Effects of hard metal on nitric oxide pathways and airway reactivity to methacholine in rat lungs.
To examine whether the development of hard metal (HM)-induced occupational asthma and interstitial lung disease involves alterations in nitric oxide (NO) pathways, we examined the effects of an industrial HM mixture on NO production, interactions between HM and lipopolysaccharide (LPS) on NO pathways, and alterations in airway reactivity to methacholine in rat lungs. HM (2.5 to 5 mg/100 g intratracheal) increased NO synthase (NOS; EC 1.14.23) activity of rat lungs at 24 h without increasing inducible NOS (iNOS) or endothelial NOS (eNOS) mRNA abundance or iNOS, eNOS, or brain NOS (bNOS) proteins. The increase in NOS activity correlated with the appearance histologically of nitrotyrosine immunofluorescence in polymorphonuclear leukocytes (PMN) and macrophages. Intraperitoneal injection of LPS (1 mg/kg) caused up-regulation of iNOS activity, mRNA, and protein at 8 h but not at 24 h. HM at 2.5 mg/100 g, but not at 5 mg/100 g, potentiated the LPS-induced increase in NOS activity, iNOS mRNA, and protein. However, HM decreased eNOS activity at 8 h and eNOS protein at 24 h. Whole body plethysmography on conscious animals revealed that HM caused basal airway obstruction and a marked hyporeactivity to inhaled methacholine by 6-8 h, which intensified over 30-32 h. HM-treatment caused protein leakage into the alveolar space, and edema, fibrin formation, and an increase in the number of inflammatory cells in the lungs and in the bronchoalveolar lavage. These results suggest that a HM-induced increase in NO production by pulmonary inflammatory cells is associated with pulmonary airflow abnormalities in rat lungs.
Rengasamy
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A
Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia, USA. gammada5@cdc.gov
Kommineni
C
C
Jones
J A
JA
Fedan
J S
JS
D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage; D002452:Cell Count; D002857:Chromium / Q000633:toxicity; D003035:Cobalt / Q000633:toxicity; D007501:Iron / Q000633:toxicity; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008670:Metals / Q000633:toxicity*; D016210:Methacholine Chloride / Q000008:administration & dosage; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000378:metabolism; D010993:Plethysmography, Whole Body; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012129:Respiratory Function Tests; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013535:Suspensions; D014414:Tungsten / Q000633:toxicity; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000393:Air Pollutants; D016085:Bronchoconstrictor Agents; D008670:Metals; D012333:RNA, Messenger; D013535:Suspensions; D002857:Chromium; D016210:Methacholine Chloride; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D003035:Cobalt; D014443:Tyrosine; D007501:Iron; D019001:Nitric Oxide Synthase; D014414:Tungsten