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Title: MyD88 mediates in vivo effector functions of alveolar macrophages in acute lung inflammatory responses to carbon nanotube exposure.

Authors: Frank, Evan A; Birch, M Eileen; Yadav, Jagjit S

Published In Toxicol Appl Pharmacol, (2015 Nov 01)

Abstract: Carbon nanotubes (CNTs) are rapidly emerging as high-priority occupational toxicants. CNT powders contain fibrous particles that aerosolize readily in places of manufacture and handling, posing an inhalation risk for workers. Studies using animal models indicate that lung exposure to CNTs causes prolonged inflammatory responses and diffuse alveolar injury. The mechanisms governing CNT-induced lung inflammation are not fully understood but have been suggested to involve alveolar macrophages (AMs). In the current study, we sought to systematically assess the effector role of AMs in vivo in the induction of lung inflammatory responses to CNT exposures and investigate their cell type-specific mechanisms. Multi-wall CNTs characterized for various physicochemical attributes were used as the CNT type. Using an AM-specific depletion and repopulation approach in a mouse model, we unambiguously demonstrated that AMs are major effector cells necessary for the in vivo elaboration of CNT-induced lung inflammation. We further investigated in vitro AM responses and identified molecular targets which proved critical to pro-inflammatory responses in this model, namely MyD88 as well as MAPKs and Ca(2+)/CamKII. We further demonstrated that MyD88 inhibition in donor AMs abrogated their capacity to reconstitute CNT-induced inflammation when adoptively transferred into AM-depleted mice. Taken together, this is the first in vivo demonstration that AMs act as critical effector cell types in CNT-induced lung inflammation and that MyD88 is required for this in vivo effector function. AMs and their cell type-specific mechanisms may therefore represent potential targets for future therapeutic intervention of CNT-related lung injury.

PubMed ID: 26272622 Exiting the NIEHS site

MeSH Terms: Acute Disease; Animals; Calcium/metabolism; Cells, Cultured; Chemical Phenomena; Disease Models, Animal; Interleukin-1beta/genetics; Interleukin-1beta/metabolism; JNK Mitogen-Activated Protein Kinases/genetics; JNK Mitogen-Activated Protein Kinases/metabolism; Lung/cytology; Lung/drug effects; Lung/metabolism; Macrophages, Alveolar/drug effects*; Macrophages, Alveolar/metabolism; Mice; Myeloid Differentiation Factor 88/genetics; Myeloid Differentiation Factor 88/metabolism*; Nanotubes, Carbon/toxicity*; Particle Size; Pneumonia/pathology*; Signal Transduction; Tumor Necrosis Factor-alpha/genetics; Tumor Necrosis Factor-alpha/metabolism; p38 Mitogen-Activated Protein Kinases/genetics; p38 Mitogen-Activated Protein Kinases/metabolism

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Last Reviewed: October 07, 2024