Internists
4 years of experience

Maedgen Area
3601 4th St
Lubbock, TX 79430
806-743-3150
Locations and availability (1)

Education ?

Medical School Score
University of Arkansas (2006)
  • Currently 2 of 4 apples

Awards & Distinctions ?

Associations
American Board of Internal Medicine

Affiliations ?

Dr. McLaughlin is affiliated with 2 hospitals.

Hospital Affilations

  • Covenant Plainview Hospital
  • Umc
  • Publications & Research

    Dr. McLaughlin has contributed to 14 publications.
    Title Lysophosphatidylcholines Activate G2a Inducing G(αi)₋₁-/g(αq/)₁₁- Ca²(+) Flux, G(βγ)-hck Activation and Clathrin/β-arrestin-1/grk6 Recruitment in Pmns.
    Date December 2010
    Journal The Biochemical Journal
    Excerpt

    Lyso-PCs (lysophosphatidylcholines) are a mixture of lipids that accumulate during storage of cellular blood components, have been implicated in TRALI (transfusion-related acute lung injury) and directly affect the physiology of neutrophils [PMNs (polymorphonuclear leucocytes)]. Because the G2A receptor, expressed on PMNs, has been reported to recognize lyso-PCs, we hypothesize that lyso-PC activation of G2A causes the increases in cytosolic Ca²(+) via release of G(α) and G(βγ) subunits, kinase activation, and the recruitment of clathrin, β-arrestin-1 and GRK6 (G-protein receptor kinase 6) to G2A for signal transduction. PMNs were isolated by standard techniques, primed with lyso-PCs for 5-180 s, and lysed for Western blot analysis, immunoprecipitation or subcellular fractionation, or fixed and smeared on to slides for digital microscopy. The results demonstrated that lyso-PCs cause rapid activation of the G2A receptor through S-phosphorylation and internalization resulting in G(αi)₋₁ and G(αq/)₁₁ release leading to increases in cytosolic Ca²(+), which was inhibited by an antibody to G2A or intracellular neutralization of these subunits. Lyso-PCs also caused the release of the G(βγ) subunit which demonstrated a physical interaction (FRET+) with activated Hck (haemopoietic cell kinase; Tyr⁴¹¹). Moreover, G2A recruited clathrin, β-arrestin-1 and GRK6: clathrin is important for signal transduction, GRK6 for receptor de-sensitization, and β-arrestin-1 both propagates and terminates signals. We conclude that lyso-PC activation of G2A caused release of G(αi)₋₁, G(αq/)₁₁ and G(βγ), resulting in cytosolic Ca²(+) flux, Hck activation, and recruitment of clathrin, β-arrestin-1 and GRK6.

    Title Tumor Necrosis Factor-alpha Causes Release of Cytosolic Interleukin-18 from Human Neutrophils.
    Date March 2010
    Journal American Journal of Physiology. Cell Physiology
    Excerpt

    Neutrophils (PMNs) are a vital part of host defense and are the principal leukocyte in innate immunity. Interleukin (IL)-18 is a proinflammatory cytokine with roles in both innate and adaptive immunity. We hypothesize that PMNs contain preformed IL-18, which is released in response to specific inflammatory stimuli. Isolated PMNs were stimulated with a battery of chemoattractants (5 min to 24 h), and IL-18 release was measured. PMNs were also separated into subcellular fractions and immunoblotted with antibodies against IL-18 or were fixed and probed with antibodies to IL-18 as well as to the contents of granules, intracellular organelles, and filamentous actin (F-actin), incubated with fluorescent secondary antibodies, and examined by digital microscopy. Quiescent PMNs contained IL-18 in the cytoplasm, associated with F-actin, as determined by positive fluorescence resonance energy transfer (FRET+). In turn, TNF-alpha stimulation disrupted the association of IL-18 with F-actin, induced a FRET+ interaction of IL-18 with lipid rafts, and elicited IL-18 release. Manipulation of F-actin status confirmed the relationship between IL-18 and F-actin in resting PMNs. Consequently, incubation with monomeric IL-18 binding protein inhibited TNF-alpha-mediated priming of the PMN oxidase. We conclude that human PMNs contain IL-18 associated with F-actin in the cytoplasm and TNF-alpha stimulation causes dissociation of IL-18 from F-actin, association with lipid rafts, and extracellular release. Extracellular IL-18 participates in TNF-alpha priming of the PMN oxidase as demonstrated by inhibition with the IL-18 binding protein.

