Activation of Alveolar Macrophages after Plutonium Oxide Inhalation in Rats: Involvement in the Early Inflammatory Response

Abstract

Alveolar macrophages play an important role in the distribution, clearance and inflammatory reactions after particle inhalation, which may influence long-term events such as fibrosis and tumorigenesis. The objectives of the present study were to investigate the early inflammatory events after plutonium oxide inhalation in rats and involvement of alveolar macrophages. Lung changes were studied from 3 days to 3 months after inhalation of PuO2 of different isotopic compositions (70% or 97% 239Pu) and initial lung deposits (range 2.1 to 43.4 kBq/rat). Analyses of bronchoalveolar lavages showed early increases in the numbers of granulocytes, lymphocytes and multinucleated macrophages. The activation of macrophages was evaluated ex vivo by measurement of inflammatory mediator levels in culture supernatants. TNF-alpha and chemokine MCP-1, MIP-2 and CINC-1 production was elevated from 7 days after inhalation and remained so up to 3 months. In contrast, IL-1beta, IL-6 and IL-10 production was unchanged. At 6 weeks, pulmonary macrophage numbers and activation state were increased as observed from an immunohistochemistry study of lung sections with anti-ED1. Similarly, histological analyses of lung sections also showed evidence of inflammatory responses. In conclusion, our results indicate early inflammatory changes in the lungs of PuO2-contaminated animals and the involvement of macrophages in this process. A dose-effect relationship was observed between the amount of radionuclide inhaled or retained at the time of analysis and inflammatory mediator production by alveolar macrophages 14 days after exposure. For similar initial lung deposits, the inflammatory manifestation appears higher for 97% 239Pu than for 70% 239Pu.

Macrophages as key elements of Mixed-oxide [U-Pu(O2)] distribution and pulmonary damage after inhalation?

“…Similarly to what we described after Pu contamination (Van der Meeren et al 2008, CD68 positive cells were increased after MOX. Because CD68 is expressed on all macrophages (Murray and Wynn 2011), we used specifi c markers for M1 and M2 phenotypes.…”

Cellular Senescence - its role in cancer and the response to ionizing radiation

“…There is the suggestion therefore that radiation-induced enhancement of inflammatory reactions might contribute to the development of radiation-induced disorders and premature ageing [155,161]. Indeed, it is also well known that A-bomb survivors show increased cardiovascular and respiratory diseases associated with persistent inflammation [162,163]. …”

Late-Occurring Pulmonary Pathologies Following Inhalation of Mixed Oxide (Uranium + Plutonium Oxide) Aerosol in the Rat

“…Irradiated macrophages through release of "biochemical cues" may result in cellular transformation and ultimately carcinogenesis. Evidence for macrophage activation both immunohistochemical and cytokine production at early times (14 d) after plutonium oxide inhalation (5-10 kBq) has been recently demonstrated (Van der Meeren et al 2008). However, inflammatory responses may not always be concomitant with epithelial proliferation, as Taya et al (1993) showed in mice proliferation of epithelial cells at least 1 mo after exposure.…”