Systemic Corticosteroid Treatment Reduces Bronchial Mucosal Activation of Activator Protein-1 (AP-1) Components In Cortlcosterold Sensitive, but Not Resistant Asthmatics

摘要

Background: Over expression of the transcriptional regulatory factor activator protein-1 (AP-1) may contribute to T-cell corticosteroid refractoriness in corticosteroid resistant asthma. We hypothesized that clinically corticosteroid resistant asthma is accompanied by failure of systemic corticosteroid to inhibit phosphorylation of c-jun and c-jun N-terminal kinase (JNK) in bronchial mucosal cells. Methods: Enumeration of total (CD45~+) leukocytes and cells expressing c-fos and total and phosphorylated c-jun and JNK in bronchial biopsy sections from 9 corticosteroid sensitive and 17 resistant asthmatics taken before and after oral prednisolone (40 mg/1.72 nr body surface area daily for 14 days) using specific antibodies, immunohistochemistry and image analysis. Results: At baseline, mean total (CD45~+) mucosal leukocytes, total cells expressing phosphorylated c-jun and JNK and mean percentages of cells in which these molecules were phosphorylaled were similar in both groups, whereas mean total numbers of c-fos immunoreactive cells were elevated in the corticosteroid resistant asthmatics (p = .04). Following prednisolone, the mean total cells expressing phosphorylated c-jun and JNK, as well as mean percentages of cells in which these molecules were phosphorylated were significantly reduced in the corticosleroid sensitive (p < .02), but not the resistant asthmatics. Mean total CD45~+ leukocytes and c-fos immunoreactive cells were not significantly altered in either group. Conclusions: Clinical corticosteroid responsiveness in asthma is accompanied by reduced phosphorylation of bronchial mucosal c-jun and JNK, a phenomenon not seen in resistant patients. Dysregulation of AP-1 activation leading to clinical corticosleroid resistance may reflect identifiable environmental influences and is a target for future therapy.