    Title Amantadine Inhibits Platelet-activating Factor Induced Clathrin-mediated Endocytosis in Human Neutrophils.
    Date December 2009
    Journal American Journal of Physiology. Cell Physiology
    Excerpt

    Receptor signaling is integral for adhesion, emigration, phagocytosis, and reactive oxygen species production in polymorphonuclear neutrophils (PMNs). Priming is an important part of PMN emigration, but it can also lead to PMN-mediated organ injury in the host. Platelet-activating factor (PAF) primes PMNs through activation of a specific G protein-coupled receptor. We hypothesize that PAF priming of PMNs requires clathrin-mediated endocytosis (CME) of the PAF receptor (PAFr), and, therefore, amantadine, known to inhibit CME, significantly antagonizes PAF signaling. PMNs were isolated by standard techniques to >98% purity and tested for viability. Amantadine (1 mM) significantly inhibited the PAF-mediated changes in the cellular distribution of clathrin and the physical colocalization [fluorescence resonance energy transfer positive (FRET+)] of early endosome antigen-1 and Rab5a, known components of CME and similar to hypertonic saline, a known inhibitor of CME. Furthermore, amantadine had no effect on the PAF-induced cytosolic calcium flux; however, phosphorylation of p38 MAPK was significantly decreased. Amantadine inhibited PAF-mediated changes in PMN physiology, including priming of the NADPH oxidase and shape change with lesser inhibition of increases in CD11b surface expression and elastase release. Furthermore, rimantadine, an amantadine analog, was a more potent inhibitor of PAF priming of the N-formyl-methionyl-leucyl-phenylalanine-activated oxidase. PAF priming of PMNs requires clathrin-mediated endocytosis that is inhibited when PMNs are pretreated with either amantadine or rimantadine. Thus, amantadine and rimantadine have the potential to ameliorate PMN-mediated tissue damage in humans.

    Title Platelet-activating Factor-mediated Endosome Formation Causes Membrane Translocation of P67phox and P40phox That Requires Recruitment and Activation of P38 Mapk, Rab5a, and Phosphatidylinositol 3-kinase in Human Neutrophils.
    Date September 2008
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    Neutrophils (polymorphonuclear leukocytes, PMNs) are vital to innate immunity and receive proinflammatory signals that activate G protein-coupled receptors (GPCRs). Because GPCRs transduce signals through clathrin-mediated endocytosis (CME), we hypothesized that platelet-activating factor (PAF), an effective chemoattractant that primes the PMN oxidase, would signal through CME, specifically via dynamin-2 activation and endosomal formation resulting in membrane translocation of cytosolic phagocyte oxidase (phox) proteins. PMNs were incubated with buffer or 2 muM PAF for 1-3 min, and in some cases activated with PMA, and O(2)(-) was measured, whole-cell lysates and subcellular fractions were prepared, or the PMNs were fixed onto slides for digital or electron microscopy. PAF caused activation of dynamin-2, resulting in endosomal formation that required PI3K and contained early endosomal Ag-1 (EEA-1) and Rab5a. The apoptosis signal-regulating kinase-1/MAPK kinase-3/p38 MAPK signalosome assembled on Rab5a and phosphorylated EEA-1 and Rab GDP dissociation inhibitor, with the latter causing Rab5a activation. Electron microscopy demonstrated that PAF caused two distinct sites for activation of p38 MAPK. EEA-1 provided a scaffold for recruitment of the p40(phox)-p67(phox) complex and PI3K-dependent Akt1 phosphorylation of these two phox proteins. PAF induced membrane translocation of p40(phox)-p67(phox) localizing to gp91(phox), which was PI3K-, but not p47(phox)-, dependent. In conclusion, PAF transduces signals through CME, and such GPCR signaling may allow for pharmacological manipulation of these cells to decrease PMN-mediated acute organ injury.

