OXYGEN RADICAL PRODUCTION BY ALVEOLAR INFLAMMATORY CELLS IN IDIOPATHIC PULMONARY FIBROSIS

Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory interstitial lung disease characterized by the accumulation of alveolar macrophages (AMs) and neutrophils in the lower respiratory tract, parenchymal cell injury, and fibrosis of the alveolar structure. Reactive oxygen intermediates (ROI) are claimed to be a major cause of tissue damage in IPF; however, the source of ROI has not been unequivocally identified. AMs, as well as neutrophils, are capable of releasing these agents. The contributions of these possible sources are not known. To address this question, we evaluated the spontaneous and stimulated (PMA or zymosan) ROI release of total bronchoalveolar cells and isolated AMs in 14 patients with IPF by means of luminol-enhanced chemiluminescence. Bronchoalveolar lavage (BAL) cells from 17 individuals without any signs of inflammation served as controls. In comparison with the controls, the spontaneous as well as the stimulated ROI release of total BAL cells in IPF are markedly increased (20,736.9 ± 5,079.3 versus 2,509.5 ± 300.6 counts/10 s/2 · 105 cells, spontaneously, IPF versus control; 106,819.3 ± 33,802.8 versus 8,919 ± 1,357.9 PMA induced; 41,597.1 ± 8,442.6 versus 6,223.8 ± 1,025.1 zymosan induced, p < 0.001). Measurement of the ROI release of purified AMs revealed that these cells produce the bulk part of ROI released by BAL cells (84%). In spite of the fact that, on a per cell basis, the ROI release of neutrophils is 1.7-fold of that of AMs, there is no correlation between the ROI production of total BAL cells and the percentage of neutrophils in BAL, demonstrating a minor role of these cells in the generation of the total ROI burden in IPF. Additionally, it was not possible to suppress the ROI release by 10-6 M prednisolone; however, some cases of clinically effective therapy with prednisolone resulted in a marked decrease of the ROI burden. Our results demonstrate that in IPF, AMs and neutrophils produce heigtened amounts of ROI; the most important source, however, are AMs.