Effects of Amiodarone-Induced Phospholipidosis on Pulmonary Host Defense Functions in Rats

Reasor, Mark J.; McCloud, Christy M.; DiMatteo, Michael; Schafer, Rosana; Ima, Azine; Lemaire, Irma

doi:10.3181/00379727-211-43979

Cited by 31 publications

(17 citation statements)

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“…Others have shown no impairment of pulmonary host defence mechanisms in the rat, 39 nor changes in the phagocytosis of heat-killed yeast cells 39 by AM with a foamy appearance. Results from our model differ from these other studies in that we showed that amiodarone significantly impaired the ability of the macrophages to phagocytose microspheres.…”

Section: Discussionmentioning

confidence: 95%

The effect of in vitro exposure to antisense oligonucleotides on macrophage morphology and function

Brasey

Igue

Djemame

et al. 2011

J Nucleic Acids Invest

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Antisense oligonucleotides (AON) delivered via inhalation are in drug development for respiratory diseases. In rodents and monkeys, repeated exposure to high doses of inhaled phosphorothioate (PS) AON can lead to microscopic changes in the lungs, including accumulation of alveolar macrophages in the lower airway that have a foamy appearance. The functional consequences that result from this morphological change are unclear as there is controversy whether the vacuoles/inclusion bodies reflect normal clearance of the inhaled AON or are early indicators of lung toxicity. The morphological and functional responses of macrophage to PS AON were characterized in vitro using the comparator drug amiodarone, as a known inducer of foamy macrophages.

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Section: Discussionmentioning

confidence: 95%

The effect of in vitro exposure to antisense oligonucleotides on macrophage morphology and function

Brasey

Igue

Djemame

et al. 2011

J Nucleic Acids Invest

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“…Actually, experimental listeriosis has been a widely accepted method for studying cellmediated immune responses (27)(28)(29). Several reports have shown that the Listeria infection model is also applicable to the respiratory system for assessing pulmonary host defense mechanisms (20,25,(30)(31)(32) and the importance of cytokines in resistance to bacterial infection (33)(34)(35). The present study demonstrates that Listeria induces innate pulmonary immunity and may initiate T-cell-mediated immune responses in Brown-Norway rats, thus allowing one to characterize the mechanism(s) by which DEP exposure alters the pulmonary host defense system.…”

Section: Discussionmentioning

confidence: 99%

Alteration of pulmonary immunity to Listeria monocytogenes by diesel exhaust particles (DEPs). I. Effects of DEPs on early pulmonary responses.

Yin

Schafer

Jane

et al. 2002

Environ Health Perspect

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Diesel exhaust particles (DEPs), generated by heavy-duty diesel engines in various industries, can adsorb over 450 different organic compounds, including mutagenic and carcinogenic polycyclic aromatic hydrocarbons (1). With diameters < 2 µm, these fine respirable particles can remain airborne for long periods of time and deposit in great numbers deeply in the lungs. For these reasons, exposure of truckers, railroad and construction workers, and engine mechanics to DEPs is an occupational health concern. A report from the U.S. Department of Labor showed that the worst-case mean exposures to DEPs in underground metal and nonmetal mines are about 2,000 µg/m 3 , with maximum measurements as high as 3,650 µg/m 3 (2). Epidemiologic studies have also shown a consistent association between elevated levels of particulate matter in ambient air and increased incidence of pulmonary infections (3) or increased respiratory mortality and morbidity in high-risk groups (4,5). Because DEPs are a major component of particulate air pollution in most industrialized urban areas, their effect on pulmonary infections is of great environmental and occupational concern.The principal function of pulmonary host defense mechanisms is to clear inhaled particles or microorganisms from the lungs and prevent infections. Among the various cell types involved in the innate immune system, alveolar macrophages (AMs) are responsible for the clearance of inhaled particles and/or microorganisms from the distal airways and alveolar spaces. These cells engulf inhaled particles or microorganisms and become activated to release reactive oxygen species (ROS), cytokines, and a variety of mediators that are capable of killing microorganisms (6,7). It has been well documented that AM-derived proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), provide innate resistance to bacterial infection, promote the inflammatory process by recruiting neutrophils into the air spaces, and stimulate these phagocytes to release ROS and enzymes (7,8). A successful pulmonary host defense, on the other hand, also needs specific cell-mediated immunity (9). In this aspect, studies have already shown that AMs, through their secretion of cytokines in response to specific antigen exposure, provide a critical link between these two systems. For example, Hsieh et al. (10) showed that the production of IL-12 by macrophages is a key process for the development of the appropriate CD4 + T helper (Th) subset during the immune response to Listeria monocytogenes infection. IL-12, in fact, not only initiates but also plays an important role in maintaining the Th1 response (11). This cytokine is produced very rapidly after infection, thus serving as an early marker for the study of DEP effect(s) on cell-mediated immunity.Studies from our laboratory as well as from others have suggested that DEPs may suppress host immunity by suppressing mucociliary clearance and the phagocytic activity of AMs (12,13), reducing interferon production in response to viral ...