    Title Soluble Cd40 Ligand Accumulates in Stored Blood Components, Primes Neutrophils Through Cd40, and is a Potential Cofactor in the Development of Transfusion-related Acute Lung Injury.
    Date October 2006
    Journal Blood
    Excerpt

    Transfusion-related acute lung injury (TRALI) is a form of posttransfusion acute pulmonary insufficiency that has been linked to the infusion of biologic response modifiers (BRMs), including antileukocyte antibodies and lipids. Soluble CD40 ligand (sCD40L) is a platelet-derived proinflammatory mediator that accumulates during platelet storage. We hypothesized that human polymorpho-nuclear leukocytes (PMNs) express CD40, CD40 ligation rapidly primes PMNs, and sCD40L induces PMN-mediated cytotoxicity of human pulmonary microvascular endothelial cells (HMVECs). Levels of sCD40L were measured in blood components and in platelet concentrates (PCs) implicated in TRALI or control PCs that did not elicit a transfusion reaction. All blood components contained higher levels of sCD40L than fresh plasma, with apheresis PCs evidencing the highest concentration of sCD40L followed by PCs from whole blood, whole blood, and packed red blood cells (PRBCs). PCs implicated in TRALI reactions contained significantly higher sCD40L levels than control PCs. PMNs express functional CD40 on the plasma membrane, and recombinant sCD40L (10 ng/mL-1 mug/mL) rapidly (5 minutes) primed the PMN oxidase. Soluble CD40L promoted PMN-mediated cytotoxicity of HMVECs as the second event in a 2-event in vitro model of TRALI. We concluded that sCD40L, which accumulates during blood component storage, has the capacity to activate adherent PMNs, causing endothelial damage and possibly TRALI in predisposed patients.

    Title Platelet-activating Factor-induced Clathrin-mediated Endocytosis Requires Beta-arrestin-1 Recruitment and Activation of the P38 Mapk Signalosome at the Plasma Membrane for Actin Bundle Formation.
    Date July 2006
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    Clathrin-mediated endocytosis (CME) is a common pathway used by G protein-linked receptors to transduce extracellular signals. We hypothesize that platelet-activating factor (PAF) receptor (PAFR) ligation requires CME and causes engagement of beta-arrestin-1 and recruitment of a p38 MAPK signalosome that elicits distinct actin rearrangement at the receptor before endosomal scission. Polymorphonuclear neutrophils were stimulated with buffer or 2 microM PAF (1 min), and whole cell lysates or subcellular fractions were immunoprecipitated or slides prepared for colocalization and fluorescent resonance energy transfer analysis. In select experiments, beta-arrestin-1 or dynamin-2 were neutralized by intracellular introduction of specific Abs. PAFR ligation caused 1) coprecipitation of the PAFR and clathrin with beta-arrestin-1, 2) fluorescent resonance energy transfer-positive interactions among the PAFR, beta-arrestin-1, and clathrin, 3) recruitment and activation of the apoptosis signal-regulating kinase-1/MAPK kinase-3/p38 MAPK (ASK1/MKK3/p38 MAPK) signalosome, 4) cell polarization, and 5) distinct actin bundle formation at the PAFR. Neutralization of beta-arrestin-1 inhibited all of these cellular events, including PAFR internalization; conversely, dynamin-2 inhibition only affected receptor internalization. Selective p38 MAPK inhibition globally abrogated actin rearrangement; however, inhibition of MAPK-activated protein kinase-2 and its downstream kinase leukocyte-specific protein-1 inhibited only actin bundle formation and PAFR internalization. In addition, ASK1/MKK3/p38 MAPK signalosome assembly appears to occur in a novel manner such that the ASK1/p38 MAPK heterodimer is recruited to a beta-arrestin-1 bound MKK3. In polymorphonuclear neutrophils, leukocyte-specific protein-1 may play a role similar to fascin for actin bundle formation. We conclude that PAF signaling requires CME, beta-arrestin-1 recruitment of a p38 MAPK signalosome, and specific actin bundle formation at the PAFR for transduction before endosomal scission.

