Subchronic Oral Cadmium Exposure Exerts both Stimulatory and Suppressive Effects on Pulmonary Inflammation/Immune Reactivity in Rats

Objective The aim of this study is to investigate the effects of oral cadmium(Cd) ingestion on the pulmonary immune response. Methods Determination of Cd content in lungs and histopathological evaluation of the tissue was performed in rats following 30-day oral Cd administration(5 and 50 mg/L). Antioxidant enzyme defense(superoxide dismutase and catalase), cell infiltration, and production of tumor necrosis factor(TNF) and interferon(IFN)-γ, as well as the activity of myeloperoxidase(MPO), nitric oxide(NO), and various cytokines [interleukin(IL)-1β, IL-6, IL-10, and IL-17] were investigated. Results Cd caused tissue damage and cell infiltration in the lungs, and this damage was more pronounced at higher doses. Cd deposition resulted in lung inflammation characterized by a dose-dependent IL-1β increase in lung homogenates, increased TNF levels at both doses, and IL-6 stimulation at low doses with inhibition observed at higher doses. Cd exerted differential effects on lung leukocytes isolated by enzyme digestion, and these effects were characterized by a lack of change in the production of reactive oxygen and nitrogen species, an inhibition of IL-1β and TNF, and stimulation of MPO and IFN-γ. The higher capacity of Cd-exposed lung cells to respond to the opportunistic pathogen Staphylococcus epidermidis was demonstrated in vitro. Conclusion The potential of ingested Cd to exert both proinflammatory and immunosuppressive effects on pulmonary tissue inflammation and immune reactivity highlights the complex immunomodulatory actions of this metal.

Pulmonary Immune Responses to Aspergillus Fumigatus in Rats

Objective To evaluate immunologic mechanisms underlying Aspergillus fumigatus pulmonary infections in immunocompetent Dark Agouti （DA） and Albino Oxford （AO） rats recognized as being susceptible to some inflammatory diseases in different manners. Methods Lung fungal burden （quantitative colony forming units, CFU, assay）, leukocyte infiltration （histology, cell composition） and their function （phagocytosis, oxidative activity, CDllb adhesion molecule expression） and cytokine interferon-y （IFN-y） and interleukin-17 and -4 （IL-17 and IL-4） lung content were evaluated following infection （intratracheally, lxl07 conidia）. Results Slower reduction of fungal burden was observed in AO rats in comparison with that in DA rats, which was coincided with less intense histologically evident lung cell infiltration and leukocyte recovery as well as lower level of most of the their activities including intracellular myeloperoxidase activity, the capacity of nitroblue tetrazolium salt reduction and CDllb adhesion molecule expression （except for phagocytosis of conidia） in these rats. Differential patterns of changes in proinflammatory cytokine levels （unchanged levels of IFN-v and transient increase of IL-17 in AO rats vs continuous increase of both cytokines in DA rats） and unchanged levels of IL-4 were observed. Conclusion Genetically-based differences in the pattern of antifungal lung leukocyte activities and cytokine milieu, associated with differential efficiency of fungal elimination might be useful in the future use of rat models in studies of pulmonary aspergillosis.

Aryl Hydrocarbon Receptor is Involved in the Proinflammatory Cytokine Response to Cadmium

Objective To investigate involvement of the aryl hydrocarbon receptor(Ah R)in the immunomodulatory effects of cadmium(Cd).Methods The effect of Cd on Ah R activation(CYP1 A1 and CYP1 B1 m RNA expression)was examined in lung leukocytes of Cd-exposed rats(5 and 50 mg/L,30 d orally)and by in vitro leukocyte exposure.The involvement of Ah R signaling in the effects of Cd on the interleukin(IL)-1β,IL-6,and tumor necrosis factor(TNF)lung leukocyte response was investigated in vitro using the receptor antagonist CH-223191.Results Cd increased CYP1 B1(in vivo and in vitro)and CYP1 A1(in vitro)m RNA,indicating Ah R involvement in the action of Cd.In response to Cd,lung leukocytes increased IL-6 and decreased TNF at the gene expression and protein levels,but decreased IL-1βproduction due to reduced NLRP3.The Ah R antagonist CH-223191 abrogated the observed effects of Cd on the cytokine response.The absence of Ah R reactivity and cytokine response to Cd of leukocytes from the lungs of a rat strain that is less sensitive to Cd toxicity coincided with a high Ah R repressor m RNA level.Conclusion Ah R signaling is involved in the lung leukocyte proinflammatory cytokine response to Cd.The relevance of the Ah R to the cytokine response to Cd provides new insight into the mechanisms of Cd immunotoxicity.