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In vitro systems toxicology approach to investigate the effects of repeated cigarette smoke exposure on human buccal and gingival organotypic epithelial tissue cultures.

Schlage WK, Iskandar AR, Kostadinova R, Xiang Y, Sewer A, Majeed S, Kuehn D, Frentzel S, Talikka M, Geertz M, Mathis C, Ivanov N, Hoeng J, Peitsch MC - Toxicol. Mech. Methods (2014)

Bottom Line: CS exposure was associated with increased secretion of inflammatory mediators, induction of cytochrome P450s activity and overall weak toxicity in both tissues.Gene-set analysis further indicated that the CS-induced pathways in the in vitro buccal tissue models resembled those in the in vivo buccal biopsies of smokers from a published dataset.These findings support the translatability of systems responses from in vitro to in vivo and demonstrate the applicability of oral organotypical tissue models for an impact assessment of CS on various tissues exposed during smoking, as well as for impact assessment of reduced-risk products.

View Article: PubMed Central - PubMed

Affiliation: Philip Morris International R&D, Philip Morris Products S.A. , Neuchâtel , Switzerland.

ABSTRACT
Smoking has been associated with diseases of the lung, pulmonary airways and oral cavity. Cytologic, genomic and transcriptomic changes in oral mucosa correlate with oral pre-neoplasia, cancer and inflammation (e.g. periodontitis). Alteration of smoking-related gene expression changes in oral epithelial cells is similar to that in bronchial and nasal epithelial cells. Using a systems toxicology approach, we have previously assessed the impact of cigarette smoke (CS) seen as perturbations of biological processes in human nasal and bronchial organotypic epithelial culture models. Here, we report our further assessment using in vitro human oral organotypic epithelium models. We exposed the buccal and gingival organotypic epithelial tissue cultures to CS at the air-liquid interface. CS exposure was associated with increased secretion of inflammatory mediators, induction of cytochrome P450s activity and overall weak toxicity in both tissues. Using microarray technology, gene-set analysis and a novel computational modeling approach leveraging causal biological network models, we identified CS impact on xenobiotic metabolism-related pathways accompanied by a more subtle alteration in inflammatory processes. Gene-set analysis further indicated that the CS-induced pathways in the in vitro buccal tissue models resembled those in the in vivo buccal biopsies of smokers from a published dataset. These findings support the translatability of systems responses from in vitro to in vivo and demonstrate the applicability of oral organotypical tissue models for an impact assessment of CS on various tissues exposed during smoking, as well as for impact assessment of reduced-risk products.

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Perturbation of various biological networks and subnetworks upon 40.7% CS exposure in the gingival (GI) and buccal (BU) tissues. Illustration of the decomposition of Stress network (A), Pulmonary Inflammation network (C) and Necroptosis network (E) into their subnetworks. Gray areas in the illustration indicate the subnetworks that were not significantly perturbed. Normalized NPA values indicated the levels of impact on the biological processes designated as Stress, Pulmonary Inflammation and Necroptosis networks and their subnetworks are shown in B, D and F, respectively. Bar charts above the gray area, those that were statistically significantly impacted (described in the “Materials and methods” section). Abbreviations: NPA, network perturbation amplitude, TNFR1, tumor necrosis factor receptor 1; RIPK-ROS, receptor-interacting serine/threonine-protein kinase-reactive oxygen species.
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f6: Perturbation of various biological networks and subnetworks upon 40.7% CS exposure in the gingival (GI) and buccal (BU) tissues. Illustration of the decomposition of Stress network (A), Pulmonary Inflammation network (C) and Necroptosis network (E) into their subnetworks. Gray areas in the illustration indicate the subnetworks that were not significantly perturbed. Normalized NPA values indicated the levels of impact on the biological processes designated as Stress, Pulmonary Inflammation and Necroptosis networks and their subnetworks are shown in B, D and F, respectively. Bar charts above the gray area, those that were statistically significantly impacted (described in the “Materials and methods” section). Abbreviations: NPA, network perturbation amplitude, TNFR1, tumor necrosis factor receptor 1; RIPK-ROS, receptor-interacting serine/threonine-protein kinase-reactive oxygen species.

Mentions: The network-based systems biology approach was used to further assess the transcriptomic data from the tissues exposed to the higher concentration of CS (40.7%). The whole-systems impacts are expressed as BIF (see “Materials and methods” section; Figure 5), which reflect the overall impact (perturbation) levels in the tissues-exposed to the higher concentration of CS (40.7%) as compared to the air-exposed tissues (Figures 5 and 6). Greatest systems impact of CS was observed at the 4 h post-exposure time-point in both tissues (Figure 5).Figure 5.


