Recently, "low-dose and long-term" erythromycin treatment has been reported as effective on diffuse panbronchiolitis (DPB), but its mechanism is still obscure. Patients with DPB were found to have significantly higher percentages of neutrophils in the pre-erythromycin treatment bronchoalveolar lavage fluid (BALF) than healthy nonsmoking volunteers (p < 0.001). They showed a significant reduction in BALF neutrophil percentages after erythromycin treatment (p < 0.01). The neutrophil chemotactic activity (NCA) was significantly elevated in BALF obtained from 19 patients with DPB compared with that from healthy volunteers (p < 0.001). A significant reduction in the NCA was observed in post-erythromycin treatment BALF of 11 patients with DPB (p < 0.001). Additionally, there was a significant correlation between the reduction of NCA and neutrophil percentage in pre- and post-erythromycin treatment BALF (r = 0.726, p < 0.05). Finally, we investigated the effect of erythromycin on the intrapulmonary influx of neutrophils by intratracheal injection of lipopolysaccharide (LPS) and interleukin-8 (IL-8) in mice. The intrapulmonary influx of neutrophils was significantly suppressed (p < 0.001) in mice intraperitoneally injected with erythromycin at 5 mg per animal 2 h before intratracheal injection of LPS (control group: 6.5 +/- 1.6 x 10(5) versus erythromycin-treated group: 1.7 +/- 0.5 x 10(5)), but not 10 h before lung challenge. This inhibition was observed at 6 h after lung challenge and became maximal with 84% suppression at 24 h. Week-long administration of erythromycin did not alter the intrapulmonary influx of neutrophils. The number of neutrophils in the peripheral blood was not affected by erythromycin, indicating that the drug was not toxic.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Abstractwhich may contribute to the pulmonary involvement in patients with sarcoidosis. Background -Sarcoidosis is a systemic (Thorax 1997;52:431-437) granulomatous disorder of unknown origin characterised by accumulation of T Keywords: adhesion molecules, chemokines, pullymphocytes and macrophages in multiple monary sarcoidosis.organs. Several cytokines and adhesion molecules may contribute to the accumulation of T lymphocytes in pulmonary sarcoidosis. The distribution of T Sarcoidosis is a chronic systemic disorder charlymphocyte subsets, T cell bearing CD11a acterised by the presence of non-caseating and chemokines such as regulated on granulomas and accumulation of T lymphoactivation normal T expressed and se-cytes and macrophages in multiple organs. 1 T lymphocytes, alveolar macrophages, and sevcreted (RANTES), macrophage inflameral cytokines are thought to play an important matory peptide 1 (MIP-1 ), and role in sarcoidosis, 2-4 although the aetiology of macrophage chemoattractant protein 1 the disease is still unknown. Recent studies (MCP-1) in bronchoalveolar lavage (BAL) using monoclonal antibodies to cell surface fluid and peripheral blood were compared antigens have demonstrated the presence of in untreated patients with sarcoidosis and subsets of T cells and expression of cell adnormal subjects.hesion molecules on peripheral blood lymMethods -Flow cytometric analysis with phocytes such as CD11a/CD18 (lymphocyte monoclonal antibodies to cell surface anfunction associated antigen 1, LFA-1) in sartigens was used to identify T lymphocyte coidosis. 5 Furthermore, analysis of bronchosubsets in the BAL fluid of untreated alveolar lavage (BAL) fluid in patients with patients with sarcoidosis (n=40) -either pulmonary sarcoidosis has also shown the preswithout (group A, n=12) or with (group B, ence of activated CD4+ and CD8+ T lymn=28) radiological evidence of pulmonary phocytes expressing HLA-DR antigen, 6 7 involvement -and in 22 normal subjects.increased alveolar macrophages, and preThe level of different chemokines was dominance of CD29+ memory T cells. 5 8 9 estimated by enzyme linked immunoLeucocyte adhesion molecules such as LFAsorbent assay (ELISA).1 of the 2 family are involved in leucocyteResults -A high percentage of CD3+ cells, endothelial adherence in the lung, 10 and the CD4+ cells expressing HLA-DR antigen, mechanism of T cell migration into the lung is and a high CD4/CD8 ratio were detected also initially dependent on the presence of in the BAL fluid of patients compared with adhesion molecules of both endothelial cells normal subjects. In particular, CD4+ and leucocytes. The 2 family shares a common CD29+ memory T cells were significantly chain (CD18) which is combined with three increased in patients with sarcoidosis. different chains (LFA-1, CD11a; Mac-1, Furthermore, these cells were higher in CD11b; p150/95, CD11c), and intercellular those in group B than group A. The level sible interaction between activated mem-phages. RANTES is a selective chemotactic