    Title Transfusion-related Acute Lung Injury.
    Date June 2006
    Journal Blood Reviews
    Excerpt

    Transfusion-related acute lung injury (TRALI) is a life-threatening adverse event of transfusion, which has an increasing incidence in the United States and is the leading cause of transfusion-related death. TRALI and acute lung injury (ALI) share a common clinical definition except that TRALI is temporally- and mechanistically-related to transfusion of blood or blood components. A number of different models have been proposed to explain the pathogenesis. The first is an antibody-mediated event whereby transfusion of anti-HLA, class I or class II, or anti-granulocyte antibodies into patients whose leukocytes express the cognate antigens. The antibody:antigen interaction causes complement-mediated pulmonary sequestration and activation of neutrophils (PMNs) resulting in TRALI. The second is a two-event model: the first event is the clinical condition of the patient resulting in pulmonary endothelial activation and PMN sequestration, and the second event is the transfusion of a biologic response modifier (including anti-granulocyte antibodies, lipids, and CD40 ligand) that activates these adherent PMNs resulting in endothelial damage, capillary leak, and TRALI. These hypotheses are discussed with respect to animal models and human studies that provide the experimental and clinical relevance. The definition of TRALI, patient predisposition, treatment, prevention and reporting guidelines are also examined.

    Title Structural Organization of the Neutrophil Nadph Oxidase: Phosphorylation and Translocation During Priming and Activation.
    Date February 2006
    Journal Journal of Leukocyte Biology
    Excerpt

    The reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is part of the microbicidal arsenal used by human polymorphonuclear neutrophils (PMNs) to eradicate invading pathogens. The production of a superoxide anion (O2-) into the phagolysosome is the precursor for the generation of more potent products, such as hydrogen peroxide and hypochlorite. However, this production of O2- is dependent on translocation of the oxidase subunits, including gp91phox, p22phox, p47phox, p67phox, p40phox, and Rac2 from the cytosol or specific granules to the plasma membrane. In response to an external stimuli, PMNs change from a resting, nonadhesive state to a primed, adherent phenotype, which allows for margination from the vasculature into the tissue and chemotaxis to the site of infection upon activation. Depending on the stimuli, primed PMNs display altered structural organization of the NADPH oxidase, in that there is phosphorylation of the oxidase subunits and/or translocation from the cytosol to the plasma or granular membrane, but there is not the complete assembly required for O2- generation. Activation of PMNs is the complete assembly of the membrane-linked and cytosolic NADPH oxidase components on a PMN membrane, the plasma or granular membrane. This review will discuss the individual components associated with the NADPH oxidase complex and the function of each of these units in each physiologic stage of the PMN: rested, primed, and activated.

    Title The Influence of Socio-economic Factors on Helicobacter Pylori Infection Rates of Students in Rural Zambia.
    Date November 2003
    Journal The Central African Journal of Medicine
    Excerpt

