531 research outputs found
Ethanol Feeding Inhibits Proinflammatory Cytokine Expression from Murine Alveolar Macrophages Ex Vivo
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66427/1/j.1530-0277.1997.tb04440.x.pd
Mononuclear Cell Adherence Induces Neutrophil Chemotactic Factor/Interleukinâ8 Gene Expression
The accumulation of polymorphonuclear cells (PMN) in tissue is an essential element of the inflammatory response that is important in host defense. Adherence to endothelium constitutes the first step in PMN migration from the vascular compartment to the interstitium. We demonstrate that human peripheral blood mononuclear cells (PBMC) adherent to plastic can result in expression of interleukinâ8 (ILâ8), a potent PMN chemoattractant and activating cytokine. Northern blot analyses showed PBMC adherent to plastic expressed ILâ8 steadyâstate mRNA levels by 30 min, peaked at 8 h, and then decreased over the next 16 h. In contrast, nonadherent PBMC (cultured in teflon chambers) expressed less than 25% of the maximal ILâ8 steadyâstate mRNA levels as compared with adherent PBMC. Adherent PBMCâassociated ILâ8 determined by immunohistochemistry, supernatant chemotactic bioactivity, and extracellular antigenic ILâ8 paralleled ILâ8 mRNA expression. Antigenic and bioactive ILâ8 were significantly apparent by 4â8 h, respectively, and increased significantly to maximal levels by 24 h. Furthermore, adherent PBMC ILâ8 gene expression was suppressed by either concomitant treatment with actinomycinâD or cycloheximide, yet specific neutralizing antibodies directed against either ILâ1ÎČ or tumor necrosis factor (TNF)âα failed to alter adherenceâinduced steadyâstate ILâ8 mRNA levels. These data support the hypothesis that PBMC adherence is an important signal for the production of ILâ8, and may be essential to the development of the inflammatory response through the elicrtation of PMN.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141636/1/jlb0287.pd
CâC chemokineâinduced eosinophil chemotaxis during allergic airway inflammation
The production of eosinophilâspecific chemotactic factors during allergic airway responses may be a pivotal event resulting in eosinophil accumulation, activation, and airway damage. Recent studies have identified specific chemokines that may play crucial roles in recruitment of eosinophils to the site of allergic reactions. In this study we have utilized an established model of schistosome egg antigen (SEA)âmediated allergic responses to examine the role of specific CâC chemokines [macrophage inflammatory proteinâ1α (MIPâ1α), RANTES, and monocyte chemoattractant proteinâ1 (MCPâ1)] in eosinophil recruitment. We have previously identified a role for MIPâ1α in eosinophil accumulation in the lung and airway during allergic airway inflammation. We extend those studies using in vitro eosinophil chemotaxis to establish that both MIPâ1α and RANTES are potent eosinophil chemotactic factors in lungs during allergic airway responses. Morphometric analysis demonstrated a peribronchial accumulation of eosinophils within the lungs beginning at 8 h, peaking at 24 h, and plateauing at 48â96 h after allergen (SEA) challenge. Utilizing wholeâlung homogenates from allergenâchallenged mice, in vitro eosinophil chemotactic assays demonstrated significant increases in eosinophil chemotactic activity with 8âh lung homogenates and peak activity with samples from 24âh lung homogenates. These data correlated with the morphometric analysis of peribronchial eosinophil accumulation in situ. When lung homogenates from allergenâchallenged mice were preincubated in vitro with antibodies specific for MIPâ1α, RANTES, or MCPâ1, a significant reduction in eosinophil chemotaxis was observed with only MIPâ1α and RANTES neutralization. Altogether, these studies indicate that RANTES and MIPâ1α are major eosinophil chemotactic factors produced during allergic airway responses. J. Leukoc. Biol. 60:573â578; 1996.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141543/1/jlb0573.pd
Ethanol Feeding Impairs Innate Immunity and Alters the Expression of Th1- and Th2-Phenotype Cytokines in Murine Klebsiella Pneumonia
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65658/1/j.1530-0277.1998.tb04303.x.pd
Hypermethylation of ribosomal DNA in human breast carcinoma
We examined the methylation status of the transcribed domain of ribosomal DNA (rDNA) in 58 patients with breast cancer. The mean percent of methylation was significantly higher in breast tumours than that of normal control samples (P< 0.0001). This increased rDNA methylation was associated with oestrogen receptor non-expression (P< 0.0273) and with moderately or poorly differentiated tumours as compared to well differentiated tumours (P< 0.0475). Our results suggest that rDNA can be a useful marker for monitoring aberrant methylation during breast tumour progression. © 2000 Cancer Research Campaig
A role for CâC chemokines in fibrotic lung disease
