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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.


One of Loops 1, 2, 3, and 4 is activated while the others are broken.(a) Loop 1, 2, or 4 alone causes CODP while Loop 3 does not. (b) As Loop 1 is activated, M1 (red solid line) predominates over M2 (red dashed line). While Loop 4 is activated, both M1 (blue solid line) and M2 (blue dashed line) are relatively low. (c) In the case where Loop 1 is activated, Tg is predominant over T8 or T17. (d) The activation of Loop 4 leads to the predominance of T8 and T17 over Tg.
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pone.0163192.g012: One of Loops 1, 2, 3, and 4 is activated while the others are broken.(a) Loop 1, 2, or 4 alone causes CODP while Loop 3 does not. (b) As Loop 1 is activated, M1 (red solid line) predominates over M2 (red dashed line). While Loop 4 is activated, both M1 (blue solid line) and M2 (blue dashed line) are relatively low. (c) In the case where Loop 1 is activated, Tg is predominant over T8 or T17. (d) The activation of Loop 4 leads to the predominance of T8 and T17 over Tg.

Mentions: Loops 1, 2 and 4, which all include the TD node, can amplify the immune response to CS and enhance the TD outcome when they are activated. As Loop 1, 2 or 4 is necessary for COPD progression under the condition given in Table A in S1 File discussed above, we also carried out simulations to investigate whether one of these loops is sufficient for COPD when other positive feedback loops are broken. Here, k3 = 1.9×106 cell/(ml day), kI6,TD = 22.0pmol/(cell day), and KTg,I6 = 2.3 pmol/L are used for Loop 1, 2, and 4, respectively. The other parameter values are given in Table A in S1 File (dTD = 2.9×10−3/day). The results show that activation of Loop 1, 2, or 4 can lead to COPD [Fig 12(A)]. Again, Loop 3 alone is not able to drive COPD progression by modification of kI12, M1.


Probing Cellular and Molecular Mechanisms of Cigarette Smoke-Induced Immune Response in the Progression of Chronic Obstructive Pulmonary Disease Using Multiscale Network Modeling
One of Loops 1, 2, 3, and 4 is activated while the others are broken.(a) Loop 1, 2, or 4 alone causes CODP while Loop 3 does not. (b) As Loop 1 is activated, M1 (red solid line) predominates over M2 (red dashed line). While Loop 4 is activated, both M1 (blue solid line) and M2 (blue dashed line) are relatively low. (c) In the case where Loop 1 is activated, Tg is predominant over T8 or T17. (d) The activation of Loop 4 leads to the predominance of T8 and T17 over Tg.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0163192.g012: One of Loops 1, 2, 3, and 4 is activated while the others are broken.(a) Loop 1, 2, or 4 alone causes CODP while Loop 3 does not. (b) As Loop 1 is activated, M1 (red solid line) predominates over M2 (red dashed line). While Loop 4 is activated, both M1 (blue solid line) and M2 (blue dashed line) are relatively low. (c) In the case where Loop 1 is activated, Tg is predominant over T8 or T17. (d) The activation of Loop 4 leads to the predominance of T8 and T17 over Tg.
Mentions: Loops 1, 2 and 4, which all include the TD node, can amplify the immune response to CS and enhance the TD outcome when they are activated. As Loop 1, 2 or 4 is necessary for COPD progression under the condition given in Table A in S1 File discussed above, we also carried out simulations to investigate whether one of these loops is sufficient for COPD when other positive feedback loops are broken. Here, k3 = 1.9×106 cell/(ml day), kI6,TD = 22.0pmol/(cell day), and KTg,I6 = 2.3 pmol/L are used for Loop 1, 2, and 4, respectively. The other parameter values are given in Table A in S1 File (dTD = 2.9×10−3/day). The results show that activation of Loop 1, 2, or 4 can lead to COPD [Fig 12(A)]. Again, Loop 3 alone is not able to drive COPD progression by modification of kI12, M1.

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.