Effects of amiodarone-induced phospholipidosis on pulmonary host defense functions in rats.

The effect of the induction of pulmonary phospholipidosis by amiodarone on selected pulmonary host defense functions was studied in male Fischer-344 rats. One week of daily amiodarone treatment resulted in a 4.5-fold increase in total phospholipid in alveolar macrophages recovered from the lungs by bronchoalveolar lavage. The presence of the phospholipidosis had no effect on the phagocytosis of heat-killed yeast cells, the induction of luminol-dependent chemiluminescence, or the spontaneous release of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), or spontaneous and LPS-stimulated release of IL-1 by alveolar macrophages in vitro. In contrast, the LPS-stimulated release of IL-6 and TNF-alpha by phospholipidotic alveolar macrophages was enhanced compared with control cells. The pulmonary clearance of Listeria monocytogenes following intratracheal administration of the bacteria was not affected by the phospholipidotic condition. It appears that, in the context of the functions studied, the induction of pulmonary phospholipidosis by amiodarone does not impair pulmonary host defense processes in rats, and may actually be associated with the augmentation of some activities.

Subchronic pulmonary inflammation and fibrosis induced by silica in rats are attenuated by amiodarone.

A previous study demonstrated that the acute phase of silica-induced lung injury in rats can be attenuated by concomitant administration of amiodarone, a cationic amphiphilic drug that inhibits phospholipase activity in the lungs. The purpose of the present study was to determine whether continued amiodarone administration could inhibit subchronic silica-induced lung injury and fibrosis. Male Fischer-344 rats were administered amiodarone (150 mg/kg, p.o., 5 days/week) for 14 days and were then instilled with silica (100 mg/kg) intratracheally. Amiodarone treatment then continued for 60 days. Injury was evaluated by parameters in bronchoalveolar lavage fluid and fibrosis was assessed by lung hydroxyproline content and trichrome staining of collagen. Within the bronchoalveolar lavage fluid, amiodarone treatment resulted in significant decreases in silica-induced elevations in albumin levels, lactate dehydrogenase activity, beta-glucuronidase activity, and neutrophil influx. Amiodarone treatment resulted in significant reductions in silica-induced increases in lung weight and hydroxyproline levels; the diminution of fibrosis due to amiodarone treatment was confirmed histologically. These results indicate that subchronic pulmonary inflammation and fibrosis induced by silica in the rat can be attenuated by the concomitant administration of amiodarone.

Comparative evaluation of amiodarone-induced phospholipidosis and drug accumulation in Fischer-344 and Sprague-Dawley rats.

Amiodarone (AD) and its major metabolite, desethylamiodarone (desethylAD), are both phospholipogenic. The present study was undertaken to evaluate the comparative susceptibilities of male Fischer-344 and Sprague-Dawley rats to AD-induced phospholipidosis in alveolar macrophages (AMs), liver and kidney tissue and the concomitant accumulation of AD and desethylAD in these cells, tissues and plasma. Rats were administered AD (100 mg/kg/day, p.o.) for 1 week. Plasma concentrations of AD and desethylAD were approximately 4- and 12-fold higher, respectively, in Fischer-344s compared to Sprague-Dawleys 24 h after the last dose. AD and desethylAD levels in AMs were approximately 12- and 25-fold higher, respectively, in Fischer-344s than Sprague-Dawleys. In the liver and kidney, levels of both compounds were also significantly higher in Fischer-344s than Sprague-Dawleys. Ultrastructural features indicative of phospholipidosis were not observed consistently in any tissue except AMs from treated Fischer-344s. AM total phospholipid increased nearly 5-fold in Fischer-344s, while Sprague-Dawleys showed no increase over control. AMs from both strains incubated with 10 microM AD or desethylAD in vitro were not significantly different in their accumulation of the compounds. When incubated with AD or desethylAD, the lysosomal phospholipases A1 partially purified from AMs of both strains were equally sensitive to inhibition as measured by the drug concentration giving 50% inhibition in activity (IC50). The results of this study indicate that at the same administered dose, AD and desethylAD, accumulate to higher tissue levels and are more phospholipogenic in male Fischer-344 rats than in male Sprague-Dawley rats. The basis for the high susceptibility of Fischer-344 rats to AM-induced phospholipidosis is unknown at present but appears not to be related to biochemical or cellular features of the AMs.

In vivo and in vitro reversibility of chlorphentermine-induced phospholipidosis in rat alveolar macrophages.

Chlorphentermine (CP) is a cationic, amphiphilic drug (CAD) that has been studied widely for its ability to induce phospholipidosis, a disorder characterized by excessive accumulation of cellular phospholipid and ultrastructural development of lysosomal lamellar bodies (LLBs) in the cell. The accumulation of inducing drug correlates with increasing phospholipids. In the present study, we examined the reversibility of this disorder in rat alveolar macrophages (AMs) following a 7-day treatment (30 mg/kg/day, ip). The reversibility of phospholipidosis was examined under in vivo conditions and under in vitro conditions in cell cultures for a period of up to 12 days. There was a marked reduction in cellular CP levels and phospholipid content after 4 days of recovery, both in vivo and in vitro; however, there was no indication of significant loss of LLBs. Beyond this time point, ultrastructural recovery from phospholipidosis lagged behind the biochemical recovery temporally and was somewhat less rapid in vitro than in vivo. By 12 days of recovery, AMs from both groups had recovered biochemically, but a moderate level of LLBs was still present in some AMs in the in vitro recovery group. The results of this study indicate that there are more similarities than differences when comparing the recovery of phospholipidotic cells in vitro to that occurring in vivo. We conclude that the use of cell cultures may prove valuable in studying the reversibility of CAD-induced phospholipidosis.

Acute silica toxicity: attenuation by amiodarone-induced pulmonary phospholipidosis.

Exposure to the toxic mineral dust silica has been shown to produce an acute inflammatory response in the lungs of both humans and laboratory animals. Coating silica with phospholipids reduces its toxicity when studied with in vitro systems. The drug amiodarone increases phospholipid within the cells, airways, and alveoli of the lungs. This increase in phospholipid is due to amiodarone's ability to inhibit phospholipase activity within alveolar macrophages (AMs) and whole lung. The purpose of this study was to determine whether the amiodarone-induced increase in pulmonary phospholipid would protect the lungs from acute damage caused by the intratracheal instillation of silica. Treatment of male Fischer 344 rats with amiodarone for 14 days caused an increase in phospholipid content in bronchoalveolar lavage fluid and AMs compared to vehicle-treated controls. The rats were then instilled with silica or saline vehicle. At both 1 and 14 days after silica exposure, pulmonary phospholipidosis was associated with a marked reduction in acute silica-induced pulmonary damage as assessed by biochemical parameters in bronchoalveolar lavage fluid, however, the influx of neutrophils into the airspaces was not reduced. Four times more phospholipid was bound to the silica recovered from amiodarone-treated rats compared to controls. The results of these in vivo experiments indicate that pulmonary phospholipidosis attenuates the acute damage associated with the intratracheal instillation of silica in rats. By using an in vitro cell culture system, we demonstrated that, in contrast to control AMs, phospholipidotic AMs were significantly more resistant to the cytotoxicity of surfactant-coated silica.(ABSTRACT TRUNCATED AT 250 WORDS)