Plasma cells and IL-4 in chronic bronchitis and chronic obstructive pulmonary disease.

RATIONALE: Airway wall inflammation, IL-4, and mucus hypersecretion are thought to be associated. OBJECTIVES: To quantify bronchial inflammatory cells in smokers with chronic bronchitis (CB) with and without airflow obstruction (AO), determining the cells expressing IL-4 and IL-5 and their association with submucosal gland mucin. METHODS: We applied immunohistochemistry to identify, and double-labeling to colocalize, IL-4 and IL-5 to distinct inflammatory cells in resected bronchi from (1) 11 asymptomatic smokers (AS), (2) 11 smokers with CB, and (3) 10 smokers with CB and AO. MEASUREMENTS AND MAIN RESULTS: There were greater numbers of mucosal and gland CD45(+) leukocytes in CB (epithelium, 673/mm(2); subepithelium, 698/mm(2); gland, 517/mm(2)) than in AS (331, 237, and 178/mm(2), respectively; p < 0.01 for all) or CB + AO (375, 243, and 215/mm(2), respectively; p < 0.05 for all). There were greater numbers of subepithelial and submucosal gland plasma cells in CB (subepithelium, 110/mm(2); gland, 213/mm(2)) compared with AS (38 and 41/mm(2), respectively; p < 0.01 for both), and more subepithelial mast cells in CB (204/mm(2)) than in AS (65/mm(2); p < 0.01) or CB + AO (115/mm(2); p < 0.01). In CB, the percentage of gland occupied by mucin was positively correlated with the numbers of interstitial CD45(+) cells, plasma cells, and IL-4 protein(+) cells. In CB, 69 and 62% of gland-associated plasma cells expressed IL-4 and IL-5, respectively. CONCLUSIONS: Inflammatory cells are increased in bronchial submucosal glands and mucosa of large airways in smokers with CB. Gland-associated plasma cells express IL-4, and these likely promote mucus hypersecretion.

Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease.

Cilomilast (Ariflo), a new oral phosphodiesterase-4 selective inhibitor, improves lung function in chronic obstructive pulmonary disease (COPD). We have evaluated its antiinflammatory effects in 59 patients with COPD randomized to receive cilomilast, 15 mg two times a day, or placebo for 12 weeks. Induced sputum differential cell counts were obtained at baseline and at five further visits. Interleukin-8 and neutrophil elastase were measured in sputum supernatant. Bronchial biopsies obtained at baseline and at Week 10 were immunostained and counted for neutrophils, CD8+ and CD4+ T-lymphocyte subsets, and CD68+ macrophages. Cells expressing the genes for interleukin-8 and tumor necrosis factor-alpha were identified by in situ hybridization and quantified. Compared with placebo, analysis of variance (ANOVA) of the change from baseline showed that cilomilast did not alter any sputum endpoint or FEV1. However, bronchial biopsies demonstrated that cilomilast treatment was associated with reductions in CD8+ (p = 0.001; ANOVA) and CD68+ cells (p < 0.05; ANOVA). In addition, by Poisson analysis, comparison of cell counts analyzed as a ratio of active to placebo demonstrated reductions of CD8+ (48% p < 0.01) and CD68+ (47% p = 0.001) cells. This is the first demonstration of reduction by any agent of airway tissue inflammatory cells characteristic of COPD. Phosphodiesterase-4 inhibitors represent a promising new class of substances for use in antiinflammatory treatment of this disease.