Biomedical subjects

William R Henderson

Publications and source records attributed to William R Henderson.

11 recordsLinked to original sources

PubMed2003

Hypothermia in the management of traumatic brain injury. A systematic review and meta-analysis.

OBJECTIVE: Brain injury remains the leading cause of death in cases of trauma in North America and Europe. This article critically appraised and summarised all published and peer-reviewed, randomised, controlled trials of the use of hypothermia in traumatic brain injury. DESIGN: To be included, a study had to be a published, randomised, controlled trial of the use of hypothermia in the management of traumatic brain injury. Pooling of data and meta-analysis of results occurred. SETTING: Conducted at a tertiary level Canadian teaching hospital. PATIENTS AND PARTICIPANTS: Patients were combined from eight randomised, controlled trials to generate a population of 748 severely head-injured patients. MEASUREMENTS AND RESULTS: Eight studies provided data on the efficacy of hypothermia in the management of traumatic brain injury. The pooled odds ratio of mortality in the hypothermic group was 0.81 (95%CI =0.59-1.13, p=0.22). The OR of a poor neurological outcome (GOS 1,2 or 3) was 0.75 (95% CI=0.56-1.01, p=0.06). The odds ratio for pneumonia in the normothermic group was 0.42 (95%CI =0.25-0.70, p=0.001). CONCLUSIONS: Although meta-analysis suggests that iatrogenic hypothermia may confer a marginal benefit in neurological outcome, there does not appear to be clear evidence of lower mortality rates in unselected traumatic brain injury patients. Prolonged hypothermia may confer a benefit, particularly in patients with elevated intracranial pressure refractory to conventional manipulations. Conclusions regarding the use of hypothermia are controversial and not strongly supported by the available evidence.

Brain Injuries↗

PubMed2003

A broad-spectrum caspase inhibitor attenuates allergic airway inflammation in murine asthma model.

Asthma is characterized by acute and chronic airway inflammation, and the severity of the airway hyperreactivity correlates with the degree of inflammation. Many of the features of lung inflammation observed in human asthma are reproduced in OVA-sensitized/challenged mice. T lymphocytes, particularly Th2 cells, are critically involved in the genesis of the allergic response to inhaled Ag. In addition to antiapoptotic effects, broad-spectrum caspase inhibitors inhibit T cell activation in vitro. We investigated the effect of the broad-spectrum caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), on airway inflammation in OVA-sensitized/challenged mice. OVA-sensitized mice treated with z-VAD-fmk immediately before allergen challenge showed marked reduction in inflammatory cell infiltration in the airways and pulmonary blood vessels, mucus production, and Th2 cytokine production. We hypothesized that the caspase inhibitor prevented T cell activation, resulting in the reduction of cytokine production and eosinophil infiltration. Treatment with z-VAD-fmk in vivo prevented subsequent T cell activation ex vivo. We propose that caspase inhibitors may offer a novel therapeutic approach to T cell-dependent inflammatory airway diseases.

Aerosols↗

PubMed2003

Chemogenomic identification of Ref-1/AP-1 as a therapeutic target for asthma.

Asthma is characterized by an oxidantantioxidant imbalance in the lungs leading to activation of redox-sensitive transcription factors, nuclear factor kappaB (NF-kappaB), and activator protein-1 (AP-1). To develop therapeutic strategies for asthma, we used a chemogenomics approach to screen for small molecule inhibitor(s) of AP-1 transcription. We developed a beta-strand mimetic template that acts as a reversible inhibitor (pseudosubstrate) of redox proteins. This template incorporates an enedione moiety to trap reactive cysteine nucleophiles in the active sites of redox proteins. Specificity for individual redox factors was achieved through variations in X and Y functionality by using a combinatorial library approach. A limited array (2 x 6) was constructed where X was either NHCH(3) or NHCH(2) Ph and Y was methyl, phenyl, m-cyanophenyl, m-nitrophenyl, m-acetylaniline, or m-methylbenzoate. These analogs were evaluated for their ability to inhibit transcription in transiently transfected human lung epithelial A549 cells from either an AP-1 or NF-kappaB reporter. A small-molecule inhibitor, PNRI-299, was identified that selectively inhibited AP-1 transcription (IC(50) of 20 microM) without affecting NF-kappaB transcription (up to 200 microM) or thioredoxin (up to 200 microM). The molecular target of PNRI-299 was determined to be the oxidoreductase, redox effector factor-1 by an affinity chromatography approach. The selective redox effector factor-1 inhibitor, PNRI-299, significantly reduced airway eosinophil infiltration, mucus hypersecretion, edema, and IL-4 levels in a mouse asthma model. These data validate AP-1 as an important therapeutic target in allergic airway inflammation.

Animals↗

PubMed2003

CCR8 is not essential for the development of inflammation in a mouse model of allergic airway disease.