    OBJECTIVES: Although prevalence of disease in sub-Saharan Africa is often quite high and attracts much research, relatively little is known about less critical maladies. We examined Helicobacter pylori infected students in rural Zambia. We attempted to determine if any socio-economic or co-occurring diseases were correlated to H. pylori infection. Understanding the context in which H. pylori infections occur may increase our understanding of this organism. DESIGN: We conducted a screening survey with diagnostic tests of primary and secondary school students to determine rates of H. pylori infection. We then correlated these rates to socio-economic factors such as income and tobacco use. We also explored the correlation of H. pylori to HIV and malaria. SETTING: Zimba, Zambia. SUBJECTS: Eighty seven primary and secondary school students. MAIN OUTCOME MEASURE: Correlation of H. pylori to socio-economic factors. RESULTS: H. pylori infection was common (60.9%) and was consistent with rates found in other African countries. We found no significant correlation between H. Pylori and disease and socio-economic variables. CONCLUSION: In the studied population H. pylori infection does not appear to be correlated with the measured socio-economic or disease variables.

    Title Binding Characteristics of the Selective Alpha 2-adrenoceptor Antagonist [3h]idazoxan to Rat Olfactory Cortex Membranes.
    Date April 1986
    Journal European Journal of Pharmacology
    Excerpt

    [3H]Idazoxan binding to membranes prepared from rat olfactory cortex obeyed saturation kinetics and was to a single population of sites. Although the density of sites was dependent on the incubation medium, binding was of high affinity (KD approximately 5.5 nM) with a Hill coefficient close to unity. Competition studies with a range of adrenoceptor agonists and antagonists confirmed that [3H]idazoxan binding was to alpha 2-adrenoceptors. Neither chemical lesions with the neurotoxin kainic acid nor chronic unilateral bulbectomy significantly altered any of the [3H]idazoxan binding parameters. These findings suggest that alpha 2-adrenoceptors are not located on the lateral olfactory tract terminals or pyramidal cells of the olfactory cortex.

    Title Prostacyclin Synthesis and Deacylation of Phospholipids in Human Endothelial Cells: Comparison of Thrombin, Histamine and Ionophore A23187.
    Date July 1985
    Journal Thrombosis Research
    Excerpt

    Thrombin, histamine and ionophore A23187 stimulated human endothelial cells to release arachidonic acid and synthesize prostaglandins. To compare the activation of arachidonic acid release by these three stimuli in endothelial cells, we examined the intracellular lipid metabolism by prelabeling the cells with [14C]stearic acid and [3H]arachidonic acid. Thrombin stimulated the loss of 3H and 14C label from intracellular phospholipids. At the same time [3H]arachidonic acid and prostaglandins were released into the incubation medium. Thin layer chromatography analysis indicated that prostacyclin is the major metabolite formed followed by PGF2 alpha, PGE2, HHT and PGD2. In addition, several intracellular lipid metabolites were accumulated. These include: phosphatidic acid and 1,2-diacylglycerol detected by increase of both 14C and 3H radioactivity; lysophosphatidylinositol, lysophosphatidylethanolamine, and to a smaller extent lysophosphatidylcholine and lysophosphatidylserine detected by increase of 14C radioactivity. Like thrombin, both histamine and ionophore A23187 also stimulated release of arachidonic acid and synthesis of prostaglandins. Despite the different nature of the agonists, the type and the relative amount of prostaglandins synthesized in response to histamine and A23187 were similar to that stimulated by thrombin. The relative extents of hydrolysis of phospholipids and the accumulation of phosphatidic acid, 1,2-diacylglycerol and lysophospholipids are similar to that of 3H radioactivity and prostacyclin released into the medium and follow the order: ionophore A23187 greater than thrombin greater than histamine. These results suggest that in human endothelial cells, histamine, thrombin and ionophore A23187 directly or indirectly activated both phospholipase C and phospholipase A2 and these activations most likely involve mobilization of Ca2+.

