Biomedical subjects

Mark M Wurfel

Publications and source records attributed to Mark M Wurfel.

9 recordsLinked to original sources

PubMed2007

Microarray-based analysis of ventilator-induced lung injury.

Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are a frequent cause of intensive care unit admission, affecting over 200,000 patients in the United States each year. Mechanical ventilation is a life-saving intervention in the setting of ARDS and ALI, but clinical trials have demonstrated that mechanical ventilation with excessive tidal volumes plays a role in promoting and perpetuating lung injury and leads to excess mortality. This process has been labeled ventilator-induced lung injury (VILI), but the molecular mechanisms driving this process and its interactions with predisposing risk factors such as sepsis and chemical injury remain incompletely understood. Genome-wide measurements of gene expression using microarray technology represent a powerful tool to examine the pathophysiology of VILI. Several recent studies have used this approach to study VILI in isolation and associated with endotoxin instillation or saline lavage. These studies and others examining gene expression profiles in epithelial cells subjected to cyclic stretch have provided novel insights on the molecular mechanisms underlying VILI. This review will summarize these findings and discuss implications for future studies.

Animals↗

PubMed2006

The Duffy antigen modifies systemic and local tissue chemokine responses following lipopolysaccharide stimulation.

The Duffy blood group Ag (dfy) binds selective CXC and CC chemokines at high affinity and is expressed on erythrocytes and endothelial cells. However, it does not transmit a signal via G proteins, as occurs with other seven-transmembrane receptors. We hypothesized that dfy functions as a chemokine reservoir and regulates inflammation by altering soluble chemokine concentrations in the blood and tissue compartments. We determined whether Duffy Ag "loss-of-function" phenotypes (human and murine) are associated with alterations in plasma chemokine concentrations during the innate inflammatory response to LPS. Plasma CXCL8 and CCL2 concentrations from humans homozygous for the GATA-1 box polymorphism, a dfy polymorphism that abrogates erythrocyte chemokine binding, were higher than in heterozygotes following LPS stimulation of their whole blood in vitro. Similarly, dfy(-/-) mice showed higher plasma MIP-2 concentrations than dfy(+/+) mice following LPS stimulation of whole blood in vitro. We then determined the relative contributions of erythrocyte and endothelial Duffy Ag in modifying chemokine concentrations and neutrophil recruitment in the lungs following intratracheal LPS administration in dfy(-/-) and dfy(+/+) mice reconstituted with dfy(-/-) or dfy(+/+) marrow. Mice lacking endothelial dfy expression had higher MIP-2 and keratinocyte chemoattractant concentrations in the airspaces. Mice lacking erythrocyte dfy had higher MIP-2 and keratinocyte chemoattractant concentrations in the lung tissue vascular space, but lower plasma chemokine concentrations associated with attenuated neutrophil recruitment into the airspaces. These data indicate that dfy alters soluble chemokine concentrations in blood and local tissue compartments and enhances systemic bioavailability of chemokines produced during local tissue inflammation.

Adolescent↗

PubMed2005

Genetic pleiotropy between asthma and obesity in a community-based sample of twins.

BACKGROUND: Asthma and obesity are common conditions that are strongly associated. This association might be due to shared genetic or environmental causes. OBJECTIVE: We sought to determine whether a shared genetic cause is responsible for the association between asthma and obesity and to estimate the magnitude of shared genetic cause. METHODS: The analyses were performed with 1001 monozygotic and 383 dizygotic same-sex twin pairs within the University of Washington Twin Registry. The presence of asthma was determined by self-report of a physician diagnosis of asthma, and body mass index (BMI) was calculated by using self-reported height and weight. Obesity was defined as a BMI of 30 or greater. The association between asthma and BMI was assessed by means of mixed-effects ordinal regression. Twin correlations examined the association of asthma and obesity. Univariate and bivariate structural equation models estimated the components of variance attributable to genetic and environmental effects. RESULTS: A strong association between asthma and BMI was identified in the sample population (P < .001). Substantial heritability was detected for asthma (53%) and obesity (77%), which is indicative of additive genetic influences on each disorder. The best-fitting model of shared components of variance indicated that 8% of the genetic component of obesity is shared with asthma. CONCLUSION: The covariation between obesity and asthma is predominantly caused by shared genetic risk factors for both conditions.

