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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

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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 = 1.67) population dynamics.Dynamics of (a)T8, Tg, T17, T2, and T1, and (b) TD.
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pone.0163192.g004: CS-induced (S = 1.67) population dynamics.Dynamics of (a)T8, Tg, T17, T2, and T1, and (b) TD.

Mentions: Eqs 1–12 are applied in the following discussion with the parameters given in Table A in S1 File. The time course of the simulations is marked in days and units of cell populations and cytokine concentrations are in terms of cells per milliliter (cells/ml) and pmol per liter (pmol/L). The initial conditions of the variables for all activated cells and secreted cytokines are set to zero. CS-induced immune response and COPD progression are dependent upon the dose of CS inhalation [54]. Figs 2–4 respectively show the time courses of the changes in the immune cells, cytokines and tissue damage (TD) in response to CS at a relatively high level of the cigarette smoking intensity, S (S = 1.67). Here, S is defined as the ratio of a CS dose to the minimal CS dose required to cause COPD with the parameters given in Table A in S1 File.


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 = 1.67) 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.g004: CS-induced (S = 1.67) population dynamics.Dynamics of (a)T8, Tg, T17, T2, and T1, and (b) TD.
Mentions: Eqs 1–12 are applied in the following discussion with the parameters given in Table A in S1 File. The time course of the simulations is marked in days and units of cell populations and cytokine concentrations are in terms of cells per milliliter (cells/ml) and pmol per liter (pmol/L). The initial conditions of the variables for all activated cells and secreted cytokines are set to zero. CS-induced immune response and COPD progression are dependent upon the dose of CS inhalation [54]. Figs 2–4 respectively show the time courses of the changes in the immune cells, cytokines and tissue damage (TD) in response to CS at a relatively high level of the cigarette smoking intensity, S (S = 1.67). Here, S is defined as the ratio of a CS dose to the minimal CS dose required to cause COPD with the parameters given in Table A in S1 File.

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.