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Combined exposure to cigarette smoke and nontypeable Haemophilus influenzae drives development of a COPD phenotype in mice.

Ganesan S, Comstock AT, Kinker B, Mancuso P, Beck JM, Sajjan US - Respir. Res. (2014)

Bottom Line: CS/HK-NTHi-exposed mice also expressed increased levels of mucin genes and cytokines compared to mice in other groups.CS/HK-NTHi-exposed mice infected with RV demonstrated increased viral persistence, sustained neutrophilia, and further increments in mucin gene and chemokine expression compared to other groups.These findings indicate that in addition to CS, bacteria may also contribute to development of COPD, particularly changes in airways.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, 1150 W, Medical Center Dr,, Ann Arbor, MI 48109-5688, USA. usajjan@umich.edu.

ABSTRACT

Background: Cigarette smoke (CS) is the major etiologic factor of chronic obstructive pulmonary disease (COPD). CS-exposed mice develop emphysema and mild pulmonary inflammation but no airway obstruction, which is also a prominent feature of COPD. Therefore, CS may interact with other factors, particularly respiratory infections, in the pathogenesis of airway remodeling in COPD.

Methods: C57BL/6 mice were exposed to CS for 2 h a day, 5 days a week for 8 weeks. Mice were also exposed to heat-killed non-typeable H. influenzae (HK-NTHi) on days 7 and 21. One day after the last exposure to CS, mice were sacrificed and lung inflammation and mechanics, emphysematous changes, and goblet cell metaplasia were assessed. Mice exposed to CS or HK-NTHi alone or room air served as controls. To determine the susceptibility to viral infections, we also challenged these mice with rhinovirus (RV).

Results: Unlike mice exposed to CS or HK-NTHi alone, animals exposed to CS/HK-NTHi developed emphysema, lung inflammation and goblet cell metaplasia in both large and small airways. CS/HK-NTHi-exposed mice also expressed increased levels of mucin genes and cytokines compared to mice in other groups. CS/HK-NTHi-exposed mice infected with RV demonstrated increased viral persistence, sustained neutrophilia, and further increments in mucin gene and chemokine expression compared to other groups.

Conclusions: These findings indicate that in addition to CS, bacteria may also contribute to development of COPD, particularly changes in airways. Mice exposed to CS/HK-NTHi are also more susceptible to subsequent viral infection than mice exposed to either CS or HK-NTHi alone.

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Related in: MedlinePlus

Expression of mucin genes and goblet cell metaplasia in CS/HK-NTHi-exposed mice following RV-infection. CS/HK-NTHi-exposed mice were infected with RV or equal volume of sham and sacrificed 4 days later. (A to C) Total lung RNA was isolated, reverse transcribed and subjected to qPCR using gene specific primers and expressed as fold change over house-keeping gene, G3PDH. Data in E to G represents mean ± SD calculated from 5–6 mice per group (* different from sham infected mice, p ≤ 0.05, unpaired t test). (D and E) Paraffin lung sections from sham- or RV-infected animals were stained with PAS. Arrows point to PAS positive goblet cells. Images are representative of 3 animals per group.
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Figure 7: Expression of mucin genes and goblet cell metaplasia in CS/HK-NTHi-exposed mice following RV-infection. CS/HK-NTHi-exposed mice were infected with RV or equal volume of sham and sacrificed 4 days later. (A to C) Total lung RNA was isolated, reverse transcribed and subjected to qPCR using gene specific primers and expressed as fold change over house-keeping gene, G3PDH. Data in E to G represents mean ± SD calculated from 5–6 mice per group (* different from sham infected mice, p ≤ 0.05, unpaired t test). (D and E) Paraffin lung sections from sham- or RV-infected animals were stained with PAS. Arrows point to PAS positive goblet cells. Images are representative of 3 animals per group.

Mentions: To assess the effects of RV infection on airways obstruction, we examined the expression of mucin genes, Gob5, goblet cell metaplasia in small airways, and responses to methacholine challenge. Irrespective of infection, mice exposed to RA, CS or RA/HK-NTHi did not show changes in the expression of Muc5B, Muc5AC or Gob5 (data not shown). In contrast, CS/HK-NTHi-exposed mice infected with RV showed additional increases in the expression of Muc5AC (p = 0.041) and Gob5 (p = 0.003), but not muc2B compared to similarly-exposed sham-infected mice (Figure 7A to7C). CS/HK-NTHi-exposed mice infected with RV also showed a further increment in PAS-positive cells in the small airways compared to sham-infected mice, implying that enhanced mucus expression may be due to increased goblet cell metaplasia in these mice (Figure 7D and7E). In contrast, mice exposed to RA, CS or RA/HK-NTHi infected with RV did not show an increase in either the expression of mucin genes or the number of goblet cells in the airway epithelium (data not shown).


