Rochelle G. Lindemeyer

Differential Expression of TRAIL and TRAIL Receptors in Allergic Asthmatics Following Segmental Antigen Challenge: Evidence for a Role of TRAIL in Eosinophil Survival

Asthma is a chronic lung disease exhibiting airway obstruction, hyperresponsiveness, and inflammation, characterized by the infiltration of eosinophils into the airways and the underlying tissue. Prolonged eosinophilic inflammation depends on the balance between the cell’s inherent tendency to undergo apoptosis and the local eosinophil-viability enhancing activity. TRAIL, a member of the TNF family, induces apoptosis in most transformed cells; however, its role in health and disease remains unknown. To test the hypothesis that Ag-induced inflammation is associated with TRAIL/TRAIL-R interactions, we used a segmental Ag challenge (SAC) model in ragweed-allergic asthmatics and nonasthmatic patients and analyzed bronchoalveolar lavage (BAL) material for 2 wk. In asthmatic patients, the level of TRAIL in BAL fluid dramatically increased 24 h after SAC, which significantly correlated with BAL eosinophil counts. Immunohistochemical analysis of bronchial biopsies from asthmatic patients demonstrated that TRAIL staining was increased in epithelial, airway smooth muscle, and vascular smooth muscle cells and throughout the interstitial tissue after SAC. This was confirmed by quantitative immunocytochemical image analysis of BAL eosinophils and alveolar macrophages, which demonstrated that expression levels of TRAIL and DcR2 increased, whereas expression levels of the TRAIL-Rs DR4 and DR5 decreased in asthmatic subjects after SAC. We also determined that TRAIL prolongs eosinophil survival ex vivo. These data provide the first in vivo evidence that TRAIL expression is increased in asthmatics following Ag provocation and suggest that modulation of TRAIL and TRAIL-R interactions may play a crucial role in promoting eosinophil survival in asthma.

TRAIL in the airways.

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is an important immunomodulatory factor that may play a role in the structural changes observed in the asthmatic airways. In vitro as well as in vivo studies have evidenced a dual role for TRAIL: it can either function as a pro- or anti-inflammatory cytokine on inflammatory cells, participating in the initiation and resolution of inflammatory and immune responses. TRAIL is expressed in the airways by inflammatory cells infiltrated in the bronchial mucosa, as well as by structural cells of the airway wall including fibroblasts, epithelial, endothelial, and smooth muscle cells. By releasing TRAIL, these different cell types may then participate in the increased levels of TRAIL observed in bronchoalveolar lavage fluid from asthmatic patients. Taken together, this suggests that TRAIL may play a role in inflammation in asthma. However, concerning its role is dual in the modulation of inflammation, further studies are needed to elucidate the precise role of TRAIL in the airways.

Phentolamine Mesylate for Accelerating Recovery from Lip and Tongue Anesthesia

Phentolamine mesylate, at dosages from 0.4 to 0.8 mg in adults and adolescents and at dosages from 0.2 to 0.4 mg in children aged 4 to 11 years, has been proven to be safe and effective for the reversal of soft tissue anesthesia (lip and tongue numbness) and the associated functional deficits resulting from a local dental anesthetic injection containing a vasoconstrictor. Its ability to block a-adrenergic receptors on blood vessels induces vasodilation and enhances the redistribution of the local anesthetic away from the injection site. The low dosages administered for dental local anesthetic reversal in all likelihood accounts for the lack of significant cardiovascular effects that are associated with the medical use of the drug for hypertensive conditions associated with catecholamine excess.