Chemokine receptors play an important role in the trafficking of various immune cell types to sites of inflammation. Several chemokine receptors are differentially expressed in Th1 and Th2 effector populations. Th2 cells selectively express CCR3, CCR4, and CCR8, which could direct their trafficking to sites of allergic inflammation. Additionally, increased expression of the CCR8 ligand, TCA-3, has been detected in affected lungs in a mouse model of asthma. In this study, CCR8-deficient mice were generated to address the biological role of CCR8 in a model of allergic airway disease. Using two different protocols of allergen challenge, we demonstrate that absence of CCR8 does not affect the development of pulmonary eosinophilia and Th2 cytokine responses. In addition, administration of anti-TCA-3-neutralizing Ab during allergen sensitization and rechallenge failed to inhibit airway allergic inflammation. These results suggest that CCR8 does not play an essential role in the pathogenesis of inflammation in this mouse model of allergic airway disease.

Animals↗

PubMed2003

Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling.

A new paradigm for asthma pathogenesis is presented in which exaggerated inflammation and remodeling in the airways are a consequence of abnormal injury and repair responses arising from a subject's susceptibility to components of the inhaled environment. An epithelial-mesenchymal trophic unit becomes activated to drive pathologic remodeling and smooth muscle proliferation through complex cytokine interactions. Histamine, prostanoids, and cysteinyl leukotrienes (CysLTs) are potent contractile agonists of airway smooth muscle (ASM). The CysLTs appear to play a central role in regulating human ASM motor tone and phenotypic alterations, manifested as hypertrophy and hyperplasia in chronic severe asthma. The CysLTs augment growth factor-induced ASM mitogenesis through activation of CysLT receptors. Although they mediate their contractile effects by increasing phosphoinositide turnover and inducing increased cytosolic calcium, new data suggest that part of the contractile effect may be independent of calcium mobilization. Prostaglandin E(2), the predominant eicosanoid product of the airway epithelium, is a potent inhibitor of mitogenesis, collagen synthesis, and mesenchymal cell chemotaxis and therefore can suppress inflammation and fibroblast activation. The capacity of the epithelium for CysLT synthesis is inversely related to its ability to make PGE(2). The ASM is capable of expressing both leukotriene-synthesizing enzymes and CysLT receptors, and cytokines upregulate the receptor expression. This may be an explanation for the CysLTs promoting airway hyperresponsiveness in asthma. The CysLTs play an important role in the airway remodeling seen in persistent asthma that includes increases of airway goblet cells, mucus, blood vessels, smooth muscle, myofibroblasts, and airway fibrosis. Evidence from a mouse model of asthma demonstrated that CysLT(1) receptor antagonists inhibit the airway remodeling processes, including eosinophil trafficking to the lungs, eosinophil degranulation, T(H)2 cytokine release, mucus gland hyperplasia, mucus hypersecretion, smooth muscle cell hyperplasia, collagen deposition, and lung fibrosis.

Anti-Asthmatic Agents↗

PubMed2002

Platelet-activating factor and Escherichia coliO157:H7 infections.

The role of platelet-activating factor (PAF), a phospholipid inflammatory mediator, in Escherichia coli O157:H7-associated hemolytic uremic syndrome (HUS) is unknown. PAF is synthesized by diverse cells and is degraded by PAF-acetylhydrolase (PAF-AH). Deficient PAF-AH activity results from a G-->T transversion at position 994 of exon 9. We examined children infected with E. coliO157:H7 to determine if PAF levels or the PAF-AH ( G994T) mutation reflects the risk of developing HUS. Plasma PAF concentrations were determined using chloroform/methanol extraction, thin layer chromatography purification, and scintillation proximity assay in 10 patients with uncomplicated infection (UI), 10 infected patients who subsequently developed HUS (pre-HUS), 5 HUS patients, and 8 healthy controls. The PAF-AH ( G994T) allele frequency was determined in 52 UI children, 15 with HUS, and 11 controls. Wilcoxon rank sum tests were performed to test differences in location (median) of pairs of groups. PAF levels were higher in the UI ( P=0.04) and pre-HUS ( P=0.01) groups than in healthy controls. No subject had the PAF-AH ( G994T) allele. Thus, elevated plasma PAF levels occur in E. coliO157:H7-infected children, even without HUS, but diminish when HUS develops. The PAF-AH ( G994T) allele does not contribute to the risk of developing HUS.

Blood Cell Count↗

PubMed2002

A small molecule inhibitor of redox-regulated NF-kappa B and activator protein-1 transcription blocks allergic airway inflammation in a mouse asthma model.

An oxidant/antioxidant imbalance is seen in the lungs of patients with asthma. This oxidative stress in asthmatic airways may lead to activation of redox-sensitive transcription factors, NF-kappaB and AP-1. We examined the effect of the small molecule inhibitor of redox-regulated NF-kappaB and AP-1 transcription, MOL 294 on airway inflammation and airway hyperreactivity (AHR) in a mouse model of asthma. MOL 294 is a potent nonpeptide inhibitor of NF-kappaB and AP-1 based upon a beta-strand template that binds to and inhibits the cellular redox protein thioredoxin. BALB/c mice after i.p. OVA sensitization (day 0) were challenged with intranasal OVA on days 14, 25, 26, and 27. MOL 294, administered intranasal on days 25-27, blocked the airway inflammatory response to OVA assessed 24 h after the last OVA challenge on day 28. MOL 294 reduced eosinophil, IL-13, and eotaxin levels in bronchoalveolar lavage fluid and airway tissue eosinophilia and mucus hypersecretion. MOL 294 also decreased AHR in vivo to methacholine. These results support redox-regulated transcription as a therapeutic target in asthma and demonstrate that selective inhibitors can reduce allergic airway inflammation and AHR.