Adult↗

PubMed2005

Identification of high and low responders to lipopolysaccharide in normal subjects: an unbiased approach to identify modulators of innate immunity.

LPS stimulates a vigorous inflammatory response from circulating leukocytes that varies greatly from individual to individual. The goal of this study was to use an unbiased approach to identify differences in gene expression that may account for the high degree of interindividual variability in inflammatory responses to LPS in the normal human population. We measured LPS-induced cytokine production ex vivo in whole blood from 102 healthy human subjects and identified individuals who consistently showed either very high or very low responses to LPS (denoted lps(high) and lps(low), respectively). Comparison of gene expression profiles between the lps(high) and lps(low) individuals revealed 80 genes that were differentially expressed in the presence of LPS and 21 genes that were differentially expressed in the absence of LPS (p < 0.005, ANOVA). Expression of a subset of these genes was confirmed using real-time RT-PCR. Functional relevance for one gene confirmed to be expressed at a higher level in lps(high), adipophilin, was inferred when reduction in adipophilin mRNA by small interfering RNA in the human monocyte-like cell line THP-1 resulted in a modest but significant reduction in LPS-induced MCP-1 mRNA expression. These data illustrate a novel approach to the identification of factors that determine interindividual variability in innate immune inflammatory responses and identify adipophilin as a novel potential regulator of LPS-induced MCP-1 production in human monocytes.

Adolescent↗

PubMed2005

TLR-4 pathway mediates the inflammatory response but not bacterial elimination in E. coli pneumonia.

We examined the role of Toll-like receptor (TLR)-4 in modifying the lung inflammatory response and its effects on the bacterial recovery from the lungs following inhaled Escherichia coli in two different strains of TLR-4 mutant mice that are hyporesponsive to LPS. The C57BL/10ScN(tlr4(lps-del)) mice containing a deletion mutation in the TLR-4 gene showed lower proinflammatory cytokine levels, lower lung MPO activity, and less parenchymal and peribronchial inflammation compared with the C57BL/10ScSn mice, a related TLR-4 wild-type substrain. However, the C57BL/10ScN(tlr4(lps-del)) mutant showed lower bacterial recovery in the lungs following inhaled E. coli associated with a rapid but transient increase in air space neutrophil counts at 6 h. In comparison, the C3H/HeJ(tlr4(Lps-d)) mutant mice containing a Pro712His substitution in TLR-4 demonstrated lower proinflammatory cytokine levels, lower lung MPO activity, and lower neutrophil accumulation in the air spaces but showed no differences in the bacterial burden of inhaled E. coli at 6 h, when compared with the TLR-4 wild-type C3H/HeSnJ mice. Thus two different TLR-4 mutants showed attenuated inflammatory responses in the lungs, but the reduced inflammatory responses were not consistently associated with either improved or impaired bacterial elimination from the lungs. Our findings indicate that the inflammatory response to inhaled E. coli is TLR-4 dependent, but bacterial elimination depends on other factors in addition to TLR-4.

Administration, Inhalation↗

PubMed2005

Inflammatory basis of exercise-induced bronchoconstriction.

RATIONALE: Exercise-induced bronchoconstriction (EIB) is a highly prevalent condition with unclear pathogenesis. Two competing theories of the pathogenesis of EIB differ regarding the inflammatory basis of this condition. OBJECTIVES: Our goals were to establish whether epithelial cell and mast cell activation with release of inflammatory mediators occurs during EIB and how histamine and cysteinyl leukotriene antagonists alter the airway events occurring during EIB. METHODS: Induced sputum was used to measure mast cell mediators and eicosanoids at baseline and 30 minutes after exercise challenge in 25 individuals with asthma with EIB. In a randomized, double-blind crossover study, the cysteinyl leukotriene antagonist montelukast and antihistamine loratadine or two matched placebos were administered for two doses before exercise challenge. MAIN RESULTS: The percentage of columnar epithelial cells in induced sputum at baseline was associated with the severity of EIB. After exercise challenge, histamine, tryptase, and cysteinyl leukotrienes significantly increased and prostaglandin E(2) and thromboxane B(2) significantly decreased in the airways, and there was an increase in columnar epithelial cells in the airways. The concentration of columnar epithelial cells was associated with the levels of histamine and cysteinyl leukotrienes in the airways. Treatment with montelukast and loratadine inhibited the release of cysteinyl leukotrienes and histamine into the airways, but did not inhibit the release of columnar epithelial cells into the airways. CONCLUSIONS: These data indicate that epithelial cells, mast cell mediators, and eicosanoids are released into the airways during EIB, supporting an inflammatory basis for EIB.

