ABSTRACT
To assist the community provider in understanding and accessing Veterans Affairs (VA) resources, this commentary describes basic information regarding care of veterans. It highlights questions that may be incorporated into routine history taking, provides military culture resources, and clarifies pharmaceutical benefits. Table 2 is a quick reference guide to locate VA-based information on the Internet.
Subject(s)
Community Health Services/organization & administration , Community-Institutional Relations , United States Department of Veterans Affairs/organization & administration , Veterans , Humans , North Carolina , United StatesABSTRACT
Chronic obstructive pulmonary disease (COPD) is associated with persistent inflammation and oxidative stress in susceptible individuals. Using microarray analysis of bronchial biopsy samples from patients with COPD and controls, we identified Wnt4 as being up-regulated in COPD. Analysis of bronchial biopsy samples showed a very strong correlation between Wnt4 and IL8 gene expression, suggesting that Wnt4 plays a role in chronic lung inflammation. In vitro, Wnt4 induced proliferation and inflammation in human epithelial cells (BEAS-2B) and normal primary human bronchial epithelial cells in a concentration-dependent manner. This effect was enhanced in the presence of interleukin-1ß (IL-1ß) as a result of activation of the p38 and c-Jun NH2-terminal kinase mitogen-activated protein kinase pathways. Hydrogen peroxide, but not proinflammatory stimuli, up-regulated Wnt4 expression in epithelial cells. In monocytic THP-1 and primary airway smooth muscle cells, Wnt4 induced inflammation and enhanced the inflammatory response to lipopolysaccharide and IL-1ß but did not induce proliferation. In addition, these other cell types did not have enhanced Wnt4 expression in response to hydrogen peroxide. Our results indicate that airway epithelial activation, due to oxidative stress, may lead to Wnt4 induction. Wnt4, in turn, acts through the noncanonical pathway to activate epithelial cell remodeling and IL8 gene expression, leading to neutrophil infiltration and inflammation.
Subject(s)
Pulmonary Disease, Chronic Obstructive/genetics , Wnt4 Protein/metabolism , Adult , Aged , Animals , Bronchi/metabolism , Case-Control Studies , Cell Line , Cells, Cultured , Disease Models, Animal , Female , Humans , Inflammation Mediators/metabolism , Inflammation Mediators/physiology , Interleukin-8/physiology , Male , Mice , Mice, Inbred C57BL , Middle Aged , Pulmonary Disease, Chronic Obstructive/etiology , Pulmonary Disease, Chronic Obstructive/metabolism , Up-Regulation , Wnt4 Protein/antagonists & inhibitors , Wnt4 Protein/biosynthesisABSTRACT
It has been hypothesized that the main determinant of the intranuclear mobility of transcription factors is their ability to bind DNA. In the present study, we have extensively tested the relationship between the intranuclear mobility of the NF-kappaB subunit p65 and binding to its consensus target sequence. The affinity of p65 for this binding site is altered by mutation of specific acetylation sites, so these mutants provide a model system to study the relationship between specific DNA binding affinity and intranuclear mobility. DNA binding affinity was measured in vitro using an enzyme-linked immunosorbent assay-based method, and intranuclear mobility was measured using the fluorescence recovery after photobleaching technique on yellow fluorescent protein-tagged p65 constructs. A negative correlation was observed between DNA binding affinity and intranuclear mobility of p65 acetylation site mutants. However, moving the yellow fluorescent protein tag from the C terminus of p65 to the N terminus resulted in an increased mobility but did not significantly affect DNA binding affinity. Thus, all changes in DNA binding affinity produce alterations in mobility, but not vice versa. Finally, a positive correlation was observed between mobility and the randomness of the intranuclear distribution of p65. Our data are in line with a model in which the intranuclear mobility and distribution of a transcription factor are determined by its affinity for specific DNA sequences, which may be altered by protein-protein interactions.
