title: Role of the alveolar macrophage in lung injury: studies with ultrafine particles.
abstract: We conducted a series of experiments with ultrafine particles (approximately 20 nm) and larger particles (less than 200 nm) of "nuisance" dusts to evaluate the involvement of alveolar macrophages (AM) in particle-induced lung injury and particle translocation in rats. After intratracheal instillation of both ultrafine particles and larger particles of TiO2, we found a highly increased interstitial access of the ultrafine particles combined with a large acute inflammatory reaction as determined by lung lavage parameters. An additional experiment revealed that intratracheal instillation of phagocytized ultrafine TiO2 particles (inside AM) prevented both the pulmonary inflammatory reaction and the interstitial access of the ultrafine particles. Another experiment showed that the influx of polymorphonuclear cells (PMN) into the alveolar space unexpectedly decreased with higher doses of ultrafine particles, whereas alveolar epithelial permeability (protein leakage) increased. The divergence between PMN influx into the alveolar space and changes in alveolar epithelial permeability implies that they are separate events. Pulmonary inflammatory parameters determined by lung lavage analysis correlated best with the surface area of the retained particles rather than with their mass, volume, or numbers. Because higher doses resulted in an increased interstitialized fraction of particles, we suggest that inflammatory events induced by particles in the interstitial space can modify the inflammation in the alveolar space detectable by lung lavage. Our results demonstrate the dual role of AM for modifying particle-induced lung injury, i.e., both preventing such injury and contributing to it. We conclude that the increased pulmonary toxicity of ultrafine particles is related to their larger surface area and to their increased interstitial access.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Environmental Health Sciences Center, School of Medicine and Dentistry, University of Rochester, NY 14642.
authors.forename: G
authors.initials: G
authors.lastname: Oberdörster
authors.forename: J
authors.initials: J
authors.lastname: Ferin
authors.forename: R
authors.initials: R
authors.lastname: Gelein
authors.forename: S C
authors.initials: SC
authors.lastname: Soderholm
authors.forename: J
authors.initials: J
authors.lastname: Finkelstein
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000737:chemistry / Q000187:drug effects; D007322:Instillation, Drug; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D010316:Particle Size; D011009:Pneumoconiosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D011506:Proteins / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D014025:Titanium / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D011506:Proteins; C009495:titanium dioxide; D014025:Titanium