Combined exposure to cigarette smoke and nontypeable Haemophilus influenzae drives development of a COPD phenotype in mice.

Ganesan S, Comstock AT, Kinker B, Mancuso P, Beck JM, Sajjan US - Respir. Res. (2014)

Expression of mucin genes and goblet cell metaplasia in CS/HK-NTHi-exposed mice following RV-infection. CS/HK-NTHi-exposed mice were infected with RV or equal volume of sham and sacrificed 4 days later. (A to C) Total lung RNA was isolated, reverse transcribed and subjected to qPCR using gene specific primers and expressed as fold change over house-keeping gene, G3PDH. Data in E to G represents mean ± SD calculated from 5–6 mice per group (* different from sham infected mice, p ≤ 0.05, unpaired t test). (D and E) Paraffin lung sections from sham- or RV-infected animals were stained with PAS. Arrows point to PAS positive goblet cells. Images are representative of 3 animals per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3926338&req=5

Figure 7: Expression of mucin genes and goblet cell metaplasia in CS/HK-NTHi-exposed mice following RV-infection. CS/HK-NTHi-exposed mice were infected with RV or equal volume of sham and sacrificed 4 days later. (A to C) Total lung RNA was isolated, reverse transcribed and subjected to qPCR using gene specific primers and expressed as fold change over house-keeping gene, G3PDH. Data in E to G represents mean ± SD calculated from 5–6 mice per group (* different from sham infected mice, p ≤ 0.05, unpaired t test). (D and E) Paraffin lung sections from sham- or RV-infected animals were stained with PAS. Arrows point to PAS positive goblet cells. Images are representative of 3 animals per group.
Mentions: To assess the effects of RV infection on airways obstruction, we examined the expression of mucin genes, Gob5, goblet cell metaplasia in small airways, and responses to methacholine challenge. Irrespective of infection, mice exposed to RA, CS or RA/HK-NTHi did not show changes in the expression of Muc5B, Muc5AC or Gob5 (data not shown). In contrast, CS/HK-NTHi-exposed mice infected with RV showed additional increases in the expression of Muc5AC (p = 0.041) and Gob5 (p = 0.003), but not muc2B compared to similarly-exposed sham-infected mice (Figure 7A to7C). CS/HK-NTHi-exposed mice infected with RV also showed a further increment in PAS-positive cells in the small airways compared to sham-infected mice, implying that enhanced mucus expression may be due to increased goblet cell metaplasia in these mice (Figure 7D and7E). In contrast, mice exposed to RA, CS or RA/HK-NTHi infected with RV did not show an increase in either the expression of mucin genes or the number of goblet cells in the airway epithelium (data not shown).

Bottom Line: CS/HK-NTHi-exposed mice also expressed increased levels of mucin genes and cytokines compared to mice in other groups.CS/HK-NTHi-exposed mice infected with RV demonstrated increased viral persistence, sustained neutrophilia, and further increments in mucin gene and chemokine expression compared to other groups.These findings indicate that in addition to CS, bacteria may also contribute to development of COPD, particularly changes in airways.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, 1150 W, Medical Center Dr,, Ann Arbor, MI 48109-5688, USA. usajjan@umich.edu.

ABSTRACT

Background: Cigarette smoke (CS) is the major etiologic factor of chronic obstructive pulmonary disease (COPD). CS-exposed mice develop emphysema and mild pulmonary inflammation but no airway obstruction, which is also a prominent feature of COPD. Therefore, CS may interact with other factors, particularly respiratory infections, in the pathogenesis of airway remodeling in COPD.

Methods: C57BL/6 mice were exposed to CS for 2 h a day, 5 days a week for 8 weeks. Mice were also exposed to heat-killed non-typeable H. influenzae (HK-NTHi) on days 7 and 21. One day after the last exposure to CS, mice were sacrificed and lung inflammation and mechanics, emphysematous changes, and goblet cell metaplasia were assessed. Mice exposed to CS or HK-NTHi alone or room air served as controls. To determine the susceptibility to viral infections, we also challenged these mice with rhinovirus (RV).

Results: Unlike mice exposed to CS or HK-NTHi alone, animals exposed to CS/HK-NTHi developed emphysema, lung inflammation and goblet cell metaplasia in both large and small airways. CS/HK-NTHi-exposed mice also expressed increased levels of mucin genes and cytokines compared to mice in other groups. CS/HK-NTHi-exposed mice infected with RV demonstrated increased viral persistence, sustained neutrophilia, and further increments in mucin gene and chemokine expression compared to other groups.

Conclusions: These findings indicate that in addition to CS, bacteria may also contribute to development of COPD, particularly changes in airways. Mice exposed to CS/HK-NTHi are also more susceptible to subsequent viral infection than mice exposed to either CS or HK-NTHi alone.

Show MeSH
Related in: MedlinePlus