Effects of copper nanoparticle exposure on host defense in a murine pulmonary infection model

Abstract

BackgroundHuman exposure to nanoparticles (NPs) and environmental bacteria can occur simultaneously. NPs induce inflammatory responses and oxidative stress but may also have immune-suppressive effects, impairing macrophage function and altering epithelial barrier functions. The purpose of this study was to assess the potential pulmonary effects of inhalation and instillation exposure to copper (Cu) NPs using a model of lung inflammation and host defense.MethodsWe used Klebsiella pneumoniae (K.p.) in a murine lung infection model to determine if pulmonary bacterial clearance is enhanced or impaired by Cu NP exposure. Two different exposure modes were tested: sub-acute inhalation (4 hr/day, 5 d/week for 2 weeks, 3.5 mg/m3) and intratracheal instillation (24 hr post-exposure, 3, 35, and 100 μg/mouse). Pulmonary responses were evaluated by lung histopathology plus measurement of differential cell counts, total protein, lactate dehydrogenase (LDH) activity, and inflammatory cytokines in bronchoalveolar lavage (BAL) fluid.ResultsCu NP exposure induced inflammatory responses with increased recruitment of total cells and neutrophils to the lungs as well as increased total protein and LDH activity in BAL fluid. Both inhalation and instillation exposure to Cu NPs significantly decreased the pulmonary clearance of K.p.-exposed mice measured 24 hr after bacterial infection following Cu NP exposure versus sham-exposed mice also challenged with K.p (1.4 × 105 bacteria/mouse).ConclusionsCu NP exposure impaired host defense against bacterial lung infections and induced a dose-dependent decrease in bacterial clearance in which even our lowest dose demonstrated significantly lower clearance than observed in sham-exposed mice. Thus, exposure to Cu NPs may increase the risk of pulmonary infection.

Toxicity of copper oxide nanoparticles in lung epithelial cells exposed at the air–liquid interface compared with in vivo assessment

“…CuONPs induced inflammatory responses with increased recruitment of total cells and neutrophils to the lungs as well as increased total protein and LDH activity in bronchoalveolar lavage fluid (Kim et al, 2011; Pettibone et al, 2008). Many in vitro studies have investigated the toxic effects of CuONPs on airway cells in submerged culture (Ahamed et al, 2010; Fahmy and Cormier, 2009; Karlsson et al, 2008; Midander et al, 2009; Moschini et al, 2013) or at the ALI (Kim et al, 2013).…”

“…This dosimetry calculation uses the literature approximation of 680 cm 2 for the surface area of the mouse epithelium (Pinkerton et al, 1992) and 1.12 cm 2 for the surface area of epithelial cells grown to confluence on the transwells. In our in vivo sub-acute inhalation study (Kim et al, 2011), mice were exposed 4 hr/day for 10 days and we delivered an estimated CuONP dose of 32 μg/mouse (47 ng/cm 2 ) which induced LDH release, very high chemokine production and cytotoxicity. Mice exposed to three doses of CuONP by instillation exhibited dose-dependent increases in these outcomes measured 24 hr after dosing.…”

“…With widespread applications of CuONPs, it is necessary to clearly understand the biological consequences of CuONP exposure in relation to human health. Recently, a number of studies, including two from our group, have investigated the toxic effects of CuONPs on airway cell lines in vitro and their pulmonary toxicity in animals (Elihn et al, 2013; Fahmy and Cormier, 2009; Kim et al, 2011; Kumar and Nagesha, 2013; Pettibone et al, 2008). Following whole-body inhalation exposure to CuONPs, inflammatory responses in mice were induced, including elevated cytokine production in bronchial lavage fluid, increased recruitment of inflammatory cells to the lung, and perivasculitis and alveolitis in lung (Kim et al, 2011; Pettibone et al, 2008).…”

Effect of silica and gold nanoparticles on macrophage proliferation, activation markers, cytokine production, and phagocytosis in vitro

“…Alternatively, mice exposed to Cu NPs by inhalation or instillation exhibited a significant decrease in the pulmonary bacterial clearance of Klebsiella pneumoniae (Gram-negative bacteria). 40 The above-mentioned studies were conducted using a single dose of NPs in pulmonary models. One clinical study evaluating the effect of an iron sucrose formulation demonstrated that polymorphonuclear leukocytes isolated from patients treated with the NP formulation showed less bacterial killing of E. coli ex vivo than patients administered a placebo, although the results were not significant and only occurred immediately after administration of the parenteral iron compound.…”

Kupfer und seine anorganischen Verbindungen [MAK Value Documentation in German language, 2014]

“…Jedoch werden unter den meisten Expositionsbedingungen Kupfer-Aerosole mit eher größeren Partikelgrößen (>1 μm) freigesetzt, die üblicherweise nicht zum typischen Metallrauchfieber führen. Metallrauchfieber wird bei Exposition gegen feinen Rauch (Partikelgröße <1 μm) von Metalloxiden hervorgerufen (Borak 2000 ( Kim et al 2011;Pettibone et al 2008). Da die Studien mit Nanopartikeln durchgeführt wurden, werden sie nicht zur Bewertung herangezogen.…”