Dataset Information

Tumor necrosis factor-alpha overexpression in lung disease: a single cause behind a complex phenotype.

ABSTRACT:

Rationale

Tumor necrosis factor alpha (TNF-alpha) has been implicated as a key cytokine in many inflammatory lung diseases. These effects are currently unclear, because a transgenic mouse overexpressing TNF-alpha in the lung has been shown in separate studies to produce elements of both emphysema and pulmonary fibrosis.

Objectives

We sought to elucidate the phenotypic effects of TNF-alpha overexpression in a mouse model.

Measurements

We established the phenotype by measuring lung impedance and thoracic gas volume, and using micro-computed tomography and histology.

Main results

We found that airways resistance in this mouse was not different to control mice, but that lung tissue dampening, elastance, and hysteresivity were significantly elevated. Major heterogeneous abnormalities of the parenchyma were also apparent in histologic sections and in micro-computed tomography images of the lung. These changes included airspace enlargement, loss of small airspaces, increased collagen, and thickened pleural septa. We also found significant increases in lung and chest cavity volumes in the TNF-alpha-overexpressing mice.

Conclusions

We conclude that TNF-alpha overexpression causes pathologic changes consistent with both emphysema and pulmonary fibrosis combined with a general lung inflammation, and consequently does not model any single human disease. Our study thus confirms the pleiotropic effects of TNF-alpha, which has been implicated in multiple inflammatory disorders, and underscores the necessity of using a wide range of investigative techniques to link gene expression and phenotype in animal models of disease.

SUBMITTER: Lundblad LK

PROVIDER: S-EPMC2718479 | biostudies-literature | 2005 Jun

REPOSITORIES: biostudies-literature

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Publications

Tumor necrosis factor-alpha overexpression in lung disease: a single cause behind a complex phenotype.

Lundblad Lennart K A LK Thompson-Figueroa John J Leclair Timothy T Sullivan Michael J MJ Poynter Matthew E ME Irvin Charles G CG Bates Jason H T JH

American journal of respiratory and critical care medicine 20050401 12

<h4>Rationale</h4>Tumor necrosis factor alpha (TNF-alpha) has been implicated as a key cytokine in many inflammatory lung diseases. These effects are currently unclear, because a transgenic mouse overexpressing TNF-alpha in the lung has been shown in separate studies to produce elements of both emphysema and pulmonary fibrosis.<h4>Objectives</h4>We sought to elucidate the phenotypic effects of TNF-alpha overexpression in a mouse model.<h4>Measurements</h4>We established the phenotype by measurin ...[more]

PMID: 15805183

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Project description:IntroductionDuring normal pulp tissue healing, inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) or interleukins, act in the initial 48 hours (inflammatory phase) and play important roles not only as chemo-attractants of inflammatory cells and stem/progenitor cells but also in inducing a cascade of reactions toward tissue regeneration or reparative dentin formation or both. Previous reports have shown that inflammatory cytokines regulate the differentiation capacity of dental pulp stem/progenitor cells (DPCs), but none has interrogated the impact of these cytokines on the stem cell phenotype of stem/progenitor cells. This study investigated the effects of a short-term treatment with TNF-α on the stem cell phenotype and differentiation ability of human DPCs.MethodsAn in vivo mouse model of pulp exposure was performed for analysis of expression of the mesenchymal stem cell marker CD146 in DPCs during the initial stage of inflammatory response. For in vitro studies, human DPCs were isolated and incubated with TNF-α for 2 days and passaged to eliminate TNF-α completely. Analysis of stem cell phenotype was performed by quantification of cells positive for mesenchymal stem cell markers SSEA-4 (stage-specific embryonic antigen 4) and CD146 by flow cytometry as well as by quantitative analysis of telomerase activity and mRNA levels of OCT-4 and NANOG. Cell migration, colony-forming ability, and differentiation toward odontogenesis and adipogenesis were also investigated.ResultsThe pulp exposure model revealed a strong staining for CD146 during the initial inflammatory response, at 2 days after pulp exposure. In vitro experiments demonstrated that a short-term (2-day) treatment of TNF-α increased by twofold the percentage of SSEA-4+ cells. Accordingly, STRO-1, CD146, and SSEA-4 protein levels as well as OCT-4 and NANOG mRNA levels were also significantly upregulated upon TNF-α treatment. A short-term TNF-α treatment also enhanced DPC function, including the ability to form cell colonies, to migrate, and to differentiate into odontogenic and adipogenic lineages.ConclusionsA short-term treatment with TNF-α enhanced the stem cell phenotype, migration, and differentiation ability of DPCs.

Dataset Information

Tumor necrosis factor-alpha overexpression in lung disease: a single cause behind a complex phenotype.

Rationale

Objectives

Measurements

Main results

Conclusions

Publications

Tumor necrosis factor-alpha overexpression in lung disease: a single cause behind a complex phenotype.

Similar Datasets

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