Limits...
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.

Show MeSH

Related in: MedlinePlus

Transcriptomic analysis using a network-based biological impact factor analysis. The overall biological impact calculated as biological impact factor (BIF) from all aggregated biological network models is shown in (A) for the various PE time-points following exposure to 40.7% CS in the gingival (GI) and buccal (BU) tissues. (B)–(E) show spider plots that display the normalized NPA values illustrating the quantification of the impacted biological networks for each of the post-exposure time-points. Gray areas in the center of the spider plots indicate statistically non-significant perturbation of the different networks according to the Specificity statistics, refer the “Materials and methods” section. Abbreviations: CS, cigarette smoke; PE, post-exposure.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4219813&req=5

f5: Transcriptomic analysis using a network-based biological impact factor analysis. The overall biological impact calculated as biological impact factor (BIF) from all aggregated biological network models is shown in (A) for the various PE time-points following exposure to 40.7% CS in the gingival (GI) and buccal (BU) tissues. (B)–(E) show spider plots that display the normalized NPA values illustrating the quantification of the impacted biological networks for each of the post-exposure time-points. Gray areas in the center of the spider plots indicate statistically non-significant perturbation of the different networks according to the Specificity statistics, refer the “Materials and methods” section. Abbreviations: CS, cigarette smoke; PE, post-exposure.

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)

Transcriptomic analysis using a network-based biological impact factor analysis. The overall biological impact calculated as biological impact factor (BIF) from all aggregated biological network models is shown in (A) for the various PE time-points following exposure to 40.7% CS in the gingival (GI) and buccal (BU) tissues. (B)–(E) show spider plots that display the normalized NPA values illustrating the quantification of the impacted biological networks for each of the post-exposure time-points. Gray areas in the center of the spider plots indicate statistically non-significant perturbation of the different networks according to the Specificity statistics, refer the “Materials and methods” section. Abbreviations: CS, cigarette smoke; PE, post-exposure.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: Transcriptomic analysis using a network-based biological impact factor analysis. The overall biological impact calculated as biological impact factor (BIF) from all aggregated biological network models is shown in (A) for the various PE time-points following exposure to 40.7% CS in the gingival (GI) and buccal (BU) tissues. (B)–(E) show spider plots that display the normalized NPA values illustrating the quantification of the impacted biological networks for each of the post-exposure time-points. Gray areas in the center of the spider plots indicate statistically non-significant perturbation of the different networks according to the Specificity statistics, refer the “Materials and methods” section. Abbreviations: CS, cigarette smoke; PE, post-exposure.
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