Detection of granulocyte-macrophage colony-stimulating factor in patients with pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis (PAP) is an idiopathic lung disease in which the alveolar spaces are filled with surfactant. Recently, it has been prop osed that PAP is caused by deficiency of granulocyte-macrophage colony-stim ulating factor (GM-CSF) because GM-CSF-knockout mice develop the disease. T o examine this possibility, we tested the two hypotheses that lung GM-CSF l evels are low and that alveolar macrophages (AM) do not respond to GMCSF in patients with PAP. Data from 10 adult patients with PAP who underwent ther apeutic whole-rung lavage were compared with those of 10 healthy volunteers who underwent bronchoalveolar lavage (BAL) by fiberoptic bronchoscopy. Bro nchoalveolar lavage fluid (BALF) and plasma were collected and analyzed for total protein and levels of GM-CSF, interleukin-3, and tumor necrosis fact or (TNF)-alpha. Isolated AM were cultured with or without lipopolysaccharid e (LDS) or GM-CSF, and production of gM-CSF and TNF-or was measured after 2 4 h. GM-CSF in BALF and plasma was higher in PAP than in control subjects ( p less than or equal to 0.05), and was detectable under both reducing and n onreducing conditions as a 28-kD protein in BALF from the PAP patients. GM- CSF release by unstimulated AM from PAP patients was higher than in cells f rom control subjects, but the responses to LPS were similar. Mean TNF-ol re lease by AM in response to GM-CSF was higher in control subjects than in PA P patients due to a low response in three patients. In conclusion, unbound immunoreactive GM-CSF is detectable in BALF and plasma of PAP patients. Mos t PAP patients also had intact AM responses to GM-CSF, although some may ha ve had defects in GM-CSF receptor or signal-transduction mechanisms. Althou gh these data exclude lack of GM-CSF production as a common etiology of hum an PAP, defects in GM-CSF function in PAP are under investigation.