Acetates↗

PubMed2004

Differential regulation of membrane CD14 expression and endotoxin-tolerance in alveolar macrophages.

CD14 is important in the clearance of bacterial pathogens from lungs. However, the mechanisms that regulate the expression of membrane CD14 (mCD14) on alveolar macrophages (AM) have not been studied in detail. This study examines the regulation of mCD14 on AM exposed to Escherichia coli in vivo and in vitro, and explores the consequences of changes in mCD14 expression. The expression of mCD14 was decreased on AM exposed to E. coli in vivo and AM incubated with lipopolysaccharide (LPS) or E. coli in vitro. Polymyxin B abolished LPS effects, but only partially blocked the effects of E. coli. Blockade of extracellular signal-regulated kinase pathways attenuated LPS and E. coli-induced decrease in mCD14 expression. Inhibition of proteases abrogated the LPS-induced decrease in mCD14 expression on AM and the release of sCD14 into the supernatants, but did not affect the response to E. coli. The production of tumor necrosis factor-alpha in response to a second challenge with Staphylococcus aureus or zymosan was decreased in AM after incubation with E. coli but not LPS. These studies show that distinct mechanisms regulate the expression of mCD14 and the induction of endotoxin tolerance in AM, and suggest that AM function is impaired at sites of bacterial infection.

Animals↗

PubMed2003

Duffy antigen facilitates movement of chemokine across the endothelium in vitro and promotes neutrophil transmigration in vitro and in vivo.

The Duffy Ag expressed on RBCs, capillaries, and postcapillary venular endothelial cells binds selective CXC and CC chemokines with high affinity. Cells transfected with the Duffy Ag internalize but do not degrade chemokine ligand. It has been proposed that Duffy Ag transports chemokines across the endothelium. We hypothesized that Duffy Ag participates in the movement of chemokines across the endothelium and, by doing so, modifies neutrophil transmigration. We found that the Duffy Ag transfected into human endothelial cells facilitates movement of the radiolabeled CXC chemokine, growth related oncogene-alpha/CXC chemokine ligand 1 (GRO-alpha/CXCL1), across an endothelial monolayer. In addition, neutrophil migration toward GRO-alpha/CXCL1 and IL-8 (IL-8/CXCL8) was enhanced across an endothelial monolayer expressing the Duffy Ag. Furthermore, GRO-alpha/CXCL1 stimulation of endothelial cells expressing the Duffy Ag did not affect gene expression by oligonucleotide microarray analysis. These in vitro observations are supported by the finding that IL-8/CXCL8-driven neutrophil recruitment into the lungs was markedly attenuated in transgenic mice lacking the Duffy Ag. We conclude that Duffy Ag has a role in enhancing leukocyte recruitment to sites of inflammation by facilitating movement of chemokines across the endothelium.

Amino Acid Sequence↗

PubMed2002

Genetics of pulmonary fibrosis.

Pulmonary fibrosis is a devastating disease that occurs in association with environmental exposures, several inherited diseases, collagen vascular disease, as well as in an idiopathic form. Epithelial cell damage, excessive fibroblast proliferation, upregulation of extracellular matrix production, and attenuated matrix degradation are shared pathophysiological features of these different forms of pulmonary fibrosis. Several observations suggest that genetic predisposition plays an important role in the pathophysiology of pulmonary fibrosis. There is significant inter-individual variation in the degree of pulmonary fibrosis resulting from exposure to similar levels of an inhaled fibrogenic agent. There are several inherited diseases with known genetic mutations that have high rates of pulmonary fibrosis. Idiopathic pulmonary fibrosis can occur in multiple first-degree relatives, including those separated at an early age. Finally, recent studies have identified polymorphisms within genes for cytokines, histocompatability antigens, and extracellular matrix components that are associated with the development of pulmonary fibrosis. Identification of putative pulmonary fibrosis gene/s (PF gene/s) may result in novel diagnostic and therapeutic interventions for those at risk for development of pulmonary fibrosis.

Journal Article↗