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Cigarette smoke combined with Klebsiella pneumoniae induce damage to the air‑blood barrier in chronic obstructive pulmonary disease rats via the MAPK/NF‑κB/IκBα pathway

  • Authors:
    • Yange Tian
    • Kexin Xu
    • Ruilong Lu
    • Kangchen Li
    • Xuejie Shao
    • Yixi Liao
    • Yakun Zhao
    • Zhiguang Qiu
    • Haoran Dong
    • Xuefang Liu
  • View Affiliations / Copyright

    Affiliations: Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, P.R. China
    Copyright: © Tian et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 87
    |
    Published online on: January 12, 2026
       https://doi.org/10.3892/mmr.2026.13797
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Abstract

Chronic obstructive pulmonary disease (COPD) is a respiratory disorder characterized by progressive dyspnea. Damage to the lung air‑blood barrier is a major cause of progressive dyspnea observed in COPD. Although cigarette smoke inhalation and repetitive bacterial infection cause and exacerbate COPD, their specific effects on the air‑blood barrier remain to be fully elucidated. The present study explored the effects of the air‑blood barrier in a COPD rat model induced by cigarette smoke inhalation and repetitive bacterial infection. From weeks 1‑8, Sprague‑Dawley rats were treated with cigarette smoke inhalation and repeated Klebsiella pneumoniae exposure. At the end of week 8, lung function, pulmonary pathology, mucin content, inflammation, oxidative stress and MAPK/NF‑κB/IκBα pathway indicators were detected in rats. Lung function parameters, including tidal volume, peak expiratory flow and 50% tidal volume expiratory flow showed significant decreases in COPD model rats. The pulmonary organizational structure and ultrastructure of the air‑blood barrier were also markedly damaged in COPD model rats. Due to cigarette smoke and Klebsiella pneumoniae exposure, the expression of IL‑6, malondialdehyde, mucoprotein (MUC)5AC, MUC5B, matrix metallopeptidase‑9 and angiopoietin‑2 increased in COPD rats, while the expression of IL‑10, tissue inhibitor of metalloproteinases‑1, heme oxygenase‑1, zonula occludens‑1, claudin‑5, aquaporin‑5, surfactant protein‑D and superoxide dismutase significantly decreased. Subsequently, cigarette smoke exposure and Klebsiella pneumoniae infection increased the levels of phosphorylated‑(p‑)p38, p‑ERK, p‑JNK, p‑p65 and p‑IκBα. The present study provided notable evidence that cigarette smoke and Klebsiella pneumoniae exposure exacerbated the destruction of the air‑blood barrier in COPD via the MAPK/NF‑κB/IκBα pathway.

View Figures

Figure 1

Pulmonary function and lung tissue
histopathology changes in all groups. (A) Changes in TV, PEF and
EF50. (B) Images of lung tissue histopathology. The leftmost image
for each group is ×200 magnification. Arrows indicate alveolar
rupture and alveolar fusion. Values are expressed as mean ± SE;
(n=8). *P<0.05 and **P<0.01 vs. the normal group. (C) Changes
of MAN and MLI. The values are expressed as mean ± SE, (n=8).
**P<0.01 vs. the control group. MAN, mean alveolar number; MLI,
mean linear intercept; TV, tidal volume; PEF, peak expiratory flow;
EF50, 50% TV expiratory flow.

Figure 2

Changes of ultrastructure of
air-blood barrier in all groups. (A) Structural changes of
air-blood barrier in rats in each group (scanning electron
microscope; ×30,000 magnification) (B) Structural changes of
capillary endothelial cells in rats in each group. (×30,000
magnification) (C) Structural changes of type 1 alveolar epithelial
cells in rats in each group. (D) Structural changes of type 2
alveolar epithelial cells in rats in each group. In (C) and (D),
the left image of each group is under ×8,000 magnification, and the
yellow dashed box on the right is under ×30,000 magnification. M,
chondriosome; L, lamellar body.

Figure 3

Injury of the air-blood barrier
induced in all groups. (A) The expression level of ZO-1 and
claudin-5 in the lung tissue of rats was tested using
immunohistochemistry (×200 magnification). The values are expressed
as mean ± SE; (n=8). **P<0.01 vs. normal group. (B) Protein
expression of ZO-1, claudin-5, SP-D, HO-1 and Ang-2 in the lung
tissue tested via western blotting. The values are expressed as
mean ± SE; (n=3). *P<0.05 and **P<0.01 vs. normal group. (C)
The expression level of AQP-5, SP-D and CD31 in the lung tissue
tested using immunofluorescence (×200 magnification). ZO-1, zonula
occludens-1; SP-D, surfactant protein-D; HO-1, heme oxygenase-1;
Ang-2, angiopoietin 2; AQP-5, aquaporin-5; IOD, integrated optical
density.

Figure 4

Injury of mucus hypersecretion and
oxidative damage in all groups. (A) AB-PAS staining images of the
airway in all groups (AB-PAS; ×200 magnification and ×400
magnification). Arrows indicate goblet cells. (B) The expression
level of MUC5AC and MUC5B in the airway tested using
immunohistochemistry (×200 magnification). (C) The expression of
IL-6, IL-10, TNF-α, T-SOD, MDA, MMP-9 and TIMP-1 in lung tissue and
serum of rats in all groups. The values are expressed as mean ± SE;
(n=8). *P<0.05 and **P<0.01 vs. normal group. AB-PAS, Alcian
blue-periodic acid-schiff; MUC5AC, mucoprotein-5AC; MUC5B,
mucoprotein-5B; T-SOD, total superoxide dismutase; MDA,
malondialdehyde; MMP-9, matrix metalloproteinase 9; TIMP-1, tissue
inhibitor of metalloproteinases 2; IOD, integrated optical
density.

