Differing Patterns of P-Selectin Expression in Lung Injury

Abstract

Using two models of acute lung inflammatory injury in rats (intrapulmonary deposition of immunoglobulin G immune complexes and systemic activation of complement after infusion of purified cobra venom factor), we have analyzed the requirements and patterns for upregulation of lung vascular P-selectin. In the immune complex model, upregulation of P-selectin was defined by Northern and Western blot analysis of lung homogenates, by immunostaining of lung tissue, and by vascular fixation of 125I-labeled anti-P-selectin. P-selectin protein was detected by 1 hour (long before detection of mRNA) and expression was sustained for the next 7 hours, in striking contrast to the pattern of P-selectin expression in the cobra venom factor model, in which upregulation was very transient (within the 1st hour). In the immune complex model, injury and neutrophil accumulation were P-selectin dependent. Upregulation of P-selectin was dependent on an intact complement system, and the presence of blood neutrophils was susceptible to the antioxidant dimethyl sulfoxide and required C5a but not tumor necrosis factor alpha. In contrast, in the cobra venom factor model, upregulation of P-selectin, which is C5a dependent, was also dimethyl sulfoxide sensitive but neutrophil independent. Different mechanisms that may explain why upregulation of lung vascular P-selectin is either transient or sustained are discussed.

Pressure is proinflammatory in lung venular capillaries

“…The presence of soluble P-selectin in plasma (45,46) suggests that its ectodomain may be shed from endothelial cells (37). Consistent with previous reports, P-selectin expression in lung microvessels was barely detectable at baseline (14,15). In contrast, high pressure not only increased P-selectin expression, but also increased the rate of P-selectin removal from the capillary surface.…”

“…Endothelial Weibel-Palade (WP) bodies store P-selectin (12) and undergo Ca 2+ -dependent exocytosis to express the receptor (13). Although P-selectin expression is almost undetectable in resting blood vessels (14,15), the expression is enhanced by several injury stimuli (12,16) and forms a hallmark of the early stage of inflammation (17).…”

Antisense Knockdown of Sphingosine Kinase 1 in Human Macrophages Inhibits C5a Receptor-Dependent Signal Transduction, Ca2+ Signals, Enzyme Release, Cytokine Production, and Chemotaxis

“…Activation of C5aR triggers a number of rapid proinflammatory responses, including up-regulation of cell adhesion molecules, cytokine and enzyme release, and leukocyte migration (34,35). Recently, C5a has been shown to have an immunoregulatory role able to stimulate mediators of both acute and chronic inflammation (36 -39).…”

C5a-Induced Gene Expression in Human Umbilical Vein Endothelial Cells

“…Interestingly, our microarray data did not display a change in gene expression for P-selectin (data not shown). P-selectin has been shown to be expressed very rapidly (15 minutes) in response to C5a on endothelial cells, 42 inferring that the increased expression is because of storage granule translocation rather than to a transcriptional product.…”