    Title Excitatory and Inhibitory Effects of Noradrenaline on Synaptic Transmission in the Rat Olfactory Cortex Slice.
    Date May 1984
    Journal Brain Research
    Excerpt

    An investigation has been made of the effects of noradrenaline on excitatory transmission at the lateral olfactory tract (LOT)-superficial pyramidal cell synapse of the rat olfactory cortex slice by measuring the effects of bath-applied noradrenaline on the amplitudes and latencies of the field potentials evoked on LOT stimulation. Low concentrations of noradrenaline (0.1-5 microM) facilitate transmission whereas higher doses (20-250 microM) depress transmission. Both these effects were completely blocked by non-selective alpha- and beta-adrenoceptor antagonists, by 2-amino-5-phosphonovaleric acid (an antagonist of excitatory amino acid receptors of the N-methyl-D-aspartate type) and by the methylxanthine theophylline. The depressant effects of noradrenaline were mimicked by bath application of GABA or adenosine and specifically antagonized by bicuculline and picrotoxin. In parallel experiments, noradrenaline (100 microM) significantly increased the potassium-evoked release of endogenous aspartate, glutamate and GABA, proposed transmitters of the olfactory cortex, although the effect on GABA release was specifically antagonized by 2-amino-5-phosphonovaleric acid. Noradrenaline (100 microM) also significantly increased the potassium-evoked release of D-[3H]aspartate, an effect antagonized by a number of alpha- and beta-adrenoceptor antagonists. It is concluded that at low concentrations, noradrenaline facilitates transmission at the LOT-superficial pyramidal cell synapse by increasing excitatory amino acid neurotransmitter release. This effect is mediated by both alpha- and beta-adrenoceptors although the primary site of release is unknown. At higher concentrations of noradrenaline, the increased levels of excitatory transmitters release sufficient endogenous GABA (and possibly adenosine) to cause an overall depression of transmission. These conclusions are supported by the results of a series of experiments in which the effects of noradrenaline on stimulus input-evoked field potential output relationships were assessed. It is not possible to exclude additional direct effects of noradrenaline on membrane excitability.

    Title The Gaba-receptor: Stereospecificity and Structure-activity Studies.
    Date February 1980
    Journal Advances in Experimental Medicine and Biology
    Title Leukotriene B4 and Its Metabolites Prime the Neutrophil Oxidase and Induce Proinflammatory Activation of Human Pulmonary Microvascular Endothelial Cells.
    Date
    Journal Shock (augusta, Ga.)
    Excerpt

    Leukotrienes are proinflammatory lipid mediators, derived from arachidonic acid via 5-lipoxygenase (5-LO). Leukotriene B4 (LTB4) is an effective polymorphonuclear neutrophil (PMN) chemoattractant, as well as being a major product of PMN priming. Leukotriene B4 is rapidly metabolized into products that are thought to be inactive, and little is known about the effects of LTB4 on the pulmonary endothelium. We hypothesize that LTB4 and its metabolites are effective PMN priming agents and cause proinflammatory activation of pulmonary endothelial cells. Isolated PMNs were primed (5 min, 37°C) with serial concentrations 10 to 10 M of LTB4 and its metabolites: 6-trans-LTB4, 20-OH-LTB4, and 20-COOH-LTB4, and then activated with fMLP. Primary human pulmonary microvascular endothelial cells (HMVECs) were incubated with these lipids (6 h, 37°C, 5% CO2), and intercellular adhesion molecule 1 was measured by flow cytometry. Polymorphonuclear neutrophil adhesion was measured by myeloperoxidase assays, and to ensure that these reactions were specific to the LTB4 receptors, BLT1 and BLT2 were antagonized with CP105,696 (BLT1) or silenced with siRNA (BLT1 and BLT2). Leukotriene B4 and its metabolites primed PMNs over a wide range of concentrations, depending on the specific metabolite. In addition, at high concentrations these lipids also caused increases in the surface expression of intercellular adhesion molecule 1 on HMVECs and induced HMVEC-mediated adhesion of PMNs. Silencing of BLT2 abrogated HMVEC activation, and blockade of BLT1 inhibited the observed PMN priming activity. We conclude that LTB4 and its ω-oxidation and nonenzymatic metabolites prime PMNs over a range of concentrations and activate HMVECs. These data have expanded the repertoire of causative agents in acute lung injury and postinjury multiple organ failure.


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