Fibronectin (Fn), which is released from several kinds of cells including alveolar macrophages (AM), is important in inflammatory reactions in the certain lung diseases such as idiopathic pulmonary fibrosis (IPF). Therefore, information on the mechanisms regulating Fn release from AM may be useful for elucidating the pathogenesis of these diseases and developing therapeutic modalities. We supposed that prostaglandin E₂ (PGE₂), which is known to modulate cellular functions, might be involved in regulation of Fn release, and, accordingly, we measured the release of Fn and PGE₂ from AM from normal volunteers (NV), control patients (CP), and patients with IPF. AM from patients with IPF were found to release more Fn than AM from NV (IPF: 250 ± 58.8/10⁶ cells-24 h, NV: 53.0 ± 7.3 ng/10⁶ cells·24 h) and to release less PGE₂ than the latter (IPF: 0.48 ± 0.12 ng/10⁶ cells·24 h, NV: 1.35 ± 0.24 ng/10⁶ cells·24 h). A negative correlation was found between the contents of Fn and PGE₂ in the culture media of AM from NV, CP, and patients with IPF. Lipopolysaccharide, phorbolmyristate acetate, and zymosan suppressed Fn release from AM but stimulated their PGE₂ release, and these effects were reversed by indomethacin. Exogenous PGE₂ (> 1 × 10⁻⁸ M) suppressed Fn release. The albumin-antialbumin complex stimulated Fn release but did not affect PGE₂ release. These results indicate that Fn release from AM changed in response to various stimuli, and that PGE₂ is important in suppressing Fn release from AM, suggesting a negative feedback mechanism of PGE₂ in releasing Fn.