The development of allergic inflammation is affected by many factors including adhesion molecules. Adhesion molecules contribute to cell migration, activation, and cell-cell interactions. Of the adhesion molecules identified with allergic inflammation, members of the Ig superfamily have been found to play a role and are expressed on endothelium, epithelium and leukocytes. The recently described Ig member, ICAM-3, is expressed only on leukocytes and participates in leukocyte- leukocyte adhesion. Moreover, ligation of ICAM-3 results in pro-inflammatory (antigen presentation and Cytokine secretion) and anti-inflammatory (enhancing apoptosis) effects. Little is known about the factors that regulate expression and function of ICAM-3 on eosinophils, a prevalent infiltrating leukocyte in the airways of patients with active asthma. Preliminary data have, however, demonstrated ICAM-3 to be constitutively and highly expressed on peripheral blood human eosinophils. Furthermore, ligation of ICAM-3 by specific antibodies inhibits eosinophil mRNA and protein for GM-CSF, which may thereby lead to apoptosis. Based upon previous evidence with neutrophil ICAM-3 and preliminary data, it is now hypothesized that a principle activity of ICAM-3 on eosinophils is regulation of apoptosis. To test this hypothesis, studies in Specific Aim 1 will define the expression, regulation and function of ICAM-3 using isolated blood eosinophils from normal individuals, patients with asthma and/or allergic disease, and in selected experiments cells from the airways of allergic subjects. The effect of ligated ICAM-3 on the function of these cells will be determined by the measurement of respiratory burst, degranulation, Cytokine secretion, adhesion and signal transduction. Studies in Specific Aim 2 will establish the role of ICAM-3 in modulating eosinophil apoptosis. The effect of ligation of ICAM-3 alone, or following fibronectin- or cytokine- enhanced (i.e. IL-5, GM-CSF) survival, will be determined both in blood and airway eosinophils. In addition, Specific Aim 2 will evaluate the ability of ICAM-3 expression and/or ligation to influence the binding of apoptotic eosinophils to monocyte-derived or airway macrophages. Based upon findings from these experiments, the contribution of ICAM-3 on eosinophils to allergic inflammation will be established and will provide new and novel insight into the role of this adhesion protein in regulating factors in allergic inflammation and possibly lead to new therapies in asthma.
| Kessel, Julie M; Cale, Jackie M; Verbrick, Erin et al. (2009) Antenatal betamethasone depresses maternal and fetal aldosterone levels. Reprod Sci 16:94-104 |
