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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.

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Related in: MedlinePlus

Dynamics of TD with different values of k13 and effects of cigarette smoking cessation.(a) k13< 2.6×10−2 ml/(cell day) corresponds to resistant smokers (TD<30%), while k13≥2.6×10−2 ml/(cell day) is associated with susceptible smokers. (b) Effects of smoking cessation after 2500 days of CS exposure. 2.6×10-2ml/(cell day) ≤ k13 < 0.31ml/(cell day) corresponds to reversible susceptible smokers and COPD is reversible. k13≥0.31 ml/(cell day) is associated with severely susceptible smokers. In this case, COPD is not reversible.
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pone.0163192.g009: Dynamics of TD with different values of k13 and effects of cigarette smoking cessation.(a) k13< 2.6×10−2 ml/(cell day) corresponds to resistant smokers (TD<30%), while k13≥2.6×10−2 ml/(cell day) is associated with susceptible smokers. (b) Effects of smoking cessation after 2500 days of CS exposure. 2.6×10-2ml/(cell day) ≤ k13 < 0.31ml/(cell day) corresponds to reversible susceptible smokers and COPD is reversible. k13≥0.31 ml/(cell day) is associated with severely susceptible smokers. In this case, COPD is not reversible.

Mentions: Our global sensitivity analysis shows that the TD outcome is sensitive to a subset of parameters including k13, k14, and k15 and dTD in Eq 12. Fig 9 illustrates how variations in k13 affect the transitions from resistant, reversible to severely susceptible smokers. Here, the CS dose (S = 1.67) is the same as that in the case shown in Figs 2–4. While k13 is varied, dTD = 3.4×10−3 (1/day) and the values of the other parameters in Table A in S1 File are used. The results show that when k13 is less than 2.6×10−2 ml/(cell day),TD remains at a low-level (<30%), exhibiting a COPD resistant feature seen in Fig 9(A). While k13 lies in a value range of 2.6×10−2 and 0.31 ml/(cell day), COPD occurs but smoking cessation leads to TD decreasing to the baseline shown in Fig 9(B). In this case, COPD is reversible [2]. When k13 is larger than 0.31 ml/(cell day), TD at the steady state is reduced to some extent but still remains at a high level (>30%) after smoking cessation at day 2500. A COPD patient in this case is severely susceptible [11]. Interestingly, for a severely susceptible smoker whose k13 is relatively large, the M1-induced destruction of lung tissue predominates. In this case, M1 is sufficient for the progression of COPD, consistent with experiments in mice [24, 25].


Probing Cellular and Molecular Mechanisms of Cigarette Smoke-Induced Immune Response in the Progression of Chronic Obstructive Pulmonary Disease Using Multiscale Network Modeling
Dynamics of TD with different values of k13 and effects of cigarette smoking cessation.(a) k13< 2.6×10−2 ml/(cell day) corresponds to resistant smokers (TD<30%), while k13≥2.6×10−2 ml/(cell day) is associated with susceptible smokers. (b) Effects of smoking cessation after 2500 days of CS exposure. 2.6×10-2ml/(cell day) ≤ k13 < 0.31ml/(cell day) corresponds to reversible susceptible smokers and COPD is reversible. k13≥0.31 ml/(cell day) is associated with severely susceptible smokers. In this case, COPD is not reversible.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5036797&req=5

pone.0163192.g009: Dynamics of TD with different values of k13 and effects of cigarette smoking cessation.(a) k13< 2.6×10−2 ml/(cell day) corresponds to resistant smokers (TD<30%), while k13≥2.6×10−2 ml/(cell day) is associated with susceptible smokers. (b) Effects of smoking cessation after 2500 days of CS exposure. 2.6×10-2ml/(cell day) ≤ k13 < 0.31ml/(cell day) corresponds to reversible susceptible smokers and COPD is reversible. k13≥0.31 ml/(cell day) is associated with severely susceptible smokers. In this case, COPD is not reversible.
Mentions: Our global sensitivity analysis shows that the TD outcome is sensitive to a subset of parameters including k13, k14, and k15 and dTD in Eq 12. Fig 9 illustrates how variations in k13 affect the transitions from resistant, reversible to severely susceptible smokers. Here, the CS dose (S = 1.67) is the same as that in the case shown in Figs 2–4. While k13 is varied, dTD = 3.4×10−3 (1/day) and the values of the other parameters in Table A in S1 File are used. The results show that when k13 is less than 2.6×10−2 ml/(cell day),TD remains at a low-level (<30%), exhibiting a COPD resistant feature seen in Fig 9(A). While k13 lies in a value range of 2.6×10−2 and 0.31 ml/(cell day), COPD occurs but smoking cessation leads to TD decreasing to the baseline shown in Fig 9(B). In this case, COPD is reversible [2]. When k13 is larger than 0.31 ml/(cell day), TD at the steady state is reduced to some extent but still remains at a high level (>30%) after smoking cessation at day 2500. A COPD patient in this case is severely susceptible [11]. Interestingly, for a severely susceptible smoker whose k13 is relatively large, the M1-induced destruction of lung tissue predominates. In this case, M1 is sufficient for the progression of COPD, consistent with experiments in mice [24, 25].

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.


Related in: MedlinePlus