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The effects of histamine on lung macrophages have been studied by both biologic and radioligand experiments. After overnight adherence, lung macrophages spontaneously released β-glucuronidase (β-G) at a rate of approximately 7 nmol of hydrolyzed substrate/h/million cells. Histamine at low concentrations (10−9 to 10−8 M) resulted in a consistent potentiation of this release. The concentration-effect curve of histamine was bell-shaped, reaching an optimum at 10−9 M, with concentrations greater than 10−8 M having no significant effect. At a maximally effective concentration (10−9 M), histamine evoked a 135 ± 9.6% (mean ± SE; n = 8, P < 0.001) potentiation in the total amount of β-G released during the first 60 min of incubation. This increase in β-G release represented both a slight increase in β-G synthesis as well as an increase in the percentage of β-G released. When the secreted β-G is expressed as a percentage of total content, histamine (10−9 M) evoked a 125 ± 3.2% (mean ± SE; n = 27, P < 0.0005) enhancement. The potentiation of β-G release by histamine was evident after 45 min of incubation and persisted for up to 6 h. The potentiation of β-G by histamine was sensitive to inhibition by pyrilamine (10−7 M).Computerized analysis of saturation and inhibition binding curve has shown two classes of binding sites for pyrilamine, an H1 receptor antagonist, with Kd of 4.76 ± 2.0 nM and 183 ± 24.5 nM and receptor densities of 154 ± 55.3 fmol/mg of proteins and 7.5 pmol ± 1.16/mg of proteins, respectively (mean ± SE; n = 6).These observations support the hypothesis of histamine H1 receptor-mediated effects on lung macrophages. This effect may be of significance both physiologically in the defense against infections and other disease states and indicates another mechanism by which histamine released from mast cells or basophils may participate in chronic inflammation.