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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, Muc5B and Muc5AC and Gob5. Total RNA was isolated from the lungs of mice exposed to RA, CS, HK-NTHi or CS/HK-NTHi and mRNA expression of Muc5B(A), Muc5AC(B) and Gob5(C) was assessed by qPCR and expressed as fold change over house-keeping gene, G3PDH. Data represents mean ± SD calculated from 6 mice per group (* different from RA-exposed mice, p ≤ 0.05, ANOVA; # different from CS-exposed mice, p ≤ 0.05, ANOVA; † different from HK-NTHi-exposed mice, p ≤ 0.05, ANOVA).
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Figure 5: Expression of mucin genes, Muc5B and Muc5AC and Gob5. Total RNA was isolated from the lungs of mice exposed to RA, CS, HK-NTHi or CS/HK-NTHi and mRNA expression of Muc5B(A), Muc5AC(B) and Gob5(C) was assessed by qPCR and expressed as fold change over house-keeping gene, G3PDH. Data represents mean ± SD calculated from 6 mice per group (* different from RA-exposed mice, p ≤ 0.05, ANOVA; # different from CS-exposed mice, p ≤ 0.05, ANOVA; † different from HK-NTHi-exposed mice, p ≤ 0.05, ANOVA).

Mentions: We then measured the expression of mucin genes, Muc5B and Muc5AC and a calcium-activated chloride channel that is thought to regulate mucus production and/or secretion, Gob5 (mclca3)[32] by qPCR. The expression of Muc5AC and Gob5, but not Muc5B was increased in HK-NTHi-exposed mice compared to RA-exposed, but not in CS-exposed mice (Muc5AC- RA vs HK-NTHi, p = 0.041; Gob5- RA vs HK-NTHi, p = 0.038) (Figure 5A to5C). In contrast, CS/HK-NTHi-exposed mice showed increases in Muc5B (p = 0.041) and Muc5AC (p = 0.045) as well as Gob5 (p = 0.039) compared to RA-exposed mice. Again CS/HK-NTHi mice showed the largest increases in expression in all three genes.


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, Muc5B and Muc5AC and Gob5. Total RNA was isolated from the lungs of mice exposed to RA, CS, HK-NTHi or CS/HK-NTHi and mRNA expression of Muc5B(A), Muc5AC(B) and Gob5(C) was assessed by qPCR and expressed as fold change over house-keeping gene, G3PDH. Data represents mean ± SD calculated from 6 mice per group (* different from RA-exposed mice, p ≤ 0.05, ANOVA; # different from CS-exposed mice, p ≤ 0.05, ANOVA; † different from HK-NTHi-exposed mice, p ≤ 0.05, ANOVA).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Expression of mucin genes, Muc5B and Muc5AC and Gob5. Total RNA was isolated from the lungs of mice exposed to RA, CS, HK-NTHi or CS/HK-NTHi and mRNA expression of Muc5B(A), Muc5AC(B) and Gob5(C) was assessed by qPCR and expressed as fold change over house-keeping gene, G3PDH. Data represents mean ± SD calculated from 6 mice per group (* different from RA-exposed mice, p ≤ 0.05, ANOVA; # different from CS-exposed mice, p ≤ 0.05, ANOVA; † different from HK-NTHi-exposed mice, p ≤ 0.05, ANOVA).
Mentions: We then measured the expression of mucin genes, Muc5B and Muc5AC and a calcium-activated chloride channel that is thought to regulate mucus production and/or secretion, Gob5 (mclca3)[32] by qPCR. The expression of Muc5AC and Gob5, but not Muc5B was increased in HK-NTHi-exposed mice compared to RA-exposed, but not in CS-exposed mice (Muc5AC- RA vs HK-NTHi, p = 0.041; Gob5- RA vs HK-NTHi, p = 0.038) (Figure 5A to5C). In contrast, CS/HK-NTHi-exposed mice showed increases in Muc5B (p = 0.041) and Muc5AC (p = 0.045) as well as Gob5 (p = 0.039) compared to RA-exposed mice. Again CS/HK-NTHi mice showed the largest increases in expression in all three genes.

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