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“…Experimental listeriosis has been a widely accepted method for studying T-cell-mediated macrophage activation (24). Several studies have used the rat Listeria infection model to assess pulmonary host defense mechanisms (25)(26)(27). Therefore, we use this animal model to test the hypothesis that exposure to DEP suppresses macrophage function, alters T-cell-mediated immunity, and increases the susceptibility of host-tolung infection.…”

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confidence: 99%

Diesel exhaust particles suppress macrophage function and slow the pulmonary clearance of Listeria monocytogenes in rats.

Yang

Antonini

Barger

et al. 2001

Environ Health Perspect

109

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In this study, we tested the hypothesis that exposure to diesel exhaust particles (DEP) may increase susceptibility of the host to pulmonary infection. Male Sprague-Dawley rats received a single dose of DEP (5 mg/kg), carbon black (CB, 5 mg/kg), or saline intratracheally. Three days later, the rats were inoculated intratracheally with approximately 5,000 Listeria monocytogenes and sacrificed at 3, 5, and 7 days postinfection, and we determined the number of viable Listeria in the left lobe of lungs. The remaining lungs underwent bronchoalveolar lavage (BAL) and the retrieved BAL cells were identified and counted. Luminol-dependent chemiluminescence, a measure of reactive oxygen species (ROS) formation, generated by BAL cells was monitored and the levels of nitric oxide and tumor necrosis factor (TNF)-[alpha] produced by macrophages in culture were determined. At 7 days postinfection, we excised the lung-draining lymph nodes and phenotyped the lymphocyte subpopulations. Exposure of rats to DEP, but not to CB, decreased the clearance of Listeria from the lungs. Listeria-induced generation of luminol-dependent chemiluminescence by pulmonary phagocytes decreased by exposure to DEP but not CB. Similarly, Listeria-induced production of NO by alveolar macrophages was negated at 3, 5, and 7 days after inoculation in DEP-exposed rats. In contrast, CB exposure had no effect on Listeria-induced NO production at 3 days after infection and had a substantially smaller effect than DEP at later days. Exposure to DEP or CB resulted in enlarged lung-draining lymph nodes and increased the number and percentage of CD4(+) and CD8(+) T cells. These results showed that exposure to DEP decreased the ability of macrophages to produce antimicrobial oxidants in response to Listeria, which may play a role in the increased susceptibility of rats to pulmonary infection. This DEP-induced suppression is caused partially by chemicals adsorbed onto the carbon core of DEP, because impaired macrophage function and decreased Listeria clearance were not observed following exposure to CB.

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Effects of Amiodarone-Induced Phospholipidosis on Pulmonary Host Defense Functions in Rats

Cited by 31 publications

References 0 publications

The effect of in vitro exposure to antisense oligonucleotides on macrophage morphology and function

The effect of in vitro exposure to antisense oligonucleotides on macrophage morphology and function

Alteration of pulmonary immunity to Listeria monocytogenes by diesel exhaust particles (DEPs). I. Effects of DEPs on early pulmonary responses.

Diesel exhaust particles suppress macrophage function and slow the pulmonary clearance of Listeria monocytogenes in rats.

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