Figure 5

Protein expression of p-p38, p38,
p-ERK, ERK, p-JNK, JNK, p-p65, p65, p-IκBα and IκBα in the lung
tissue tested using western blot analysis. **P<0.01 vs. normal
group. JNK, Janus kinase; p-, phosphorylated.

Figure 6

Cigarette smoke combined with
Klebsiella pneumoniae induces damage to the air-blood
barrier via the MAPK/NF-κB/IκBα pathway. TLR4, Toll-like receptor
4; MKK3, mitogen-activated protein kinase kinase 3; MKK6, dual
specificity mitogen-activated protein kinase kinase 6; SOD,
superoxide dismutase; MDA, malondialdehyde; MMP2, matrix
metalloproteinase 2; IL1R, interleukin-1 receptor type 1; P,
phosphate group.
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Copy and paste a formatted citation
Spandidos Publications style
Tian Y, Xu K, Lu R, Li K, Shao X, Liao Y, Zhao Y, Qiu Z, Dong H, Liu X, Liu X, et al: <p>Cigarette smoke combined with <em>Klebsiella pneumoniae</em> induce damage to the air‑blood barrier in chronic obstructive pulmonary disease rats via the MAPK/NF‑&kappa;B/I&kappa;B&alpha; pathway</p>. Mol Med Rep 33: 87, 2026.
APA
Tian, Y., Xu, K., Lu, R., Li, K., Shao, X., Liao, Y. ... Liu, X. (2026). <p>Cigarette smoke combined with <em>Klebsiella pneumoniae</em> induce damage to the air‑blood barrier in chronic obstructive pulmonary disease rats via the MAPK/NF‑&kappa;B/I&kappa;B&alpha; pathway</p>. Molecular Medicine Reports, 33, 87. https://doi.org/10.3892/mmr.2026.13797
MLA
Tian, Y., Xu, K., Lu, R., Li, K., Shao, X., Liao, Y., Zhao, Y., Qiu, Z., Dong, H., Liu, X."<p>Cigarette smoke combined with <em>Klebsiella pneumoniae</em> induce damage to the air‑blood barrier in chronic obstructive pulmonary disease rats via the MAPK/NF‑&kappa;B/I&kappa;B&alpha; pathway</p>". Molecular Medicine Reports 33.3 (2026): 87.
Chicago
Tian, Y., Xu, K., Lu, R., Li, K., Shao, X., Liao, Y., Zhao, Y., Qiu, Z., Dong, H., Liu, X."<p>Cigarette smoke combined with <em>Klebsiella pneumoniae</em> induce damage to the air‑blood barrier in chronic obstructive pulmonary disease rats via the MAPK/NF‑&kappa;B/I&kappa;B&alpha; pathway</p>". Molecular Medicine Reports 33, no. 3 (2026): 87. https://doi.org/10.3892/mmr.2026.13797
Copy and paste a formatted citation
x
Spandidos Publications style
Tian Y, Xu K, Lu R, Li K, Shao X, Liao Y, Zhao Y, Qiu Z, Dong H, Liu X, Liu X, et al: <p>Cigarette smoke combined with <em>Klebsiella pneumoniae</em> induce damage to the air‑blood barrier in chronic obstructive pulmonary disease rats via the MAPK/NF‑&kappa;B/I&kappa;B&alpha; pathway</p>. Mol Med Rep 33: 87, 2026.
APA
Tian, Y., Xu, K., Lu, R., Li, K., Shao, X., Liao, Y. ... Liu, X. (2026). <p>Cigarette smoke combined with <em>Klebsiella pneumoniae</em> induce damage to the air‑blood barrier in chronic obstructive pulmonary disease rats via the MAPK/NF‑&kappa;B/I&kappa;B&alpha; pathway</p>. Molecular Medicine Reports, 33, 87. https://doi.org/10.3892/mmr.2026.13797
MLA
Tian, Y., Xu, K., Lu, R., Li, K., Shao, X., Liao, Y., Zhao, Y., Qiu, Z., Dong, H., Liu, X."<p>Cigarette smoke combined with <em>Klebsiella pneumoniae</em> induce damage to the air‑blood barrier in chronic obstructive pulmonary disease rats via the MAPK/NF‑&kappa;B/I&kappa;B&alpha; pathway</p>". Molecular Medicine Reports 33.3 (2026): 87.
Chicago
Tian, Y., Xu, K., Lu, R., Li, K., Shao, X., Liao, Y., Zhao, Y., Qiu, Z., Dong, H., Liu, X."<p>Cigarette smoke combined with <em>Klebsiella pneumoniae</em> induce damage to the air‑blood barrier in chronic obstructive pulmonary disease rats via the MAPK/NF‑&kappa;B/I&kappa;B&alpha; pathway</p>". Molecular Medicine Reports 33, no. 3 (2026): 87. https://doi.org/10.3892/mmr.2026.13797
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