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Probing Cellular and Molecular Mechanisms of Cigarette Smoke-Induced Immune Response in the Progression of Chronic Obstructive Pulmonary Disease Using Multiscale Network Modeling

View Article: PubMed Central - PubMed

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder characterized by progressive destruction of lung tissues and airway obstruction. COPD is currently the third leading cause of death worldwide and there is no curative treatment available so far. Cigarette smoke (CS) is the major risk factor for COPD. Yet, only a relatively small percentage of smokers develop the disease, showing that disease susceptibility varies significantly among smokers. As smoking cessation can prevent the disease in some smokers, quitting smoking cannot halt the progression of COPD in others. Despite extensive research efforts, cellular and molecular mechanisms of COPD remain elusive. In particular, the disease susceptibility and smoking cessation effects are poorly understood. To address these issues in this work, we develop a multiscale network model that consists of nodes, which represent molecular mediators, immune cells and lung tissues, and edges describing the interactions between the nodes. Our model study identifies several positive feedback loops and network elements playing a determinant role in the CS-induced immune response and COPD progression. The results are in agreement with clinic and laboratory measurements, offering novel insight into the cellular and molecular mechanisms of COPD. The study in this work also provides a rationale for targeted therapy and personalized medicine for the disease in future.

No MeSH data available.


CS-induced (S = 0.7) population dynamics.Dynamics of (a) T8, Tg, T17, T2, and T1, and (b) TD.
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pone.0163192.g007: CS-induced (S = 0.7) population dynamics.Dynamics of (a) T8, Tg, T17, T2, and T1, and (b) TD.

Mentions: When S decreases to be less than unity, e.g., S = 0.7, the network exhibits a different dynamical feature. Upon CS exposure (S = 0.7), the network dynamical behaviors [Figs 5(B) and 6(B)] are similar (with smaller amplitudes) to those at S = 1.67 in the acute phase [Figs 2(B) and 3(B)]. After step 1, however, M1 together with other proinflammatory elements including Iα and I6 decreases to a low-level steady state (Figs 5 and 6) owing to the suppression of IL-10. Consequently, TD maintains at a rather low level (<5%) when the system reaches a steady state (Fig 7), indicating that COPD does not occur. Compared to the case of S = 1.67 (Figs 2–4), M2 (along with Tg, I10, and Iβ) (Figs 5–7) starts to predominate over M1 (with other proinflammatory components) during step 2 and remains predominant thereafter to a steady state where COPD does not occur.


Probing Cellular and Molecular Mechanisms of Cigarette Smoke-Induced Immune Response in the Progression of Chronic Obstructive Pulmonary Disease Using Multiscale Network Modeling
CS-induced (S = 0.7) population dynamics.Dynamics of (a) T8, Tg, T17, T2, and T1, and (b) TD.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036797&req=5

pone.0163192.g007: CS-induced (S = 0.7) population dynamics.Dynamics of (a) T8, Tg, T17, T2, and T1, and (b) TD.
Mentions: When S decreases to be less than unity, e.g., S = 0.7, the network exhibits a different dynamical feature. Upon CS exposure (S = 0.7), the network dynamical behaviors [Figs 5(B) and 6(B)] are similar (with smaller amplitudes) to those at S = 1.67 in the acute phase [Figs 2(B) and 3(B)]. After step 1, however, M1 together with other proinflammatory elements including Iα and I6 decreases to a low-level steady state (Figs 5 and 6) owing to the suppression of IL-10. Consequently, TD maintains at a rather low level (<5%) when the system reaches a steady state (Fig 7), indicating that COPD does not occur. Compared to the case of S = 1.67 (Figs 2–4), M2 (along with Tg, I10, and Iβ) (Figs 5–7) starts to predominate over M1 (with other proinflammatory components) during step 2 and remains predominant thereafter to a steady state where COPD does not occur.

View Article: PubMed Central - PubMed

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder characterized by progressive destruction of lung tissues and airway obstruction. COPD is currently the third leading cause of death worldwide and there is no curative treatment available so far. Cigarette smoke (CS) is the major risk factor for COPD. Yet, only a relatively small percentage of smokers develop the disease, showing that disease susceptibility varies significantly among smokers. As smoking cessation can prevent the disease in some smokers, quitting smoking cannot halt the progression of COPD in others. Despite extensive research efforts, cellular and molecular mechanisms of COPD remain elusive. In particular, the disease susceptibility and smoking cessation effects are poorly understood. To address these issues in this work, we develop a multiscale network model that consists of nodes, which represent molecular mediators, immune cells and lung tissues, and edges describing the interactions between the nodes. Our model study identifies several positive feedback loops and network elements playing a determinant role in the CS-induced immune response and COPD progression. The results are in agreement with clinic and laboratory measurements, offering novel insight into the cellular and molecular mechanisms of COPD. The study in this work also provides a rationale for targeted therapy and personalized medicine for the disease in future.

No MeSH data available.