Properties of Multinucleated Giant Cells in a Newin Vitro Model for Human Granuloma Formation

Seitzer, Ulrike; Scheel‐Toellner, Dagmar; Toellner, Kai‐Michael; Reiling, Norbert; Haas, Helmut; Galle, J.; Flad, Hans‐Dieter; Gerdes, Johannes

doi:10.1002/(sici)1096-9896(199705)182:1<99::aid-path807>3.0.co;2-x

Cited by 20 publications

(4 citation statements)

References 24 publications

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“…The proinflammatory mediators TNF-α, IL-1β, and iNOS have also been observed during the formation of immune granulomas in vivo [40] and in vitro [41]. Less is known about the mediators involved in production and healing of non-immune granulomas.…”

Section: Discussionmentioning

confidence: 99%

A 3-dimensional in vitro model of epithelioid granulomas induced by high aspect ratio nanomaterials

et al. 2011

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BackgroundThe most common causes of granulomatous inflammation are persistent pathogens and poorly-degradable irritating materials. A characteristic pathological reaction to intratracheal instillation, pharyngeal aspiration, or inhalation of carbon nanotubes is formation of epithelioid granulomas accompanied by interstitial fibrosis in the lungs. In the mesothelium, a similar response is induced by high aspect ratio nanomaterials, including asbestos fibers, following intraperitoneal injection. This asbestos-like behaviour of some engineered nanomaterials is a concern for their potential adverse health effects in the lungs and mesothelium. We hypothesize that high aspect ratio nanomaterials will induce epithelioid granulomas in nonadherent macrophages in 3D cultures.ResultsCarbon black particles (Printex 90) and crocidolite asbestos fibers were used as well-characterized reference materials and compared with three commercial samples of multiwalled carbon nanotubes (MWCNTs). Doses were identified in 2D and 3D cultures in order to minimize acute toxicity and to reflect realistic occupational exposures in humans and in previous inhalation studies in rodents. Under serum-free conditions, exposure of nonadherent primary murine bone marrow-derived macrophages to 0.5 μg/ml (0.38 μg/cm2) of crocidolite asbestos fibers or MWCNTs, but not carbon black, induced macrophage differentiation into epithelioid cells and formation of stable aggregates with the characteristic morphology of granulomas. Formation of multinucleated giant cells was also induced by asbestos fibers or MWCNTs in this 3D in vitro model. After 7-14 days, macrophages exposed to high aspect ratio nanomaterials co-expressed proinflammatory (M1) as well as profibrotic (M2) phenotypic markers.ConclusionsInduction of epithelioid granulomas appears to correlate with high aspect ratio and complex 3D structure of carbon nanotubes, not with their iron content or surface area. This model offers a time- and cost-effective platform to evaluate the potential of engineered high aspect ratio nanomaterials, including carbon nanotubes, nanofibers, nanorods and metallic nanowires, to induce granulomas following inhalation.

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Section: Discussionmentioning

confidence: 99%

A 3-dimensional in vitro model of epithelioid granulomas induced by high aspect ratio nanomaterials

et al. 2011

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“…The high number of giant cells might be related to the persistence of the fungus in the tissues. These cells are characteristically formed in response to intracellular pathogens such as mycobacteria and fungi, which are poorly handled by macrophages, 25 and are involved in granuloma formation and turnover, pathogen destruction and healing process induction 26,27 . The absence of multinucleated giant cells in granulomatous lesions may reflect an ineffective host response to infection, such as in lepromatous leprosy, coccidiodiomycosis, disseminated histoplasmosis, or Mycobacterium avium intracellulare complex infection in acquired immune deficiency syndrome 25,28 .…”

Section: Discussionmentioning

confidence: 99%

Cytokines released from blood monocytes and expressed in mucocutaneous lesions of patients with paracoccidioidomycosis evaluated before and during trimethoprim-sulfamethoxazole treatment

Parise‐Fortes

Marques²,

Soares

et al. 2006

British Journal of Dermatology

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“…15,21 The detection of cytokine transcripts by RT±PCR has also been shown, but only in an indirect manner using in vitro models. 6,22 The demonstration of cytokine gene transcription is important, considering that the cytokine presence demonstrated by immunohistology can be caused by the phagocytic and endocytic activity that these cells normally manifest, particularly in an in¯ammatory microenvironment with a high production of in¯ammatory cytokines. In this regard, we have previously shown strong MGC immunostaining to IL-1a, TNF-a and TGF-b in the lungs of tuberculous mice.…”

Section: Discussionmentioning

confidence: 99%

“…There are recent reports that demonstrate the presence of inflammatory cytokines in MGC by immunohistochemistry 15,21 . The detection of cytokine transcripts by RT–PCR has also been shown, but only in an indirect manner using in vitro models 6,22 . The demonstration of cytokine gene transcription is important, considering that the cytokine presence demonstrated by immunohistology can be caused by the phagocytic and endocytic activity that these cells normally manifest, particularly in an inflammatory microenvironment with a high production of inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory cytokine production by immunological and foreign body multinucleated giant cells

et al. 2000

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SUMMARYMultinucleated giant cells (MGC) are a common feature of granulomas. The mechanism of their formation has been studied extensively, but their function has not been completely characterized. A new method for the in vivo production of MGC was developed involving subcutaneous injection of microscopic nitrocellulose particles with adsorbed mycobacterial antigens into the footpads of sensitized BALB/c mice (immune [I]-MGC), or by nitrocellulose administration to non-sensitized mice (foreign body [FB]-MGC). The development of granulomas with a highly enriched MGC population was observed 2 weeks after the nitrocellulose injection. MGC were larger with a greater number of nuclei in I-MGC than in FB-MGC. From days 7±28 after nitrocellulose administration, the production of interleukin-1a (IL-1a) and tumour necrosis factor-a (TNF-a) was demonstrated in both MGC types by in situ reverse transcription±polymerase chain reaction (RT±PCR) and immunohistochemistry. After 2 months, the MGC had ceased production of IL-1a and TNF-a, but the expression of transforming growth factor-b (TGF-b) was very high, occurring together with extensive ®brosis. These results suggest that MGC are an active source of in¯ammatory cytokines, which can contribute to the initiation, maintenance and down-regulation of granulomatous in¯ammation induced by immunological and inert substances.

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Properties of Multinucleated Giant Cells in a Newin Vitro Model for Human Granuloma Formation

Cited by 20 publications

References 24 publications

A 3-dimensional in vitro model of epithelioid granulomas induced by high aspect ratio nanomaterials

A 3-dimensional in vitro model of epithelioid granulomas induced by high aspect ratio nanomaterials

Cytokines released from blood monocytes and expressed in mucocutaneous lesions of patients with paracoccidioidomycosis evaluated before and during trimethoprim-sulfamethoxazole treatment

Inflammatory cytokine production by immunological and foreign body multinucleated giant cells

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