The expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and more specifically vascular adhesion molecule-1 (VCAM-1) on lung fibroblasts may be important for migration of inflammatory cells through the submucosa to the airway lumen in the asthmatic inflammatory response. This study aimed to assess which cytokines are regulating ICAM-1 and VCAM-1 expression on human lung fibroblasts. For this purpose, confluent fibroblast cultures (derived from lung tissue from a nonasthmatic donor) were stimulated for 4 h with interleukin(IL)-1b, tumour necrosis factor (TNF)a, interferon (IFN)c, IL-4, IL-5 or transforming growth factor (TGF)b.IL-1b (optimal concentration (OC) 1 U . mL -1 ) and TNFa (OC 100 U . mL -1 ) both increased ICAM-1 and VCAM-1 expression. IFNc (OC 2 U . mL -1 ) increased only ICAM-1 expression and IL-4 (OC 5 ng . mL -1 ) increased only VCAM-1 expression, whereas IL-5 (20 ng . mL -1 ) and TGFb (10 ng . mL -1 ) did not influence ICAM-1 or VCAM-1 expression. ICAM-1 expression reached a plateau at 8±12 h after cytokine stimulation and remained constant for at least 24 h. VCAM-1 showed a transient increased expression within 24 h after IL-1b and TNFa stimulation. In contrast, VCAM-1 expression did not decrease after maximal expression at 4 h upon IL-4 stimulation.It is concluded that the Helper-1T-cell, type cytokine interferon c and the Helper-2 T-cell type cytokine interleukin-4 differentially regulate intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression on human lung fibroblasts. The proinflammatory cytokines interleukin-1b and tumour necrosis factor a increase both intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, without differential regulation of the expression of these adhesion molecules. Eur Respir J 1999; 14: 759±766.
E Eo os si in no op ph hi il ls s a an nd d e eo os si in no op ph hi il l--d de er ri iv ve ed d p pr ro ot te ei in ns s i in n cThe number of eosinophils, serum ECP and EDN, and urinary EDN were determined in 22 children with stable, allergic asthma, aged 4-14 yrs, and in 17 agematched healthy controls. Symptoms were monitored, the peak expiratory flow rate (PEFR) was recorded in the younger children, and lung function tests (forced expiratory volume in one second (FEV1) and the provocative concentration of histamine causing a 20% fall in FEV1 (PC20)) were performed in the older children. None of the asthmatic children had respiratory symptoms. PEFR was not significantly different in asthmatic children compared to controls. The FEV1 % predicted was significantly lower compared to controls.The number of eosinophils, serum ECP and EDN, and urinary EDN were significantly higher in asthmatic children compared with controls. After correction of serum ECP and EDN, and urinary EDN for the number of eosinophils, the differences between patients and controls disappeared. The nocturnal PEFR and the FEV1 were significantly related to urinary EDN.The results suggest that serum and urinary concentration of eosinophil-derived proteins can be determined instead of the number of eosinophils to support the diagnosis of asthma in childhood. The urinary concentration of eosinophil-derived neurotoxin can be especially valuable in young children, because in this age group quantification of lung function cannot be performed and blood sampling can be difficult.
Our results indicate that the number of eosinophils, serum ECP and EDN and urinary EDN as well as urinary NT-methyl-histamine do not reflect asthma disease activity in children with stable moderate asthma. Our data on urinary EDN warrant further study of the use of this parameter to monitor asthma in children.
The glucocorticoid budesonide and the long-acting b 2 -adrenoceptor agonist formoterol are used in asthma therapy for their anti-inflammatory and bronchodilating effects, respectively. Since expression of adhesion molecules on resident cells in the lung plays an important role in asthmatic inflammatory responses, the effects of these drugs on the cytokine-induced intercellular adhesion molecule-1 (ICAM)-1 and vascular cell adhesion molecule-1 (VCAM)-1 expression of human lung fibroblasts were investigated.Budesonide and formoterol were added in the absence or presence of interleukin (IL)-1b, tumour necrosis factor-a (TNF-a), interferon gamma (IFN-c) or IL-4 to human lung fibroblasts; ICAM-1 and VCAM-1 expression were measured after 8 h using a cell surface enzyme linked immunosorbent assay (ELISA).It was found that both budesonide and formoterol significantly inhibited (p<0.05) the increased expression of ICAM-1 and VCAM-1 after stimulation with IL-1b (maximal inhibition (median (25±75% percentiles) 50 (48±52) and 61% (42±69), respectively, with budesonide and 55 (50±73) and 86% (64±94), respectively, with formoterol (10 -7 M)), TNF-a (maximal inhibition 49 (46±57) and 57% (44±68), respectively, with budesonide and 44 (40±75) and 62% (52±83) respectively, with formoterol), IFN-c (maximal inhibition 64% (41±67) with budesonide and 39% (29±49) with formoterol for ICAM-1) and IL-4 (maximal inhibition 82% (69±92) with budesonide and 43% (33±67) with formoterol for VCAM-1) in a dose-dependent manner.The results show that budesonide, as well as formoterol, in probably clinically relevant concentrations inhibits cytokine-induced adhesion molecule expression on human lung fibroblasts from a concentration of 10 -9 M. This inhibitory effect on resident cells may have implications for the infiltration of inflammatory cells into pulmonary tissue during therapy with these drugs in asthma. Eur Respir J 2000; 15: 68±74.
Eosinophilic airway infiltration is a central feature in asthma. Eosinophils recovered from bronchoalveolar fluid show an activated phenotype, e.g., increased CD11b and decreased L-selectin expression. We investigated whether lung fibroblasts are able to activate eosinophils in vitro, and if so, which activating factor is most important. CD11b and L-selectin expression of isolated peripheral blood eosinophils were measured by flow cytometry after coculture with normal lung fibroblasts or their conditioned medium. We found that eosinophil CD11b expression increased (154% and 210%, p < 0.05) and L-selectin expression decreased (59% and 35.5%, p < 0.05) on eosinophils compared with baseline (100%) after 4 and 24 h of coculture with interleukin-1-beta (IL-1beta)-stimulated fibroblasts, respectively. Conditioned medium of stimulated fibroblasts also increased CD11b expression, but to a smaller extent (p < 0.05). L-selectin expression of eosinophils in cocultures was not different from that of eosinophils in conditioned medium. Only anti-granulocyte/macrophage colony-stimulating factor (anti-GM-CSF) reduced the activation of eosinophils in conditioned medium to almost basal levels (p < 0.05). An increase in CD11b expression is mediated by cytokines as well as direct cell contact, whereas a decrease in L-selectin expression is only mediated by cytokines. GM-CSF released by fibroblasts is an important factor in the modulation of both CD11b and L-selectin expression. These results show that lung fibroblasts can activate eosinophils by both adhesive interactions and by soluble factors.
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