Background -Diffuse panbronchiolitis is a chronic infection ofthe lower respiratory tract common among the Japanese people, with a persistent Pseudomonas aeruginosa infection in the late stage and sustained neutrophil retention in the airways. The long term effect of erythromycin was examined retrospectively in a group of patients with diffuse panbronchiolitis, with and without P aeruginosa infection, and the relationship between drug-induced bacterial clearance and clinical improvement was investigated. Methods -The history, daily volume of sputum, type of organisms in sputum cultures, pulmonary function tests, arterial blood gas tensions, and chest radiographs were compared in 16 patients with diffuse panbronchiolitis with P aeruginosa infection and 12 without. The total and differential cell counts in the bronchoalveolar lavage (BAL) fluid were compared in 14 ofthe 28 patients (five ofwhom were infected with P aeruginosa) before and after 1-12 months of treatment with erythromycin (600 mg/day). The outcome oftreatment in patients showing clearance of organisms on repeated sputum cultures was compared with that in those demonstrating persistence of bacteria in the sputum and patients with normal flora. Results -Erythromycin improved respiratory function and arterial blood gas tensions irrespective of the presence or absence of P aeruginosa in the sputum.Treatment also resulted in a reduction in the BAL fluid total cell count and the percentage of neutrophils in both groups of patients. There were no differences between patients in whom the bacteria cleared and those with persistent bacteria or patients with a normal flora with regard to the degree of improvement of respiratory function, arterial blood gas tensions, and BAL fluid cell composition.Conclusion -The results suggest that the efficacy of erythromycin in diffuse panbronchiolitis may be due to an anti-inflammatory effect, independent of P aeruginosa infection or bacterial clearance.

We have recently reported that long-term administration of erythromycin at a low dose reduced the number of neutrophils and concentrations of interleukin 8 (IL-8) in bronchoalveolar lavage fluid in patients with chronic lower respiratory tract disease. To investigate the mechanism of action of erythromycin, we evaluated its effect on IL-8 production in the 1 alpha,25-dihydroxyvitamin D3-stimulated human monocytic cell line THP-1. Erythromycin at a concentration of 10 micrograms/ml significantly reduced IL-8 production by THP-1 cells stimulated with lipopolysaccharide (10 ng/ml) and 1% normal human serum compared with the amount produced by untreated cells (untreated cells, 2,448 pg/ml; erythromycin-treated cells, 872 pg/ml). Our results suggest that erythromycin may impair IL-8 production by alveolar macrophages, ultimately reducing neutrophil accumulation in the airspace.

We evaluated the effect of erythromycin therapy on pulmonary function tests and the airway inflammatory response of patients with DPB. The number of neutrophils in BALF obtained from DPB patients was significantly higher than that of healthy volunteers. Treatment with erythromycin (600 mg/day for 12.9+/-9.5 months (mean +/- s.d.)) significantly reduced the total number of cells and neutrophils in the airway, and significantly improved pulmonary function tests. The levels of IL-1beta and IL-8 were significantly higher in DPB compared with healthy volunteers (P<0.05, P<0.05, respectively). IL-1Ra in patients is considered to have a weak inhibitory activity for IL-1beta, with approximately five-fold concentration of IL-1beta compared with that in healthy volunteers (approx. nine-fold concentration of IL-1beta). Erythromycin therapy significantly reduced these cytokines to levels comparable to those of healthy volunteers, and produced a trend toward reduction in the level of IL-1Ra in BALF. The level of IL-1beta correlated significantly with the concentration of neutrophils in BALF (r=0.72, P<0.01), as well as with the level of IL-1Ra (r=0.688, P<0.05) and IL-8 (r=0.653, P<0.05). A nearly significant or significant correlation was observed between the concentration of neutrophils and levels of IL-1Ra or IL-8 in BALF (r=0.526, P=0.053 or r=0.776, P<0.01, respectively). There was also a significant relationship between FEV(1) and the concentration of neutrophils in BALF (r=0.524, P<0.05). Our results suggest that the relative amounts of IL-1beta and IL-1Ra or IL-8 may contribute, at least in part, to the neutrophil-mediated chronic airway inflammation in patients with chronic airway disease, and long-term erythromycin therapy may down-regulate the vigorous cycle between the cytokine network and neutrophil accumulation, with resultant reduction of neutrophil-mediated inflammatory response.

SUMMARYA number of adhesion molecules participate in the recruitment of inflammatory cells to the site of inflammation, and selectins together with their ligands are important in the early transient adhesion phase. In this study, we evaluated the role of l-selectin in T lymphocyte alveolitis in patients with active pulmonary sarcoidosis. We measured serum and bronchoalveolar lavage fluid (BALF) concentrations of soluble (s)l-selectin using an ELISA. Serum and BALF concentrations of sl-selectin were significantly elevated in patients with sarcoidosis compared with control healthy subjects and idiopathic pulmonary fibrosis (IPF) patients (P , 0´05 and P , 0´01, respectively). The lymphocyte surface marker was also examined in peripheral blood and BALF by flow cytometric analysis. The percentage of CD3 1 CD62L 1 cells (l-selectin-bearing T lymphocytes) was significantly lower in peripheral blood of sarcoidosis than in that of healthy subjects (P , 0´01). In contrast, the percentage of CD3 1 CD62L 2 cells (l-selectinnegative T lymphocytes) in BALF of patients with sarcoidosis was significantly higher than in healthy subjects (P , 0´05) and IPF patients (P , 0´01). Furthermore, there was a significant correlation between serum concentrations of sl-selectin and the number of l-selectin-negative T lymphocytes in BALF (r 0´535, P , 0´01). Our results suggest that l-selectin may be involved in T lymphocyte alveolitis in patients with active pulmonary sarcoidosis.

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