In vitro systems toxicology approach to investigate the effects of repeated cigarette smoke exposure on human buccal and gingival organotypic epithelial tissue cultures.

Schlage WK, Iskandar AR, Kostadinova R, Xiang Y, Sewer A, Majeed S, Kuehn D, Frentzel S, Talikka M, Geertz M, Mathis C, Ivanov N, Hoeng J, Peitsch MC - Toxicol. Mech. Methods (2014)

Perturbation of various biological networks and subnetworks upon 40.7% CS exposure in the gingival (GI) and buccal (BU) tissues. Illustration of the decomposition of Stress network (A), Pulmonary Inflammation network (C) and Necroptosis network (E) into their subnetworks. Gray areas in the illustration indicate the subnetworks that were not significantly perturbed. Normalized NPA values indicated the levels of impact on the biological processes designated as Stress, Pulmonary Inflammation and Necroptosis networks and their subnetworks are shown in B, D and F, respectively. Bar charts above the gray area, those that were statistically significantly impacted (described in the “Materials and methods” section). Abbreviations: NPA, network perturbation amplitude, TNFR1, tumor necrosis factor receptor 1; RIPK-ROS, receptor-interacting serine/threonine-protein kinase-reactive oxygen species.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219813&req=5

f6: Perturbation of various biological networks and subnetworks upon 40.7% CS exposure in the gingival (GI) and buccal (BU) tissues. Illustration of the decomposition of Stress network (A), Pulmonary Inflammation network (C) and Necroptosis network (E) into their subnetworks. Gray areas in the illustration indicate the subnetworks that were not significantly perturbed. Normalized NPA values indicated the levels of impact on the biological processes designated as Stress, Pulmonary Inflammation and Necroptosis networks and their subnetworks are shown in B, D and F, respectively. Bar charts above the gray area, those that were statistically significantly impacted (described in the “Materials and methods” section). Abbreviations: NPA, network perturbation amplitude, TNFR1, tumor necrosis factor receptor 1; RIPK-ROS, receptor-interacting serine/threonine-protein kinase-reactive oxygen species.
Mentions: The network-based systems biology approach was used to further assess the transcriptomic data from the tissues exposed to the higher concentration of CS (40.7%). The whole-systems impacts are expressed as BIF (see “Materials and methods” section; Figure 5), which reflect the overall impact (perturbation) levels in the tissues-exposed to the higher concentration of CS (40.7%) as compared to the air-exposed tissues (Figures 5 and 6). Greatest systems impact of CS was observed at the 4 h post-exposure time-point in both tissues (Figure 5).Figure 5.

Bottom Line: CS exposure was associated with increased secretion of inflammatory mediators, induction of cytochrome P450s activity and overall weak toxicity in both tissues.Gene-set analysis further indicated that the CS-induced pathways in the in vitro buccal tissue models resembled those in the in vivo buccal biopsies of smokers from a published dataset.These findings support the translatability of systems responses from in vitro to in vivo and demonstrate the applicability of oral organotypical tissue models for an impact assessment of CS on various tissues exposed during smoking, as well as for impact assessment of reduced-risk products.

View Article: PubMed Central - PubMed

Affiliation: Philip Morris International R&D, Philip Morris Products S.A. , Neuchâtel , Switzerland.

ABSTRACT
Smoking has been associated with diseases of the lung, pulmonary airways and oral cavity. Cytologic, genomic and transcriptomic changes in oral mucosa correlate with oral pre-neoplasia, cancer and inflammation (e.g. periodontitis). Alteration of smoking-related gene expression changes in oral epithelial cells is similar to that in bronchial and nasal epithelial cells. Using a systems toxicology approach, we have previously assessed the impact of cigarette smoke (CS) seen as perturbations of biological processes in human nasal and bronchial organotypic epithelial culture models. Here, we report our further assessment using in vitro human oral organotypic epithelium models. We exposed the buccal and gingival organotypic epithelial tissue cultures to CS at the air-liquid interface. CS exposure was associated with increased secretion of inflammatory mediators, induction of cytochrome P450s activity and overall weak toxicity in both tissues. Using microarray technology, gene-set analysis and a novel computational modeling approach leveraging causal biological network models, we identified CS impact on xenobiotic metabolism-related pathways accompanied by a more subtle alteration in inflammatory processes. Gene-set analysis further indicated that the CS-induced pathways in the in vitro buccal tissue models resembled those in the in vivo buccal biopsies of smokers from a published dataset. These findings support the translatability of systems responses from in vitro to in vivo and demonstrate the applicability of oral organotypical tissue models for an impact assessment of CS on various tissues exposed during smoking, as well as for impact assessment of reduced-risk products.

Show MeSH
Related in: MedlinePlus