Administration, Intranasal↗

PubMed2002

Tryptase inhibition blocks airway inflammation in a mouse asthma model.

Release of human lung mast cell tryptase may be important in the pathophysiology of asthma. We examined the effect of the reversible, nonelectrophilic tryptase inhibitor MOL 6131 on airway inflammation and hyper-reactivity in a murine model of asthma. MOL 6131 is a potent selective nonpeptide inhibitor of human lung mast cell tryptase based upon a beta-strand template (K(i) = 45 nM) that does not inhibit trypsin (K(i) = 1,061 nM), thrombin (K(i) = 23, 640 nM), or other serine proteases. BALB/c mice after i.p. OVA sensitization (day 0) were challenged intratracheally with OVA on days 8, 15, 18, and 21. MOL 6131, administered days 18-21, blocked the airway inflammatory response to OVA assessed 24 h after the last OVA challenge on day 22; intranasal delivery (10 mg/kg) had a greater anti-inflammatory effect than oral delivery (10 or 25 mg/kg) of MOL 6131. MOL 6131 reduced total cells and eosinophils in bronchoalveolar lavage fluid, airway tissue eosinophilia, goblet cell hyperplasia, mucus secretion, and peribronchial edema and also inhibited the release of IL-4 and IL-13 in bronchoalveolar lavage fluid. However, tryptase inhibition did not alter airway hyper-reactivity to methacholine in vivo. These results support tryptase as a therapeutic target in asthma and indicate that selective tryptase inhibitors can reduce allergic airway inflammation.

Animals↗

PubMed2002

A role for cysteinyl leukotrienes in airway remodeling in a mouse asthma model.

Airway inflammation and remodeling in chronic asthma are characterized by airway eosinophilia, hyperplasia of goblet cells and smooth muscle, and subepithelial fibrosis. We examined the role of leukotrienes in a mouse model of allergen-induced chronic lung inflammation and fibrosis. BALB/c mice, after intraperitoneal ovalbumin (OVA) sensitization on Days 0 and 14, received intranasal OVA periodically Days 14-75. The OVA-treated mice developed an extensive eosinophil and mononuclear cell inflammatory response, goblet cell hyperplasia, and mucus occlusion of the airways. A striking feature of this inflammatory response was the widespread deposition of collagen beneath the airway epithelial cell layer and also in the lung interstitium in the sites of leukocytic infiltration that was not observed in the saline-treated controls. The cysteinyl leukotriene(1) (CysLT(1)) receptor antagonist montelukast significantly reduced the airway eosinophil infiltration, mucus plugging, smooth muscle hyperplasia, and subepithelial fibrosis in the OVA-sensitized/challenged mice. The presence of Charcot-Leyden-like crystals in airway macrophages and the increased interleukin (IL)-4 and IL-13 mRNA expression in lung tissue and protein in BAL fluid seen in OVA-treated mice were also inhibited by CysLT(1) receptor blockade. These data suggest an important role for cysteinyl leukotrienes in the pathogenesis of chronic allergic airway inflammation with fibrosis.

Acetates↗

PubMed2002

Leukotriene modifiers.

Leukotrienes (LTs) are 5-lipoxygenase products formed from arachidonic acid metabolism. There is compelling evidence that LTs play an important role in the pathogenesis of asthma. LTs affect vascular permeability, mucus production, and smooth muscle constriction, and may contribute to airway remodeling. In mild-to-moderate asthma, LT modifiers improve measures of airflow limitation and quality of life and reduce the frequency of asthma exacerbations and the need for short-acting bronchodilator therapy. In moderate-to-severe asthma, an LT modifier in combination with an inhaled corticosteroid results in improvements in lung function and asthma control over that achieved with an inhaled corticosteroid alone. LT modifiers are effective in the treatment of exercise-induced bronchoconstriction and aspirin-induced asthma. There are few adverse effects of LT modifiers.

Asthma↗

PubMed2002

Lipid inflammatory mediators: leukotrienes, prostaglandins, platelet-activating factor.

The lipid mediators, leukotrienes, prostaglandins, and PAF play an important role in the complex inflammatory process of airway eosinophilia, edema hypersecretion of mucus, and AHR observed in patients with asthma. These mediators are also likely key participants in the pathogenesis of other allergic diseases. An important goal of future research is to clarify the complex interactions between the lipid mediators and the inflammatory stimuli that regulate their production. Novel inhibitors and antagonists of the lipid mediators, such as the CysLT1 receptor antagonists, have recently been developed that have great promise in the treatment of allergic diseases.

Animals↗