Granuloma formation induced by low-dose chronic silica inhalation is associated with an anti-apoptotic response in Lewis rats.
Chronic human silicosis results primarily from continued occupational exposure to silica and exhibits a long asymptomatic latency. Similarly, continued exposure of Lewis rats to low doses of silica is known to cause delayed granuloma formation with limited lung inflammation and injury. On the other hand, intratracheal exposure to large doses of silica induces acute silicosis characterized by granuloma-like formations in the lung associated with apoptosis, severe alveolitis, and alveolar lipoproteinosis. To ascertain similarities/differences between acute and chronic silicosis, in this communication, we compared cellular and molecular changes in established rat models of acute and chronic silicosis. In Lewis rats, acute silicosis was induced by intratracheal instillation of 35 mg silica, and chronic silicosis through inhalation of aerosolized silica (6.2 mg/m(3), 5 d/wk for 6 wk). Animals exposed to acute high-dose silica were sacrificed at 14 d after silica instillation while chronically silica-treated animals were sacrificed between 4 d and 28 wk after silica exposure. The lung granulomas formation in acute silicosis was associated with strong inflammation, presence of TUNEL-positive cells, and increases in caspase-3 activity and other molecular markers of apoptosis. On the other hand, lungs from chronically silica-exposed animals exhibited limited inflammation and increased expression of anti-apoptotic markers, including dramatic increases in Bcl-2 and procaspase-3, and lower caspase-3 activity. Moreover, chronic silicotic lungs were TUNEL-negative and overexpressed Bcl-3 and NF-kappaB-p50 but not NF-kappaB-p65 subunits. These results suggest that, unlike acute silicosis, chronic exposures to occupationally relevant doses of silica cause significantly lower lung inflammation and elevated expression of anti-apoptotic rather than proapoptotic markers in the lung that might result from interaction between NF-kappaB-p50 and Bcl-3.
Langley
Raymond J
RJ
Immunology Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.
Mishra
Neerad C
NC
Peña-Philippides
Juan Carlos
JC
Hutt
Julie A
JA
Sopori
Mohan L
ML
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D000081242:B-Cell Lymphoma 3 Protein; D015415:Biomarkers / Q000032:analysis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D053148:Caspase 3 / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015769:Granuloma, Respiratory Tract / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D020287:In Situ Nick-End Labeling; D019570:Inhalation Exposure; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D012822:Silicon Dioxide / Q000633:toxicity*; D012829:Silicosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D013047:Specific Pathogen-Free Organisms; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; D015415:Biomarkers; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D012822:Silicon Dioxide; D053148:Caspase 3
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