SUMMARYWe investigated the contribution of T cells in diffuse panbronchiolitis (DPB) by identifying T cell subsets in BALF of 36 patients with DPB, before and after long-term treatment with macrolide antibiotics, and 16 healthy control subjects. The percentages of lymphocytes and CD3þ gd þ cells in BALF of DPB patients and control subjects were similar, but the absolute number of these cells was higher in DPB patients. Treatment resulted in a significant reduction in the absolute number of these cells. A further two-colour analysis of T cell subsets in BALF showed a significantly higher ratio and number of CD8 þ HLA-DR þ cells in DPB patients. Treatment resulted in a significant reduction of activated T cells. Most BALF CD8 þ cells were CD8The number of these cells in BALF of DPB patients (26 . 69 Ϯ 5 . 86 × 10 3 /ml) was higher than the control (2 . 02 Ϯ 0 . 38 × 10 3 /ml; P < 0 . 001), and a significant reduction was observed after treatment (7 . 69 Ϯ 2 . 59 × 10 3 /ml; P < 0 . 01). The number of CD4 þ cells was also higher in DPB patients than in controls, and most were CD4 þ CD29þ memory T cells. However, treatment did not influence the number of these cells. The number of lymphocytes, CD3 and CD4þ CD29 þ cells was higher in patients with bacterial infection than in those without bacterial infection, and interestingly, macrolide therapy reduced the number of lymphocytes,þ CD11b ¹ and CD8 þ HLA-DR þ cells, irrespective of bacterial infection. In peripheral blood, the percentage of CD8 þ HLA-DR þ cells was also higher in DPB patients than in healthy subjects, and significantly decreased after treatment. The percentage of CD8 þ CD11b ¹ cells in peripheral blood was similar in DPB patients and normal subjects, and treatment significantly reduced the percentage of these cells. Finally, the expression of the adhesion molecules CD11a/CD18 (a/b-chains of LFA-1) on lung CD3 þ cells and CD49d (a-chain of VLA) on lung CD4 þ cells was enhanced compared with that on peripheral blood in DPB patients. Our results suggest that elevation of memory T cells and activation of CD8 þ cells, mainly cytotoxic T cells, in the airway lumen of DPB patients may contribute to chronic bronchial inflammation, possibly through up-regulation of adhesion molecules. Our findings also indicate that macrolide antibiotics may have a direct or indirect suppressive effect on cytotoxic T cells, and as such, reduce inflammation and improve clinical condition.

SUMMARYTo elucidate the pathogenic mechanisms of human T-lymphotropic virus type 1 (HTLV-1)-associated lung inflammation, we conducted a histopathological and molecular analysis study using transgenic mice bearing pX region of this virus. In these mice, accumulations of inflammatory cells consisting mainly of lymphocytes were present in peribronchiolar and perivascular areas and alveolar septa, while control littermate mice did not show such changes. In situ hybridization showed that the anatomic distribution of p40 tax mRNA was similar to that of inflammatory cells, typically in peribronchiolar areas and to a lesser extent in perivascular and alveolar septa. Inflammatory cytokines, including IL-1b , tumour necrosis factor-alpha and interferon-gamma, and several chemokines, such as monocyte chemotactic protein-1 (MCP-1), RANTES, macrophage inflammatory protein-1a (MIP-1a ) and IP-10, were detected in lungs of transgenic mice but not control mice. Semiquantitative analysis using reverse transcription-polymerase chain reaction showed a significant correlation between MCP-1 mRNA expression and p40 tax mRNA, but not with other chemokines. The gene expression of the above chemokines, with the exception of MIP-1a , correlated with the severity of histopathological changes in the lung. Considered together, our results suggested that p40 tax synthesis may be involved in the development of lung lesions caused by HTLV-1 through the induction of local production of chemokines.