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Novel murine model of chronic granulomatous lung inflammation elicited by carbon nanotubes.

ABSTRACT: Lung granulomas are associated with numerous conditions, including inflammatory disorders, exposure to environmental pollutants, and infection. Osteopontin is a chemotactic cytokine produced by macrophages, and is implicated in extracellular matrix remodeling. Furthermore, osteopontin is up-regulated in granulomatous disease, and osteopontin null mice exhibit reduced granuloma formation. Animal models currently used to investigate chronic lung granulomatous inflammation bear a pathological resemblance, but lack the chronic nature of human granulomatous disease. Carbon nanoparticles are generated as byproducts of combustion. Interestingly, experimental exposures to carbon nanoparticles induce pulmonary granuloma-like lesions. However, the recruited cellular populations and extracellular matrix gene expression profiles within these lesions have not been explored. Because of the rapid resolution of granulomas in current animal models, the mechanisms responsible for persistence have been elusive. To overcome the limitations of previous models, we investigated whether a model using multiwall carbon nanoparticles would resemble chronic human lung granulomatous inflammation. We hypothesized that pulmonary exposure to multiwall carbon nanoparticles would induce granulomas, elicit a macrophage and T-cell response, and mimic other granulomatous disorders with an up-regulation of osteopontin. This model demonstrates: (1) granulomatous inflammation, with macrophage and T-cell infiltration; (2) resemblance to the chronicity of human granulomas, with persistence up to 90 days; and (3) a marked elevation of osteopontin, metalloproteinases, and cell adhesion molecules in granulomatous foci isolated by laser-capture microdissection and in alveolar macrophages from bronchoalveolar lavage. The establishment of such a model provides an important platform for mechanistic studies on the persistence of granuloma.

SUBMITTER: Huizar I

PROVIDER: S-EPMC5460893 | biostudies-other | 2011 Oct

REPOSITORIES: biostudies-other

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Novel murine model of chronic granulomatous lung inflammation elicited by carbon nanotubes.

Huizar Isham I Malur Anagha A Midgette Yasmeen A YA Kukoly Cindy C Chen Pengyu P Ke Pu Chun PC Podila Ramakrishna R Rao Apparao M AM Wingard Christopher J CJ Dobbs Larry L Barna Barbara P BP Kavuru Mani S MS Thomassen Mary Jane MJ

American journal of respiratory cell and molecular biology 20110311 4

Lung granulomas are associated with numerous conditions, including inflammatory disorders, exposure to environmental pollutants, and infection. Osteopontin is a chemotactic cytokine produced by macrophages, and is implicated in extracellular matrix remodeling. Furthermore, osteopontin is up-regulated in granulomatous disease, and osteopontin null mice exhibit reduced granuloma formation. Animal models currently used to investigate chronic lung granulomatous inflammation bear a pathological resem ...[more]

PMID: 21398620

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Project description:Mohan A, Malur A, McPeek M, Barna BP, Schnapp LM, Thomassen MJ, Gharib SA. Transcriptional survey of alveolar macrophages in a murine model of chronic granulomatous inflammation reveals common themes with human sarcoidosis. Am J Physiol Lung Cell Mol Physiol 314: L617-L625, 2018. First published December 6, 2017; doi: 10.1152/ajplung.00289.2017 . To advance our understanding of the pathobiology of sarcoidosis, we developed a multiwall carbon nanotube (MWCNT)-based murine model that shows marked histological and inflammatory signal similarities to this disease. In this study, we compared the alveolar macrophage transcriptional signatures of our animal model with human sarcoidosis to identify overlapping molecular programs. Whole genome microarrays were used to assess gene expression of alveolar macrophages in six MWCNT-exposed and six control animals. The results were compared with the transcriptional profiles of alveolar immune cells in 15 sarcoidosis patients and 12 healthy humans. Rigorous statistical methods were used to identify differentially expressed genes. To better elucidate activated pathways, integrated network and gene set enrichment analysis (GSEA) was performed. We identified over 1,000 differentially expressed between control and MWCNT mice. Gene ontology functional analysis showed overrepresentation of processes primarily involved in immunity and inflammation in MCWNT mice. Applying GSEA to both mouse and human samples revealed upregulation of 92 gene sets in MWCNT mice and 142 gene sets in sarcoidosis patients. Commonly activated pathways in both MWCNT mice and sarcoidosis included adaptive immunity, T-cell signaling, IL-12/IL-17 signaling, and oxidative phosphorylation. Differences in gene set enrichment between MWCNT mice and sarcoidosis patients were also observed. We applied network analysis to differentially expressed genes common between the MWCNT model and sarcoidosis to identify key drivers of disease. In conclusion, an integrated network and transcriptomics approach revealed substantial functional similarities between a murine model and human sarcoidosis particularly with respect to activation of immune-specific pathways.

