Mechanisms of mineral dust-induced emphysema.
Mineral dust exposure can result in emphysema and chronic airflow obstruction. We postulated that dust-induced emphysema has a pathogenesis similar to that in cigarette smoke-induced emphysema, namely, excess release of proteolytic enzymes from dust-evoked inflammatory cells, and inactivation of alpha-1-antitrypsin (A1AT) by dust-catalyzed formation of oxidants. To test this theory we examined the antiproteolytic activity of A1AT exposed to quartz in vitro and found that it was decreased in a dose-response fashion. Catalase prevented this effect, which suggested that it was mediated by quartz-generated hydrogen peroxide. We also showed that a variety of dusts could oxidize methionine to methionine sulfoxide in vitro, using either pure amino acid or whole protein. The relative order of activity was coal > quartz > titanium dioxide. Lastly, we used a new high-performance liquid chromatography technique to demonstrate that quartz, coal, and titanium dioxide produced connective tissue breakdown in rat lungs, as determined by the appearance of desmosine and hydroxyproline in lavage fluid after dust instillation. On a particle-for-particle basis, the order of dust potency was similar to that for methionine oxidation. Connective tissue breakdown was associated with elevations of both polymorphonuclear leukocytes and macrophages in lavage fluid, and it is unclear whether one or both of these types of inflammatory cell mediates this process. These observations support our theory that dust-induced emphysema and smoke-induced emphysema occur through similar mechanisms.
Churg
A
A
Department of Pathology, University of British Columbia, Vancouver, Canada. achurg@unixg.ubc.ca
Zay
K
K
Li
K
K
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002851:Chromatography, High Pressure Liquid; D003031:Coal / Q000009:adverse effects; D003238:Connective Tissue / Q000187:drug effects / Q000473:pathology; D003895:Desmosine / Q000378:metabolism; D004391:Dust / Q000009:adverse effects*; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D008715:Methionine / Q000378:metabolism; D008903:Minerals / Q000008:administration & dosage / Q000009:adverse effects*; D010084:Oxidation-Reduction; D011656:Pulmonary Emphysema / Q000139:chemically induced* / Q000378:metabolism; D011791:Quartz / Q000633:toxicity; D051381:Rats; D013552:Swine; D014025:Titanium / Q000009:adverse effects; D000515:alpha 1-Antitrypsin / Q000378:metabolism
D003031:Coal; D004391:Dust; D008903:Minerals; D000515:alpha 1-Antitrypsin; D003895:Desmosine; D011791:Quartz; C009495:titanium dioxide; D008715:Methionine; D014025:Titanium; D006909:Hydroxyproline