Pulmonary fibrosis is the end point of a chronic inflammatory process characterized by leukocyte recruitment and activation, fibroblast proliferation, and increased extracellular matrix production. Previous studies of models of pulmonary fibrosis have investigated the role of cytokines in the evolution of the fibrotic response. The involvement of tumor necrosis factor and interleukinâ1 in bleomycinâinduced lung injury, a model of idiopathic pulmonary fibrosis, has been well established, suggesting that cytokines mediate the initiation and maintenance of chronic inflammatory lesions. However, the aforementioned cytokines alone cannot account for the recruitment and activation of specific leukocyte populations found in the bleomycin model. Recently, a family of novel proinflammatory cytokines (chemokines) was cloned and characterized, yielding many putative mediators of leukocyte functions. Macrophage inflammatory proteinâ1α (MIPâ1α) and monocyte chemoattractant proteinâ1 (MCPâ1) belong to the CâC chemotactic cytokine family, a group of lowâmolecularâweight peptides. These molecules modulate chemotaxis, proliferation, and cytokine expression in leukocyte subsets. Our group has investigated the roles of MCPâ1 and MIPâ1α in the bleomycin model. Both MCPâ1 and MIPâ1α are expressed in a timeâdependent manner after bleomycin challenge, and passive immunization of these animals with either antiâMIPâ1α or antiâMCPâ1 antibodies attenuated leukocyte accumulation. In addition, we have identified specific cell types expressing MCPâ1 or MIPâ1α by in situ hybridization and immunohistochemical localization, respectively. Furthermore, our results indicate that MIPâ1α expression is mediated by alveolar macrophageâderived tumor necrosis factor, identifying an important cytokine pathway in the initiation of pulmonary fibrosis. Finally, antiâMIPâ1α therapy attenuated fibrosis, providing direct evidence for its involvement in fibrotic pathology. Our work has clearly established that the CâC chemokines MCPâ1 and MIPâ1α are expressed and contribute to the initiation and maintenance of the bleomycinâinduced pulmonary lesion. J. Leukoc. Biol. 57: 782â787; 1995.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141648/1/jlb0782.pd
Associations of the plasma lipidome with mortality in the acute respiratory distress syndrome: a longitudinal cohort study
Abstract
Background
It is unknown if the plasma lipidome is a useful tool for improving our understanding of the acute respiratory distress syndrome (ARDS). Therefore, we measured the plasma lipidome of individuals with ARDS at two time-points to determine if changes in the plasma lipidome distinguished survivors from non-survivors. We hypothesized that both the absolute concentration and change in concentration over time of plasma lipids are associated with 28-day mortality in this population.
Methods
Samples for this longitudinal observational cohort study were collected at multiple tertiary-care academic medical centers as part of a previous multicenter clinical trial. A mass spectrometry shot-gun lipidomic assay was used to quantify the lipidome in plasma samples from 30 individuals. Samples from two different days were analyzed for each subject. After removing lipids with a coefficient of variation >â30%, differences between cohorts were identified using repeated measures analysis of variance. The false discovery rate was used to adjust for multiple comparisons. Relationships between significant compounds were explored using hierarchical clustering of the Pearson correlation coefficients and the magnitude of these relationships was described using receiver operating characteristic curves.
Results
The mass spectrometry assay reliably measured 359 lipids. After adjusting for multiple comparisons, 90 compounds differed between survivors and non-survivors. Survivors had higher levels for each of these lipids except for five membrane lipids. Glycerolipids, particularly those containing polyunsaturated fatty acid side-chains, represented many of the lipids with higher concentrations in survivors. The change in lipid concentration over time did not differ between survivors and non-survivors.
Conclusions
The concentration of multiple plasma lipids is associated with mortality in this group of critically ill patients with ARDS. Absolute lipid levels provided more information than the change in concentration over time. These findings support future research aimed at integrating lipidomics into critical care medicine.https://deepblue.lib.umich.edu/bitstream/2027.42/143134/1/12931_2018_Article_758.pd
Associations of the plasma lipidome with mortality in the acute respiratory distress syndrome: a longitudinal cohort study
Abstract
Background
It is unknown if the plasma lipidome is a useful tool for improving our understanding of the acute respiratory distress syndrome (ARDS). Therefore, we measured the plasma lipidome of individuals with ARDS at two time-points to determine if changes in the plasma lipidome distinguished survivors from non-survivors. We hypothesized that both the absolute concentration and change in concentration over time of plasma lipids are associated with 28-day mortality in this population.
