Spoelstra F M, Kauffman H F, Hovenga H, Noordhoek J A, de Monchy J G, Postma D S
Departments of Allergology and Pulmonology, University Hospital Groningen, Groningen, The Netherlands.
Am J Respir Crit Care Med. 2000 Oct;162(4 Pt 1):1229-34. doi: 10.1164/ajrccm.162.4.9911077.
Budesonide and formoterol are extensively used in current asthma therapy. Budesonide is known as potent antiinflammatory agent and formoterol also appears to have some antiinflammatory properties. We investigated inhibitory effects of these drugs on eosinophil activation in vitro as induced by fibroblast-conditioned medium (FCM). We measured the modulation of expression of clonal designator (CD)11b and L-selectin with flow cytometry after 4 h or 16 h of culture of eosinophils when budesonide or formoterol was applied either directly to the eosinophils while they were stimulated with FCM (direct method) or when each drug was applied to lung fibroblasts from which conditioned medium was then administered to eosinophils (indirect method). In the direct method, budesonide (10(-)(8) M) inhibited the modulation of CD11b (44 [25th to 75th percentiles: 26 to 66]% of control) and L-selectin (30 [-13 to 48]% of control) only after 16 h, and not after 4 h. Formoterol did not directly inhibit the modulation of eosinophil CD11b and L-selectin expression. In the indirect method, both budesonide and formoterol inhibited lung fibroblast activation, resulting in diminished eosinophil activation after 4 h. Budesonide or formoterol at 10(-)(8) M inhibited upregulation of CD11b to 26 [15 to 40]% and 38 [23 to 46]%, respectively, and inhibited L-selectin shedding to 14 [-3 to 50]% and 27 [2 to 62]%, respectively, of control values. These results show that budesonide inhibits eosinophil activation primarily through effects on lung fibroblasts, presumably by inhibiting production of granulocyte-macrophage colony-stimulating factor. After longer incubation periods, budesonide also directly inhibits eosinophil activation. In contrast, formoterol can inhibit eosinophil activation only via inhibitory effects on lung fibroblasts. We did not observe an additional effect of formoterol, beyond the effects induced by budesonide under any circumstance studied. Lung fibroblasts, in addition to eosinophils, may serve as important target cells for antiinflammatory treatment in asthma.
布地奈德和福莫特罗在当前哮喘治疗中被广泛应用。布地奈德是一种强效抗炎药，福莫特罗似乎也具有一定的抗炎特性。我们研究了这些药物对成纤维细胞条件培养基（FCM）诱导的体外嗜酸性粒细胞活化的抑制作用。当布地奈德或福莫特罗在嗜酸性粒细胞用FCM刺激时直接应用于嗜酸性粒细胞（直接法），或当每种药物应用于肺成纤维细胞，然后将条件培养基给予嗜酸性粒细胞（间接法）时，我们在嗜酸性粒细胞培养4小时或16小时后，用流式细胞术测量克隆分化抗原（CD）11b和L-选择素表达的调节情况。在直接法中，布地奈德（10⁻⁸M）仅在16小时后抑制CD11b（对照组的44[第25至75百分位数：26至66]%）和L-选择素（对照组的30[-13至48]%）的调节，而在4小时后无此作用。福莫特罗未直接抑制嗜酸性粒细胞CD11b和L-选择素表达的调节。在间接法中，布地奈德和福莫特罗均抑制肺成纤维细胞活化，导致4小时后嗜酸性粒细胞活化减弱。10⁻⁸M的布地奈德或福莫特罗分别将CD11b的上调抑制至对照组的26[15至40]%和38[23至46]%，并将L-选择素的脱落分别抑制至对照组的14[-3至50]%和27[2至62]%。这些结果表明，布地奈德主要通过对肺成纤维细胞的作用抑制嗜酸性粒细胞活化，推测是通过抑制粒细胞-巨噬细胞集落刺激因子的产生。在较长的孵育期后，布地奈德也直接抑制嗜酸性粒细胞活化。相比之下，福莫特罗仅通过对肺成纤维细胞的抑制作用来抑制嗜酸性粒细胞活化。在我们研究的任何情况下，除了布地奈德诱导的作用外，我们未观察到福莫特罗的额外作用。除嗜酸性粒细胞外，肺成纤维细胞可能是哮喘抗炎治疗的重要靶细胞。
