (CLP) display transiently reduced expression of some, but not all innate genes in response to LPS. Impaired expression of TNF-α and iNOS was associated with reduced acetylation and methylation of specific histones (AcH4 and H3K4me3) and reduced binding of RNA polymerase II to the promoters of these genes. Transient impairment in LPS-induced cytokine responses in septic PM temporally correlated with induction of IRAK-M mRNA and protein, which occurred in a MyD88-dependent fashion. PM isolated from IRAK-M?/? mice were largely refractory to CLP-induced impairment in cytokine expression, chromatin remodeling, recruitment of RNA polymerase II, and induction of histone deacetylase-2 observed during sepsis. Our findings indicate that systemic sepsis induces epigenetic silencing of cytokine gene expression in lung macrophages, and IRAK-M appears to be a critical mediator of this response.
Overexpression of sICAM-1 in the Alveolar Epithelial Space Results in an Exaggerated Inflammatory Response and Early Death in Gram Negative Pneumonia
Michael P Mendez, Yeni K Monroy, Ming Du, Angela M Preston, Leslie Tolle, Yujing Lin, Kelli L VanDussen, Linda C Samuelson, Theodore J Standiford, Jeffery L Curtis, James M Beck, Paul J Christensen, Robert Paine
Respiratory Research , 2011, DOI: 10.1186/1465-9921-12-12
Abstract: Using the surfactant protein C (SPC) promoter, we developed a transgenic mouse (SPC-sICAM-1) that constitutively overexpresses sICAM-1 in the distal lung, and compared the responses of wild-type and SPC-sICAM-1 mice following intranasal inoculation with K. pneumoniae.SPC-sICAM-1 mice demonstrated increased mortality and increased systemic dissemination of organisms compared with wild-type mice. We also found that inflammatory responses were significantly increased in SPC-sICAM-1 mice compared with wild-type mice but there were no difference in lung CFU between groups.We conclude that alveolar sICAM-1 modulates pulmonary inflammation. Manipulating ICAM-1 interactions therapeutically may modulate the host response to Gram negative pulmonary infections.Intercellular adhesion molecule-1 (ICAM-1) is an ~100 kDa molecule belonging to the immunoglobulin supergene family. The membrane bound form of this protein (mICAM-1) serves as a counter-receptor for the β2 integrins, CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1), found on leukocytes. Interactions with mICAM-1 facilitate leukocyte transmigration across the endothelium [1] and over the surface of alveolar epithelial cells (AECs) in the lung [2]. Studies using gene-targeted mice lacking ICAM-1 or neutralizing antibodies have indicated that ICAM-1 is necessary for normal pulmonary host defense [3-5]. A soluble form of the molecule, soluble intercellular adhesion molecule-1 (sICAM-1), is found in serum and in the alveolar lining fluid [6-8]. sICAM-1 in the alveolar space is likely generated by proteolytic cleavage of mICAM-1 found on type I alveolar epithelial cells [9].sICAM-1 is normally present in the alveolar lining fluid of both humans and mice [6,7,10-13]. Like mICAM-1, sICAM-1 binds to LFA-1/Mac-1 and not only competes with leukocyte binding to mICAM-1 [14], but also stimulates leukocyte cytokine production [15]. We have previously demonstrated that isolated alveolar epithelial cells (AECs), which express features of the
Therapeutic Efficacy of Cintredekin Besudotox (IL13-PE38QQR) in Murine Lung Fibrosis Is Unaffected by Immunity to Pseudomonas aeruginosa Exotoxin A
Rogério S. Rosada,Ana P. Moreira,Fabiani G. Frantz,Raj K. Puri,Aquilur Rahman,Theodore J. Standiford,Carlos R. Zárate-Bladés,Célio L. Silva,Cory M. Hogaboam
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0008721
Abstract: We have previously explored a therapeutic strategy for specifically targeting the profibrotic activity of IL-13 during experimental pulmonary fibrosis using a fusion protein comprised of human IL-13 and a mutated form of Pseudomonas aeruginosa exotoxin A (IL13-PE) and observed that the intranasal delivery of IL13-PE reduced bleomycin-induced pulmonary fibrosis through its elimination of IL-13-responsive cells in the lung. The aim of the present study was to determine whether the presence of an immune response to P. aeruginosa and/or its exotoxin A (PE) would diminish the anti-fibrotic properties of IL13-PE.
Collective Coordinate Action for Charged Sigma-Model Vortices in Finite Geometries
Theodore J. Allen
Physics , 1992, DOI: 10.1142/S0217732393001537
Abstract: In this Letter the method of Lund is applied to formulate a variational principle for the motion of charged vortices in an effective non-linear Schr\"{o}dinger field theory describing finite size two-dimensional quantum Hall samples under the influence of an arbitrary perpendicular magnetic field. Freezing out variations in the modulus of the effective field yields a $U(1)$ sigma-model. A duality transformation on the sigma-model reduces the problem to finding the Green function for a related electrostatics problem. This duality illuminates the plasma analogy to the Laughlin wave function.
Intermediate range migration in the two-dimensional stepping stone model
J. Theodore Cox
Mathematics , 2010, DOI: 10.1214/09-AAP639
Abstract: We consider the stepping stone model on the torus of side $L$ in $\mathbb{Z}^2$ in the limit $L\to\infty$, and study the time it takes two lineages tracing backward in time to coalesce. Our work fills a gap between the finite range migration case of [Ann. Appl. Probab. 15 (2005) 671--699] and the long range case of [Genetics 172 (2006) 701--708], where the migration range is a positive fraction of $L$. We obtain limit theorems for the intermediate case, and verify a conjecture in [Probability Models for DNA Sequence Evolution (2008) Springer] that the model is homogeneously mixing if and only if the migration range is of larger order than $(\log L)^{1/2}$.
The V-filtration for tame unit $F$-crystals
Theodore J. Stadnik
Mathematics , 2011,
Abstract: Let X be a smooth variety over an algebraically closed field of characteristic p > 0, Z a smooth divisor, and j : U = X\Z --> X the natural inclusion. An axiomatizing of the properties of a V -filtration on a unit F-crystal is proposed and is proven to determine a unique filtration. It is shown that if M is a tame unit F-crystal on U then such a V -filtration along Z exists on j_*M. The degree zero component of the associated graded module is proven to be the (unipotent) nearby cycles functor of Grothendieck and Deligne under the Emerton-Kisin Riemann-Hilbert correspondence. A few applications to A^1 and gluing are then discussed.
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