Project description:Rationale: A well-validated animal model of sarcoidosis can help advance our understanding of the pathobiology of this complex disease. We have developed a multiwall carbon nanotube (MWCNT) based murine model that shows marked histological and inflammatory signal similarities to human sarcoidosis. In this study, we compared the alveolar immune cell transcriptional signatures of our murine model with human sarcoidosis to comprehensively assess overlapping molecular programs. Methods: Total RNA was extracted from alveolar macrophages of 6 MWCNT mice and 6 control mice and hybridized to Illumina Mouse WG-6 v2 microarrays. Transcriptional profiling of alveolar immune cells in 15 sarcoidosis patients and 12 healthy humans was previously performed using Affymetrix Human GeneChip U133A 2.0 microarrays. Rigorous statistical methods were used to identify differentially expressed genes. To better elucidate gene expression pathways, integrated network and gene set enrichment analysis (GSEA) were applied. To confirm differential expression of select network genes, we performed qPCR studies using the ABI Prism 7300 Detection. Results: We identified over 1000 genes that were differentially expressed between the control and the MWCNT mice. Gene Ontology functional analysis showed over-representation of processes primarily involved in immunity and inflammation in MCWNT mice. Applying a more comprehensive pathway analysis using GSEA to both mouse and human samples revealed upregulation of 92 gene sets in MWCNT mice and 142 gene sets in sarcoidosis patients. Commonly activated pathways in both MWCNT mice and sarcoidosis included adaptive immunity, T-cell signaling, IL-12/IL-17 signaling and oxidative phosphorylation. Differences in selective gene set enrichment between MWCNT mice and sarcoidosis patients were also observed, among them IL-27 signaling, NK-mediated cytotoxicity and proteasome pathways. We applied network analysis to differentially expressed genes common between the MWCNT model and human sarcoidosis to identify key drivers of disease and putative therapeutic targets. Conclusions: Our MWCNT murine model has an alveolar macrophage signature that varies significantly from control mice. Application of an unbiased transcriptomic approach revealed substantial functional similarities between a murine MWCNT model and human sarcoidosis particularly with respect to activation of immune-specific pathways.

Project description:Background Recurrent lower respiratory tract infection or chronic pulmonary infection often occur in children with chronic lung diseases (CLDs). By continuous lung inflammation, recurrent and chronic infection could cause irreversible airway structural and lung function damage, which eventually leads to respiratory failure and death. Methods In purpose of recapitulating persistent high-intensity lung inflammation caused by recurrent lower respiratory tract infection or chronic infection, we established a juvenile murine model with chronic lung inflammation induced by repeated intratracheal instillations of lipopolysaccharides (LPS) from Pseudomonas aeruginosa once a week for 4 weeks. Four-week-old C57BL/6N mice were divided into 4 groups, including LPS0.5 group (n=15), LPS1.0 group (n=15), Control group (n=15) and Normal group (n=15). Mice in LPS0.5 group and LPS1.0 group were instilled intratracheally with 0.5 mg/kg LPS and 1.0 mg/kg LPS respectively. Mice in control group were instilled intratracheally with LPS-free sterile 0.9% NaCl, whereas normal group received no treatment. The successful chronic lung inflammation murine model was validated via (I) pathological manifestations of chronic inflammatory mononuclear-cell infiltration and lung parenchyma damage; (II) decreased lung function. Results All mice in LPS1.0 group died before the third instillation. No death after instillation was observed in Control and LPS0.5 group. Histological analysis revealed that in LPS0.5 group, 7 days after the third instillation, most bronchus and parabronchial vessels were wrapped by infiltrating monocytes and lymphocyte and alveolar cavities were compressed, which were not observed in control and normal group. Also, ratio of forced expiratory volume in 0.1 second (FEV0.1) and forced vital capacity (FVC) in LPS0.5 group was significantly lower (P<0.0001) than both control group and normal group, suggesting ventilatory dysfunction developed after repeatedly intratracheal instillation once a week for 4 weeks. Conclusions Intratracheal instillation of 0.5 mg/kg LPS once a week for 4 weeks can cause chronic lung inflammation in young mice.

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Novel murine model of chronic granulomatous lung inflammation elicited by carbon nanotubes.

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Novel murine model of chronic granulomatous lung inflammation elicited by carbon nanotubes.

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