Modulation of silica-induced pulmonary toxicity by dexamethasone-containing liposomes.
Human exposure to silica (SI) is of great occupational concern because it is marked by pulmonary inflammation and fibrosis. Our objective was to determine if early pharmacological intervention altered the inflammatory and fibrotic responses to silica in rats. Male Fisher-344 rats received intratracheal (IT) instillations of the anti-inflammatory steroid, dexamethasone (DEX), incorporated into a novel liposomal (LIP) delivery system (DEX-LIP), or buffer as control (HBSS) on Day-1 and every fourth day until euthanization. On Day 0, the DEX-LIP group received IT instillations of SI (10 mg/100g body wt, DEX-LIP-SI); half of the HBSS group received SI (10 mg/100g body wt, HBSS-SI) and the other half saline (HBSS-SAL). On Day 10 or 20, bronchoalveolar lavage (BAL) was performed for cellular, biochemical, and functional analyses of inflammation and damage. HBSS-SI rats had significant elevations in the neutrophil cell count over HBSS-SAL rats at both times. DEX-LIP treatment markedly reduced these values, indicating that DEX-LIP protected against SI-induced inflammation. In contrast, DEX-LIP did not protect against biochemical (albumin concentration, and beta-glucuronidase and lactate dehydrogenase activities) and functional (luminol-dependent chemiluminescence) indices of SI-induced damage. At Day 20, the DEX-LIP treatment significantly reduced the SI-induced increase in right lung/total body weight ratio and right lung hydroxyproline content, a biochemical index of fibrosis. This attenuation of fibrosis was confirmed histopathologically on preserved left lungs from these same animals. These results show that administration of liposomes containing dexamethasone attenuated SI-induced pulmonary inflammation and fibrosis in rats, and that this protection is independent of some biochemical and functional parameters of damage.
DiMatteo
M
M
Department of Pharmacology and Toxicology, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown 26506-9223, USA.
Reasor
M J
MJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D003907:Dexamethasone / Q000008:administration & dosage*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D006909:Hydroxyproline / Q000032:analysis; D007442:Intubation, Intratracheal; D007958:Leukocyte Count; D008081:Liposomes / Q000008:administration & dosage*; D008168:Lung / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D008297:Male; D009504:Neutrophils; D009929:Organ Size; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D012822:Silicon Dioxide / Q000633:toxicity*
D000893:Anti-Inflammatory Agents; D004337:Drug Carriers; D008081:Liposomes; D012822:Silicon Dioxide; D003907:Dexamethasone; D006909:Hydroxyproline