Methods
Samples for this longitudinal observational cohort study were collected at multiple tertiary-care academic medical centers as part of a previous multicenter clinical trial. A mass spectrometry shot-gun lipidomic assay was used to quantify the lipidome in plasma samples from 30 individuals. Samples from two different days were analyzed for each subject. After removing lipids with a coefficient of variation >â30%, differences between cohorts were identified using repeated measures analysis of variance. The false discovery rate was used to adjust for multiple comparisons. Relationships between significant compounds were explored using hierarchical clustering of the Pearson correlation coefficients and the magnitude of these relationships was described using receiver operating characteristic curves.
Results
The mass spectrometry assay reliably measured 359 lipids. After adjusting for multiple comparisons, 90 compounds differed between survivors and non-survivors. Survivors had higher levels for each of these lipids except for five membrane lipids. Glycerolipids, particularly those containing polyunsaturated fatty acid side-chains, represented many of the lipids with higher concentrations in survivors. The change in lipid concentration over time did not differ between survivors and non-survivors.
Conclusions
The concentration of multiple plasma lipids is associated with mortality in this group of critically ill patients with ARDS. Absolute lipid levels provided more information than the change in concentration over time. These findings support future research aimed at integrating lipidomics into critical care medicine.https://deepblue.lib.umich.edu/bitstream/2027.42/143134/1/12931_2018_Article_758.pd
Therapeutic Efficacy of Cintredekin Besudotox (IL13-PE38QQR) in Murine Lung Fibrosis Is Unaffected by Immunity to Pseudomonas aeruginosa Exotoxin A
Background: 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. Methodology/Principal Findings: Fourteen days after P. aeruginosa infection, C57BL/6 mice were injected with bleomycin via the intratracheal route. Other groups of mice received 4 doses of saline or IL13-PE by either intranasal or intraperitoneal application, and were challenged i.t. with bleomycin 28 days later. At day 21 after bleomycin, all mice received either saline vehicle or IL13-PE by the intranasal route and histopatological analyses of whole lung samples were performed at day 28 after bleomycin. Intrapulmonary P. aeruginosa infection promoted a neutralizing IgG2A and IgA antibody response in BALF and serum. Surprisingly, histological analysis showed that a prior P. aeruginosa infection attenuated the development of bleomycin-induced pulmonary fibrosis, which was modestly further attenuated by the intranasal administration of IL13-PE. Although prior intranasal administration of IL13-PE failed to elicit an antibody response, the systemic administration of IL13-PE induced a strong neutralizing antibody response. However, the prior systemic sensitization of mice with IL13-PE did not inhibit the anti-fibrotic effect of IL13-PE in fibrotic mice. Conclusions: Thus, IL13-PE therapy in pulmonary fibrosis works regardless of the presence of a humoral immune response to Pseudomonas exotoxin A. Interestingly, a prior infection with P. aeruginosa markedly attenuated the pulmonary fibrotic response suggesting that the immune elicitation by this pathogen exerts anti-fibrotic effects.National Institutes of Health (NIH)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)NeoPharm, In
Overexpression of sICAM-1 in the Alveolar Epithelial Space Results in an Exaggerated Inflammatory Response and Early Death in Gram Negative Pneumonia
Abstract
Background
A sizeable body of data demonstrates that membrane ICAM-1 (mICAM-1) plays a significant role in host defense in a site-specific fashion. On the pulmonary vascular endothelium, mICAM-1 is necessary for normal leukocyte recruitment during acute inflammation. On alveolar epithelial cells (AECs), we have shown previously that the presence of normal mICAM-1 is essential for optimal alveolar macrophage (AM) function. We have also shown that ICAM-1 is present in the alveolar space as a soluble protein that is likely produced through cleavage of mICAM-1. Soluble intercellular adhesion molecule-1 (sICAM-1) is abundantly present in the alveolar lining fluid of the normal lung and could be generated by proteolytic cleavage of mICAM-1, which is highly expressed on type I AECs. Although a growing body of data suggesting that intravascular sICAM-1 has functional effects, little is known about sICAM-1 in the alveolus. We hypothesized that sICAM-1 in the alveolar space modulates the innate immune response and alters the response to pulmonary infection.
Methods
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.
Results
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.
Conclusions
We conclude that alveolar sICAM-1 modulates pulmonary inflammation. Manipulating ICAM-1 interactions therapeutically may modulate the host response to Gram negative pulmonary infections.http://deepblue.lib.umich.edu/bitstream/2027.42/112728/1/12931_2010_Article_1038.pd
- âŠ